@article {pmid20873123,
year = {2010},
author = {Wegielnik, J and Dabrowski, S and Medrzycka-Dabrowska, W and Basiński, A and , },
title = {[Cardiopulmonary resuscitation in pregnancy--European Resuscitation Council guidelines].},
journal = {Ginekologia polska},
volume = {81},
number = {8},
pages = {606-612},
pmid = {20873123},
issn = {0017-0011},
mesh = {Adult ; Advanced Cardiac Life Support/standards ; Cardiopulmonary Resuscitation/education/*standards ; Emergency Medical Services/*standards ; Europe ; Female ; First Aid/*standards ; Heart Arrest/*prevention & control ; Humans ; Poland ; Pregnancy ; Pregnancy Complications, Cardiovascular/*therapy ; Professional Competence ; Quality Assurance, Health Care/standards ; Young Adult ; },
abstract = {Cardio-pulmonary resuscitation is a life-saving technique that should be familiar to all people, even those without medical education. There are two basic life-saving levels: BLS (Basic Life Support) and ALS (Advanced Life Support). ALS a medical procedure that is restricted to medical practitioners. Cessation of circulation may happen to anyone. Cardiac arrest in case of pregnant women is a very specific state. The cause of life-threatening states during pregnancy can be connected with new infections, exacerbation of chronic diseases, as well as changes connected with the pregnancy itself. In those situations, due to physiological and anatomical changes which occur during pregnancy some modifications in the procedure of resuscitation are necessary},
}

Adult
Advanced Cardiac Life Support/standards
Cardiopulmonary Resuscitation/education/*standards
Emergency Medical Services/*standards
Europe
Female
First Aid/*standards
Heart Arrest/*prevention & control
Humans
Poland
Pregnancy
Pregnancy Complications, Cardiovascular/*therapy
Professional Competence
Quality Assurance, Health Care/standards
Young Adult

@article {pmid20150676,
year = {2010},
author = {Mahata, P},
title = {Exploratory consensus of hierarchical clusterings for melanoma and breast cancer.},
journal = {IEEE/ACM transactions on computational biology and bioinformatics},
volume = {7},
number = {1},
pages = {138-152},
doi = {10.1109/TCBB.2008.33},
pmid = {20150676},
issn = {1557-9964},
mesh = {*Algorithms ; Biomarkers, Tumor/*analysis ; Breast Neoplasms/*diagnosis/*metabolism ; Diagnosis, Computer-Assisted/*methods ; Gene Expression Profiling/methods ; Humans ; Melanoma/classification/*diagnosis/*metabolism ; Multigene Family ; Neoplasm Proteins/analysis ; },
abstract = {Finding subtypes of heterogeneous diseases is the biggest challenge in the area of biology. Often, clustering is used to provide a hypothesis for the subtypes of a heterogeneous disease. However, there are usually discrepancies between the clusterings produced by different algorithms. This work introduces a simple method which provides the most consistent clusters across three different clustering algorithms for a melanoma and a breast cancer data set. The method is validated by showing that the Silhouette, Dunne's and Davies-Bouldin's cluster validation indices are better for the proposed algorithm than those obtained by k-means and another consensus clustering algorithm. The hypotheses of the consensus clusters on both the data sets are corroborated by clear genetic markers and 100 percent classification accuracy. In Bittner et al.'s melanoma data set, a previously hypothesized primary cluster is recognized as the largest consensus cluster and a new partition of this cluster into two subclusters is proposed. In van't Veer et al.'s breast cancer data set, previously proposed "basal" and "luminal A" subtypes are clearly recognized as the two predominant clusters. Furthermore, a new hypothesis is provided about the existence of two subgroups within the "basal" subtype in this data set. The clusters of van't Veer's data set is also validated by high classification accuracy obtained in the data set of van de Vijver et al.},
}

*Algorithms
Biomarkers, Tumor/*analysis
Breast Neoplasms/*diagnosis/*metabolism
Diagnosis, Computer-Assisted/*methods
Gene Expression Profiling/methods
Humans
Melanoma/classification/*diagnosis/*metabolism
Multigene Family
Neoplasm Proteins/analysis

@article {pmid19506136,
year = {2009},
author = {Gordon, PH and Corcia, P and Lacomblez, L and Pochigaeva, K and Abitbol, JL and Cudkowicz, M and Leigh, PN and Meininger, V},
title = {Defining survival as an outcome measure in amyotrophic lateral sclerosis.},
journal = {Archives of neurology},
volume = {66},
number = {6},
pages = {758-761},
doi = {10.1001/archneurol.2009.1},
pmid = {19506136},
issn = {1538-3687},
mesh = {Amyotrophic Lateral Sclerosis/complications/drug therapy/*mortality ; Clinical Trials as Topic/*methods/standards/statistics & numerical data ; Endpoint Determination/*methods ; Humans ; Kaplan-Meier Estimate ; Naphthalenes/administration & dosage/adverse effects ; Outcome Assessment, Health Care/*methods ; Pentoxifylline/administration & dosage/adverse effects ; Pyridines/administration & dosage/adverse effects ; Respiration, Artificial/mortality/statistics & numerical data ; Respiratory Paralysis/drug therapy/etiology/*mortality ; Tracheostomy/mortality/statistics & numerical data ; Vasodilator Agents/administration & dosage/adverse effects ; },
abstract = {OBJECTIVES: To examine how respiratory interventions affect survival as an outcome measure and to define survival rate for trials in amyotrophic lateral sclerosis.

DESIGN AND SETTING: We reviewed the data of 3 phase 3 clinical trials and examined differences in times to death, tracheostomy, and permanent assisted ventilation. We assessed the outcomes with chi(2) and Fisher exact tests for categorical variables and unpaired, 2-tailed t tests for continuous variables. We used Kaplan-Meier methods to estimate the differences in survival times between interventions. A power analysis generated sample size estimates for different end points.

PATIENTS: In all, 2077 patients in 2 phase 3 trials of xaliproden and 400 patients in a phase 3 trial of pentoxifylline.

MAIN OUTCOME MEASURES: Death or combined death, tracheostomy, or permanent assisted ventilation.

RESULTS: Of 745 deaths, 611 (82.0%) were owing to respiratory failure and 134 (18.0%) to other causes. The use of respiratory interventions across centers ranged from 0% to 6.6% (P = .001) of patients for tracheostomy and 11.1% to 23.1% (P = .05) of patients for noninvasive ventilation. Twelve of 55 patients (21.8%) undergoing tracheostomy had a vital capacity of 50% or more. Mean (SD) survival time was 457.9 (3.1) days using a combined end point and 467.2 (2.9) days with death alone as the outcome (P = .02). An estimated sample size to detect a 10% difference at 18 months between groups was 490 patients per arm for the combined end point and 410 patients for death alone.

CONCLUSIONS: Tracheostomy and permanent assisted ventilation are not equivalent to death in amyotrophic lateral sclerosis. The use of respiratory interventions differs between centers, leading to variability in combined outcome assessments. The time to the end point can differ significantly depending on its definition, and combining outcomes does not reduce the estimated sample size of a trial. The death rate alone is the least variable and most easily identifiable measure of survival rate in amyotrophic lateral sclerosis.},
}

Amyotrophic Lateral Sclerosis/complications/drug therapy/*mortality
Clinical Trials as Topic/*methods/standards/statistics & numerical data
Endpoint Determination/*methods
Humans
Kaplan-Meier Estimate
Naphthalenes/administration & dosage/adverse effects
Outcome Assessment, Health Care/*methods
Pentoxifylline/administration & dosage/adverse effects
Pyridines/administration & dosage/adverse effects
Respiration, Artificial/mortality/statistics & numerical data
Respiratory Paralysis/drug therapy/etiology/*mortality
Tracheostomy/mortality/statistics & numerical data
Vasodilator Agents/administration & dosage/adverse effects

@article {pmid19212735,
year = {2009},
author = {Nolan, J and , },
title = {[Resuscitation techniques for adults (ALS). Section 4 of the Guidelines for Resuscitation 2005 of the European Resuscitation Council].},
journal = {Der Unfallchirurg},
volume = {112},
number = {2},
pages = {102-138},
doi = {10.1007/s00113-009-1583-4},
pmid = {19212735},
issn = {1433-044X},
mesh = {Adult ; Germany ; Humans ; Resuscitation/*standards ; },
}

Adult
Germany
Humans
Resuscitation/*standards

@article {pmid18413368,
year = {2009},
author = {Lambrechts, D and Poesen, K and Fernández-Santiago, R and Al-Chalabi, A and Del Bo, R and Van Vught, PW and Khan, S and Marklund, SL and Brockington, A and van Marion, I and Anneser, J and Shaw, C and Ludolph, AC and Leigh, NP and Comi, GP and Gasser, T and Shaw, PJ and Morrison, KE and Andersen, PM and Van den Berg, LH and Thijs, V and Siddique, T and Robberecht, W and Carmeliet, P},
title = {Meta-analysis of vascular endothelial growth factor variations in amyotrophic lateral sclerosis: increased susceptibility in male carriers of the -2578AA genotype.},
journal = {Journal of medical genetics},
volume = {46},
number = {12},
pages = {840-846},
doi = {10.1136/jmg.2008.058222},
pmid = {18413368},
issn = {1468-6244},
mesh = {Amyotrophic Lateral Sclerosis/*genetics/pathology ; Animals ; Disease Models, Animal ; Genetic Predisposition to Disease ; Heterozygote ; Humans ; Male ; Mice ; Motor Neurons/pathology ; Polymorphism, Single Nucleotide ; Sex Factors ; Vascular Endothelial Growth Factor A/*genetics ; },
abstract = {BACKGROUND: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding.

METHODS AND FINDINGS: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (-2578C/A, -1154G/A and -634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing.

CONCLUSIONS: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF -2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.},
}

Amyotrophic Lateral Sclerosis/*genetics/pathology
Animals
Disease Models, Animal
Genetic Predisposition to Disease
Heterozygote
Humans
Male
Mice
Motor Neurons/pathology
Polymorphism, Single Nucleotide
Sex Factors
Vascular Endothelial Growth Factor A/*genetics

@article {pmid18065789,
year = {2008},
author = {Labriola, L and Crott, R and Jadoul, M},
title = {Preventing haemodialysis catheter-related bacteraemia with an antimicrobial lock solution: a meta-analysis of prospective randomized trials.},
journal = {Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association},
volume = {23},
number = {5},
pages = {1666-1672},
doi = {10.1093/ndt/gfm847},
pmid = {18065789},
issn = {1460-2385},
mesh = {Anti-Bacterial Agents/*administration & dosage ; Bacteremia/etiology/*prevention & control ; Catheters, Indwelling/*adverse effects/*microbiology ; Gentamicins/administration & dosage ; Humans ; Prospective Studies ; Randomized Controlled Trials as Topic ; Renal Dialysis/*adverse effects/*methods ; Risk Factors ; Risk Reduction Behavior ; },
abstract = {BACKGROUND: Catheter-related bacteraemia (CRB) is a major cause of morbidity and mortality in haemodialysis patients. Interdialytic locking of catheters with antimicrobial agents has recently been investigated for the prevention of CRB. We performed a meta-analysis of randomized controlled trials (RCT) to determine the efficacy of antimicrobial lock solutions (ALS) in the prevention of CRB in haemodialysis patients.

METHODS: We collected from Medline, Web of Science, the Cochrane Library and major nephrology journals, all relevant references (January 1990-March 2007). We selected RCT comparing an ALS to a standard heparin lock in CRB prevention. We extracted data concerning study quality, patient characteristics and CRB incidence. The relative risk (RR) of CRB was calculated as Ln (CRB incidence control/CRB incidence experimental) using both a fixed- and a random-effects model.

RESULTS: Eight studies were included, involving 829 patients, 882 catheters and 90 191 catheter-days. The use of an ALS significantly decreased the risk of CRB (RR 0.32; 95% CI 0.10-0.42). Borderline heterogeneity was observed in the fixed-effects model (Q = 14.42; P = 0.071). Despite the under-representation of small negative studies, the high number of additional trials necessary to reverse the final effect strengthens the confidence in the overall results. Subgroup analyses stratified by the presence of diabetes, duration of follow-up, biochemical markers, proportion of tunnelled cuffed catheters, intranasal mupirocin use and citrate use in the ALS did not show significant differences, except a higher efficacy of gentamicin-containing lock solutions (P = 0.003).

CONCLUSIONS: The use of ALS reduces by about a factor 3 the risk of CRB in haemodialysis patients. The achieved absolute incidence is similar to the best-published figures (presumably related to stricter hygienic measures). The limited follow-up of the studies does not exclude the onset of adverse events or bacterial resistance with longer use of ALS.},
}

Anti-Bacterial Agents/*administration & dosage
Bacteremia/etiology/*prevention & control
Catheters, Indwelling/*adverse effects/*microbiology
Gentamicins/administration & dosage
Humans
Prospective Studies
Randomized Controlled Trials as Topic
Renal Dialysis/*adverse effects/*methods
Risk Factors
Risk Reduction Behavior

@article {pmid17828789,
year = {2007},
author = {Ellervik, C and Birgens, H and Tybjaerg-Hansen, A and Nordestgaard, BG},
title = {Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls.},
journal = {Hepatology (Baltimore, Md.)},
volume = {46},
number = {4},
pages = {1071-1080},
doi = {10.1002/hep.21885},
pmid = {17828789},
issn = {0270-9139},
mesh = {Case-Control Studies ; Endpoint Determination ; Genetic Predisposition to Disease ; *Genotype ; Hemochromatosis/*genetics ; Hemochromatosis Protein ; Heterozygote ; Histocompatibility Antigens Class I/genetics ; Humans ; Liver Diseases/etiology/*genetics ; Liver Neoplasms/etiology/*genetics ; Membrane Proteins/genetics ; Mutation/genetics ; Odds Ratio ; Risk Factors ; },
abstract = {UNLABELLED: Hemochromatosis genotypes have been associated with liver disease, diabetes mellitus, heart disease, arthritis, porphyria cutanea tarda, stroke, neurodegenerative disorders, cancer, and venous disease. We performed meta-analyses including 202 studies with 66,263 cases and 226,515 controls to examine associations between hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, C282Y/wild type, H63D/H63D, and H63D/wild type versus wild type/wild type and 9 overall endpoints and 22 endpoint subgroups. We also explored potential sources of heterogeneity. For liver disease, the odds ratio for C282Y/C282Y versus wild type/wild type was 3.9 (99% confidence interval: 1.9-8.1) overall, 11 (3.7-34) for hepatocellular carcinoma, 4.1 (1.2-14) for hepatitis C, and 10 (2.1-53) for nonalcoholic steatohepatitis. For porphyria cutanea tarda, the odds ratios were 48 (24-95) for C282Y/C282Y, 8.1 (3.9-17) for C282Y/H63D, 3.6 (1.8-7.3) for C282Y/wild type, 3.0 (1.6-5.6) for H63D/H63D, and 1.7 (1.0-3.1) for H63D/wild type versus wild type/wild type. Finally, for amyotrophic lateral sclerosis, the odds ratio was 3.9 (1.2-13) for H63D/H63D versus wild type/wild type. These findings were consistent across individual studies. The hemochromatosis genotypes were not associated with risk for diabetes mellitus, heart disease, arthritis, stroke, cancer, or venous disease in the overall analyses; however, the odds ratio for C282Y/C282Y versus wild type/wild type was 3.4 (1.1-11) for diabetes mellitus among North Europeans.

CONCLUSION: In aggregate, clinically ascertained cases who are homozygous for the C282Y mutation are associated with a 4-11-fold risk of liver disease, whereas all 5 hemochromatosis genotypes are associated with a 2-48-fold risk of porphyria cutanea tarda, and H63D/H63D is associated with a 4-fold risk of amyotrophic lateral sclerosis. These results, mainly from case-control studies, cannot necessarily be extrapolated to the general population.},
}

Case-Control Studies
Endpoint Determination
Genetic Predisposition to Disease
*Genotype
Hemochromatosis/*genetics
Hemochromatosis Protein
Heterozygote
Histocompatibility Antigens Class I/genetics
Humans
Liver Diseases/etiology/*genetics
Liver Neoplasms/etiology/*genetics
Membrane Proteins/genetics
Mutation/genetics
Odds Ratio
Risk Factors

@article {pmid17653919,
year = {2007},
author = {Ludolph, AC and Bendotti, C and Blaugrund, E and Hengerer, B and Löffler, JP and Martin, J and Meininger, V and Meyer, T and Moussaoui, S and Robberecht, W and Scott, S and Silani, V and Van Den Berg, LH and , },
title = {Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: report on the 142nd ENMC international workshop.},
journal = {Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases},
volume = {8},
number = {4},
pages = {217-223},
doi = {10.1080/17482960701292837},
pmid = {17653919},
issn = {1748-2968},
mesh = {Amyotrophic Lateral Sclerosis/*drug therapy ; Animals ; *Disease Models, Animal ; Drug Evaluation, Preclinical/*methods ; Humans ; Mice ; Mice, Transgenic ; Superoxide Dismutase/genetics ; },
abstract = {A transgenic animal model for anterior horn cell loss was established in 1994. This model is based on the insertion of a high copy number of disease-causing human Cu/Zn SOD mutations into the intact mouse genome. It serves to establish hypotheses for the pathogenesis of anterior horn cell death, but also to test potential pharmacological approaches to therapy in human ALS. Today, more than 100 -- published and unpublished -- compounds have been tested in this animal model, a large part of them being reported as successful. However, it proved to be difficult to translate these therapeutic successes in the animal model into human trials. Also, a number of disease-modifying strategies were difficult to reproduce, even by the same group. On the other hand, the step from mice to men means a huge investment for the sponsors of clinical trials and the scientific community. Therefore, establishment of standard methods for drug testing in ALS models is mandatory. In this workshop, clinical and preclinical researchers established in the field of ALS/MND met in Holland in March 2006 in order to establish guidelines for the community for drug testing in mouse models.},
}

Amyotrophic Lateral Sclerosis/*drug therapy
Animals
*Disease Models, Animal
Drug Evaluation, Preclinical/*methods
Humans
Mice
Mice, Transgenic
Superoxide Dismutase/genetics

@article {pmid17060069,
year = {2006},
author = {Liversidge, HM and Chaillet, N and Mörnstad, H and Nyström, M and Rowlings, K and Taylor, J and Willems, G},
title = {Timing of Demirjian's tooth formation stages.},
journal = {Annals of human biology},
volume = {33},
number = {4},
pages = {454-470},
doi = {10.1080/03014460600802387},
pmid = {17060069},
issn = {0301-4460},
mesh = {Adolescent ; Aging/*physiology ; Asia ; Australia ; Canada ; Child ; Child, Preschool ; Europe ; Female ; Humans ; Male ; Sex Characteristics ; Time Factors ; Tooth/anatomy & histology/*growth & development ; },
abstract = {BACKGROUND: Global differences in Demirjian et al.'s method of assessing dental maturity are thought to be due to population differences.

AIM: The aim of this study was to investigate the timing of individual tooth formation stages in children from eight countries.

RESEARCH DESIGN: This was a meta-analysis of previously published data from retrospective cross-sectional studies of dental maturity.

METHOD: Data of mandibular permanent developing teeth from panoramic radiographs (Demirjian's stages) were combined from Australia, Belgium, Canada, England, Finland, France, South Korea and Sweden (n = 9002, ages 2-16.99 years). Age-of-attainment was calculated using logistic regression for each group by sex and meta-analysis of the total. Overlapping 95% confidence intervals of the means was interpreted as no significant difference.

RESULTS: Mean ages for each group and total were significantly different in 65 out of 509 comparisons (p < 0.05). Some of these were of small sample size but there was no consistent pattern. Apex closure of the first molar was significantly later in children from Quebec and this might explain differences found in the dental maturity score.

CONCLUSIONS: These results suggest no major differences in the timing of tooth formation stages between these children. This fails to explain previous findings of differences using Demirjian's dental maturity method.},
}

Adolescent
Aging/*physiology
Asia
Australia
Canada
Child
Child, Preschool
Europe
Female
Humans
Male
Sex Characteristics
Time Factors
Tooth/anatomy & histology/*growth & development

@article {pmid1718581,
year = {1991},
author = {Brooks, BR},
title = {The role of axonal transport in neurodegenerative disease spread: a meta-analysis of experimental and clinical poliomyelitis compares with amyotrophic lateral sclerosis.},
journal = {The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques},
volume = {18},
number = {3 Suppl},
pages = {435-438},
doi = {10.1017/s0317167100032625},
pmid = {1718581},
issn = {0317-1671},
mesh = {Amyotrophic Lateral Sclerosis/*physiopathology ; Axonal Transport/*physiology ; Follow-Up Studies ; Humans ; Meta-Analysis as Topic ; Poliomyelitis/*physiopathology ; Sex Factors ; Time Factors ; },
abstract = {ALS symptom spread results from local spread of the neuronal degeneration because contiguous areas are more quickly involved than non-contiguous areas. Local spread to contiguous areas of motor neuron dysfunction is faster at the brainstem, cervical and lumbar regions than spread to non-contiguous areas. The time for caudal-rostral symptomatic spread of ALS to involve a distant region is a function of the distance of that region from the site of onset. The time for spread to the bulbar region is shorter following arm onset than leg onset. Spread to non-contiguous areas is faster within the spinal cord than from the spinal cord to the bulbar region. These kinetics are consistent with axonal transport of the etiological agent in a manner similar to spread of poliovirus in poliomyelitis patients. Spread from the bulbar region to the spinal cord, on the other hand, occurs faster than symptom spread from the limb region to the bulbar region in limb onset patients. This rapid limb involvement following bulbar onset is more dramatic in males compared with females. Females with leg onset, on the other hand, show more rapid involvement of the opposite leg, either arm or bulbar structures than males. Gender effects may determine the course of ALS depending on the original site of onset.},
}

Amyotrophic Lateral Sclerosis/*physiopathology
Axonal Transport/*physiology
Follow-Up Studies
Humans
Meta-Analysis as Topic
Poliomyelitis/*physiopathology
Sex Factors
Time Factors

@article {pmid17128083,
year = {2006},
author = {},
title = {[Proceedings of the Consensus Conference on Amyotrophic Lateral Sclerosis, 23-24 November 2005, Nice, France].},
journal = {Revue neurologique},
volume = {162 Spec No 2},
number = {},
pages = {4S11-391},
pmid = {17128083},
issn = {0035-3787},
mesh = {*Amyotrophic Lateral Sclerosis/therapy ; Humans ; },
}

*Amyotrophic Lateral Sclerosis/therapy
Humans

@article {pmid41546910,
year = {2026},
author = {Elyasi, L and Wężyk, M},
title = {Exosome-derived microRNAs from stem cells from human exfoliated deciduous teeth (SHED): Emerging therapeutics for neurodegenerative disorders.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {195},
number = {},
pages = {119001},
doi = {10.1016/j.biopha.2026.119001},
pmid = {41546910},
issn = {1950-6007},
abstract = {Neurodegenerative diseases (NDDs) cause progressive damage of brain structures, resulting in a loss of function and, eventually, the patient's death. Current therapeutic strategies are limited to late stages of the disease, culminating in palliative care, while tackling the underlying causes of neurodegeneration could halt or at least slow down the disease at an early stage. In this vein, stem cell transplantation therapies are emerging as a promising alternative, as such as cells can penetrate the central nervous system, engraft, differentiate, and secrete neurotrophic, neuro-regenerative, and neuroprotective factors. Stem cells derived from human exfoliated deciduous teeth (SHED) have demonstrated significant regenerative potential in various biological systems and pathological conditions, showing high proliferative capacity and multipotency to differentiate into neuronal cells both in vivo and in vitro, apparently functioning through exosome-derived microRNAs (exos-miRs). Here, we summarize recent reports on specific miRs from SHED's exosomes, which exert diverse regulatory functions counteracting oxidative stress, and provide immunomodulatory and neurotrophic benefits contributing to the treatment of neurodegeneration in NDDs. We discuss clinical and preclinical evidence supporting the potential of SHED cells in the treatment of NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), spinal cord injury, focal cerebral ischemia, and peripheral nerve damage. We also highlight that the use of SHED in NDDs treatment remains largely underexplored, opening a wide field for further research. We suggest deeper studies on the role of SHED-exos-miRs in NDDs, including their proneurotrophic activity, reduction of genotoxic neuronal stress, and disruption of proinflammatory signaling pathways.},
}

@article {pmid41538578,
year = {2026},
author = {Khan, M and Saeed, U and Piracha, ZZ and Ozsahin, I and Shao-Chun, C},
title = {Innovative public-health strategies for neurodegenerative disease: leveraging diversified ultraviolet irradiation as a next-generation therapy.},
journal = {Brazilian journal of biology = Revista brasleira de biologia},
volume = {85},
number = {},
pages = {e297765},
doi = {10.1590/1519-6984.297765},
pmid = {41538578},
issn = {1678-4375},
mesh = {Humans ; *Neurodegenerative Diseases/radiotherapy/therapy ; *Ultraviolet Therapy/methods ; *Ultraviolet Rays ; *Public Health ; Oxidative Stress/radiation effects ; },
abstract = {Neurodegenerative diseases (NDs) such as Alzheimer's, Parkinson's, Huntington's disease, and amyotrophic lateral sclerosis are escalating worldwide, straining healthcare systems and leaving patients with therapies that are largely palliative. Emerging evidence positions diversified ultraviolet (UV) irradiation as a groundbreaking, non-invasive strategy to counter these disorders. Beyond its traditional use in sterilization, specific UV spectra, UV-B (280-320 nm), UV-C (200-280 nm), and far-UV (207-222 nm), are now recognized for modulating oxidative stress, restoring mitochondrial function, correcting apoptotic dysregulation, and enhancing DNA repair. Innovative approaches such as riboflavin-mediated phototherapy and photobiomodulation (PBM) show the capacity to disaggregate toxic protein aggregates like β-amyloid and α-synuclein, boost antioxidant defenses, stimulate neurotrophic factors, and quell neuroinflammation. Preclinical models and early clinical trials reveal preserved cognition, enhanced neurogenesis, and reduced disease biomarkers, suggesting real translational promise. From a public-health perspective, UV-based interventions offer a cost-effective, scalable option for aging populations and resource-limited settings, especially when integrated with community-level health technologies and remote delivery platforms. Continued investigation of optimal dosing, long-term safety, and mechanistic pathways will be pivotal to unlock the full therapeutic and population-wide impact of this novel modality.},
}

Humans
*Neurodegenerative Diseases/radiotherapy/therapy
*Ultraviolet Therapy/methods
*Ultraviolet Rays
*Public Health
Oxidative Stress/radiation effects

@article {pmid41534661,
year = {2026},
author = {Costa, I and Barbosa, DJ and Remião, F and Sousa, ME and Silva, R},
title = {A dive into the untapped potential of marine compounds in counteracting neurodegeneration.},
journal = {Pharmacology & therapeutics},
volume = {},
number = {},
pages = {108982},
doi = {10.1016/j.pharmthera.2026.108982},
pmid = {41534661},
issn = {1879-016X},
abstract = {Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis, are characterized by the progressive breakdown and eventual loss of synapses and neurons, primarily driven by the accumulation of pathologically altered proteins within the brain and spinal cord. These diseases have complex and multifactorial etiologies, involving a broad spectrum of pathophysiological mechanisms, many of which remain incompletely understood. Nonetheless, several key pathways are consistently implicated across these conditions, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis. Given their rising prevalence and the persistent lack of effective disease-modifying therapies, the development of novel therapeutic strategies capable of targeting multiple pathophysiological processes is of critical importance for delaying or halting disease progression. In this context, marine natural compounds have emerged as promising candidates for counteracting neurodegeneration, owing to their ability to modulate key pathophysiological hallmarks of distinct neurodegenerative diseases. Derived from a wide range of marine organisms - including algae, sponges, fungi, and cyanobacteria - these bioactive molecules possess unique chemical structures and exhibit a broad spectrum of neuroprotective effects. Many have demonstrated potent antioxidant, anti-apoptotic, and mitochondrial-stabilizing activities in preclinical models. This review highlights recent advances in the discovery and characterization of marine-derived compounds with therapeutic potential in neurodegenerative diseases, contextualizing their pathologic mechanisms.},
}

@article {pmid41532955,
year = {2026},
author = {Bernal-Vicente, BN and Ponce, I and Ríos-Castro, E and Moreno-Castilla, P and Tovar-Y-Romo, LB},
title = {Unveiling the Proteomic Landscape of Extracellular Vesicles: Implications for Neurodegeneration and Neuroprotection.},
journal = {Journal of neurochemistry},
volume = {170},
number = {1},
pages = {e70350},
pmid = {41532955},
issn = {1471-4159},
support = {IN214723//Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México/ ; },
mesh = {Humans ; *Extracellular Vesicles/metabolism ; *Proteomics/methods ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Neuroprotection/physiology ; Biomarkers/metabolism ; },
abstract = {Extracellular vesicles (EVs) are instrumental mediators of intercellular communication and molecular exchange in neurodegenerative and neurovascular diseases. This review integrates recent advances in EV proteomics to elucidate their roles in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), and ischemic stroke. Across these conditions, EVs carry disease-relevant proteins that reflect and influence key pathological processes such as synaptic dysfunction, neuroinflammation, blood-brain barrier (BBB) disruption, and cell death. Proteomic profiling of brain- and biofluid-derived EVs has uncovered specific biomarkers and signaling pathways, ranging from tau and α-synuclein in AD and PD to mutant SOD1 in ALS and complement activation in stroke and TBI. Moreover, cell-type-specific EVs (e.g., from neurons, astrocytes, microglia, and stem cells) have been shown to exert either protective or deleterious effects, modulating apoptosis, axonal regeneration, and immune responses. Recent evidence highlights the translational potential of EVs as non-invasive biomarkers and therapeutic vectors across multiple disorders. By mapping shared and divergent proteomic signatures in EVs, we review the mechanistic relevance and clinical utility of EVs in neurodegeneration and CNS injury.},
}

Humans
*Extracellular Vesicles/metabolism
*Proteomics/methods
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Neuroprotection/physiology
Biomarkers/metabolism

@article {pmid37939113,
year = {2024},
author = {Wang, Z and Liu, YL and Chen, Y and Siegel, L and Cappelleri, JC and Chu, H},
title = {Double-Negative Results Matter: A Reevaluation of Sensitivities for Detecting SARS-CoV-2 Infection Using Saliva Versus Nasopharyngeal Swabs.},
journal = {American journal of epidemiology},
volume = {193},
number = {3},
pages = {548-560},
pmid = {37939113},
issn = {1476-6256},
support = {R01 LM012982/LM/NLM NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; },
mesh = {Humans ; *COVID-19/diagnosis ; SARS-CoV-2 ; Negative Results ; Saliva ; Nasopharynx ; },
abstract = {In a recent systematic review, Bastos et al. (Ann Intern Med. 2021;174(4):501-510) compared the sensitivities of saliva sampling and nasopharyngeal swabs in the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by assuming a composite reference standard defined as positive if either test is positive and negative if both tests are negative (double negative). Even under a perfect specificity assumption, this approach ignores the double-negative results and risks overestimating the sensitivities due to residual misclassification. In this article, we first illustrate the impact of double-negative results in the estimation of the sensitivities in a single study, and then propose a 2-step latent class meta-analysis method for reevaluating both sensitivities using the same published data set as that used in Bastos et al. by properly including the observed double-negative results. We also conduct extensive simulation studies to compare the performance of the proposed method with Bastos et al.'s method for varied levels of prevalence and between-study heterogeneity. The results demonstrate that the sensitivities are overestimated noticeably using Bastos et al.'s method, and the proposed method provides a more accurate evaluation with nearly no bias and close-to-nominal coverage probability. In conclusion, double-negative results can significantly impact the estimated sensitivities when a gold standard is absent, and thus they should be properly incorporated.},
}

Humans
*COVID-19/diagnosis
SARS-CoV-2
Negative Results
Saliva
Nasopharynx

@article {pmid37431780,
year = {2023},
author = {Potente, C and Chumbley, J and Xu, W and Levitt, B and Cole, SW and Ravi, S and Bodelet, JS and Gaydosh, L and Harris, KM and Shanahan, MJ},
title = {Socioeconomic Inequalities and Molecular Risk for Aging in Young Adulthood.},
journal = {American journal of epidemiology},
volume = {192},
number = {12},
pages = {1981-1990},
pmid = {37431780},
issn = {1476-6256},
support = {P01 HD031921/HD/NICHD NIH HHS/United States ; R01 AG043404/AG/NIA NIH HHS/United States ; P30 AG017265/AG/NIA NIH HHS/United States ; R01 AG033590/AG/NIA NIH HHS/United States ; P2C HD050924/HD/NICHD NIH HHS/United States ; R01 HD087061/HD/NICHD NIH HHS/United States ; },
mesh = {Adult ; Adolescent ; Humans ; Young Adult ; Longitudinal Studies ; *Social Class ; *Aging/genetics ; Smoking ; Income ; Socioeconomic Factors ; },
abstract = {Diverse manifestations of biological aging often reflect disparities in socioeconomic status (SES). In this paper, we examine associations between indicators of SES and an mRNA-based aging signature during young adulthood, before clinical indications of aging are common. We use data from wave V (2016-2018) of the National Longitudinal Study of Adolescent to Adult Health, a nationally representative study of adults aged 33-43 years, with transcriptomic data from a subset of 2,491 participants. Biological aging is measured using 1) a composite transcriptomic aging signature previously identified by Peters et al.'s out-of-sample meta-analysis (Nat Commun. 2015;6:8570) and 2) 9 subsets that represent functional pathways of coexpressed genes. SES refers to income, education, occupation, subjective social status, and a composite measure combining these 4 dimensions. We examine hypothesized mechanisms through which SES could affect aging: body mass index, smoking, health insurance status, difficulty paying bills, and psychosocial stress. We find that SES-especially the composite measure and income-is associated with transcriptomic aging and immune, mitochondrial, ribosomal, lysosomal, and proteomal pathways. Counterfactual mediational models suggest that the mediators partially account for these associations. The results thus reveal that numerous biological pathways associated with aging are already linked to SES in young adulthood.},
}

Adult
Adolescent
Humans
Young Adult
Longitudinal Studies
*Social Class
*Aging/genetics
Smoking
Income
Socioeconomic Factors

@article {pmid35652455,
year = {2022},
author = {Fels, JA and Casalena, G and Konrad, C and Holmes, HE and Dellinger, RW and Manfredi, G},
title = {Gene expression profiles in sporadic ALS fibroblasts define disease subtypes and the metabolic effects of the investigational drug EH301.},
journal = {Human molecular genetics},
volume = {31},
number = {20},
pages = {3458-3477},
pmid = {35652455},
issn = {1460-2083},
support = {R35 NS122209/NS/NINDS NIH HHS/United States ; },
mesh = {*Amyotrophic Lateral Sclerosis/metabolism ; Antioxidants/metabolism ; Drugs, Investigational/metabolism/therapeutic use ; Fibroblasts/metabolism ; Humans ; Transcriptome/genetics ; },
abstract = {Metabolic alterations shared between the nervous system and skin fibroblasts have emerged in amyotrophic lateral sclerosis (ALS). Recently, we found that a subgroup of sporadic ALS (sALS) fibroblasts (sALS1) is characterized by metabolic profiles distinct from other sALS cases (sALS2) and controls, suggesting that metabolic therapies could be effective in sALS. The metabolic modulators nicotinamide riboside and pterostilbene (EH301) are under clinical development for the treatment of ALS. Here, we studied the transcriptome and metabolome of sALS cells to understand the molecular bases of sALS metabotypes and the impact of EH301. Metabolomics and transcriptomics were investigated at baseline and after EH301 treatment. Moreover, weighted gene coexpression network analysis (WGCNA) was used to investigate the association of the metabolic and clinical features. We found that the sALS1 transcriptome is distinct from sALS2 and that EH301 modifies gene expression differently in sALS1, sALS2 and the controls. Furthermore, EH301 had strong protective effects against metabolic stress, an effect linked to the antiinflammatory and antioxidant pathways. WGCNA revealed that the ALS functional rating scale and metabotypes are associated with gene modules enriched for the cell cycle, immunity, autophagy and metabolic genes, which are modified by EH301. The meta-analysis of publicly available transcriptomic data from induced motor neurons by Answer ALS confirmed the functional associations of genes correlated with disease traits. A subset of genes differentially expressed in sALS fibroblasts was used in a machine learning model to predict disease progression. In conclusion, multiomic analyses highlighted the differential metabolic and transcriptomic profiles in patient-derived fibroblast sALS, which translate into differential responses to the investigational drug EH301.},
}

*Amyotrophic Lateral Sclerosis/metabolism
Antioxidants/metabolism
Drugs, Investigational/metabolism/therapeutic use
Fibroblasts/metabolism
Humans
Transcriptome/genetics

@article {pmid35196023,
year = {2022},
author = {Hop, PJ and Zwamborn, RAJ and Hannon, E and Shireby, GL and Nabais, MF and Walker, EM and van Rheenen, W and van Vugt, JJFA and Dekker, AM and Westeneng, HJ and Tazelaar, GHP and van Eijk, KR and Moisse, M and Baird, D and Al Khleifat, A and Iacoangeli, A and Ticozzi, N and Ratti, A and Cooper-Knock, J and Morrison, KE and Shaw, PJ and Basak, AN and Chiò, A and Calvo, A and Moglia, C and Canosa, A and Brunetti, M and Grassano, M and Gotkine, M and Lerner, Y and Zabari, M and Vourc'h, P and Corcia, P and Couratier, P and Mora Pardina, JS and Salas, T and Dion, P and Ross, JP and Henderson, RD and Mathers, S and McCombe, PA and Needham, M and Nicholson, G and Rowe, DB and Pamphlett, R and Mather, KA and Sachdev, PS and Furlong, S and Garton, FC and Henders, AK and Lin, T and Ngo, ST and Steyn, FJ and Wallace, L and Williams, KL and , and , and Neto, MM and Cauchi, RJ and Blair, IP and Kiernan, MC and Drory, V and Povedano, M and de Carvalho, M and Pinto, S and Weber, M and Rouleau, GA and Silani, V and Landers, JE and Shaw, CE and Andersen, PM and McRae, AF and van Es, MA and Pasterkamp, RJ and Wray, NR and McLaughlin, RL and Hardiman, O and Kenna, KP and Tsai, E and Runz, H and Al-Chalabi, A and van den Berg, LH and Van Damme, P and Mill, J and Veldink, JH},
title = {Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.},
journal = {Science translational medicine},
volume = {14},
number = {633},
pages = {eabj0264},
pmid = {35196023},
issn = {1946-6242},
support = {G0300329/MRC_/Medical Research Council/United Kingdom ; R56 NS073873/NS/NINDS NIH HHS/United States ; SHAW/APR18/864-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; /DH_/Department of Health/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; MC_PC_17115/MRC_/Medical Research Council/United Kingdom ; SHAW/NOV14/985-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; R01 NS073873/NS/NINDS NIH HHS/United States ; MCLAUGHLIN/OCT15/957-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics ; Cholesterol ; DNA Methylation/genetics ; Epigenesis, Genetic ; Genome-Wide Association Study ; Humans ; *Neurodegenerative Diseases/genetics ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.},
}

*Amyotrophic Lateral Sclerosis/genetics
Cholesterol
DNA Methylation/genetics
Epigenesis, Genetic
Genome-Wide Association Study
Humans
*Neurodegenerative Diseases/genetics

@article {pmid34873335,
year = {2021},
author = {van Rheenen, W and van der Spek, RAA and Bakker, MK and van Vugt, JJFA and Hop, PJ and Zwamborn, RAJ and de Klein, N and Westra, HJ and Bakker, OB and Deelen, P and Shireby, G and Hannon, E and Moisse, M and Baird, D and Restuadi, R and Dolzhenko, E and Dekker, AM and Gawor, K and Westeneng, HJ and Tazelaar, GHP and van Eijk, KR and Kooyman, M and Byrne, RP and Doherty, M and Heverin, M and Al Khleifat, A and Iacoangeli, A and Shatunov, A and Ticozzi, N and Cooper-Knock, J and Smith, BN and Gromicho, M and Chandran, S and Pal, S and Morrison, KE and Shaw, PJ and Hardy, J and Orrell, RW and Sendtner, M and Meyer, T and Başak, N and van der Kooi, AJ and Ratti, A and Fogh, I and Gellera, C and Lauria, G and Corti, S and Cereda, C and Sproviero, D and D'Alfonso, S and Sorarù, G and Siciliano, G and Filosto, M and Padovani, A and Chiò, A and Calvo, A and Moglia, C and Brunetti, M and Canosa, A and Grassano, M and Beghi, E and Pupillo, E and Logroscino, G and Nefussy, B and Osmanovic, A and Nordin, A and Lerner, Y and Zabari, M and Gotkine, M and Baloh, RH and Bell, S and Vourc'h, P and Corcia, P and Couratier, P and Millecamps, S and Meininger, V and Salachas, F and Mora Pardina, JS and Assialioui, A and Rojas-García, R and Dion, PA and Ross, JP and Ludolph, AC and Weishaupt, JH and Brenner, D and Freischmidt, A and Bensimon, G and Brice, A and Durr, A and Payan, CAM and Saker-Delye, S and Wood, NW and Topp, S and Rademakers, R and Tittmann, L and Lieb, W and Franke, A and Ripke, S and Braun, A and Kraft, J and Whiteman, DC and Olsen, CM and Uitterlinden, AG and Hofman, A and Rietschel, M and Cichon, S and Nöthen, MM and Amouyel, P and , and , and , and , and Traynor, BJ and Singleton, AB and Mitne Neto, M and Cauchi, RJ and Ophoff, RA and Wiedau-Pazos, M and Lomen-Hoerth, C and van Deerlin, VM and Grosskreutz, J and Roediger, A and Gaur, N and Jörk, A and Barthel, T and Theele, E and Ilse, B and Stubendorff, B and Witte, OW and Steinbach, R and Hübner, CA and Graff, C and Brylev, L and Fominykh, V and Demeshonok, V and Ataulina, A and Rogelj, B and Koritnik, B and Zidar, J and Ravnik-Glavač, M and Glavač, D and Stević, Z and Drory, V and Povedano, M and Blair, IP and Kiernan, MC and Benyamin, B and Henderson, RD and Furlong, S and Mathers, S and McCombe, PA and Needham, M and Ngo, ST and Nicholson, GA and Pamphlett, R and Rowe, DB and Steyn, FJ and Williams, KL and Mather, KA and Sachdev, PS and Henders, AK and Wallace, L and de Carvalho, M and Pinto, S and Petri, S and Weber, M and Rouleau, GA and Silani, V and Curtis, CJ and Breen, G and Glass, JD and Brown, RH and Landers, JE and Shaw, CE and Andersen, PM and Groen, EJN and van Es, MA and Pasterkamp, RJ and Fan, D and Garton, FC and McRae, AF and Davey Smith, G and Gaunt, TR and Eberle, MA and Mill, J and McLaughlin, RL and Hardiman, O and Kenna, KP and Wray, NR and Tsai, E and Runz, H and Franke, L and Al-Chalabi, A and Van Damme, P and van den Berg, LH and Veldink, JH},
title = {Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.},
journal = {Nature genetics},
volume = {53},
number = {12},
pages = {1636-1648},
pmid = {34873335},
issn = {1546-1718},
support = {MR/L501542/1/MRC_/Medical Research Council/United Kingdom ; R56 NS073873/NS/NINDS NIH HHS/United States ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; G0701075/MRC_/Medical Research Council/United Kingdom ; G-1307/PUK_/Parkinson's UK/United Kingdom ; MC_UU_00011/1/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; SMITH/APR16/847-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/J004758/1/MRC_/Medical Research Council/United Kingdom ; MC_PC_17115/MRC_/Medical Research Council/United Kingdom ; MC_UU_00011/4/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; G0901254/MRC_/Medical Research Council/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; SHAW/APR15/970-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; MR/K01417X/1/MRC_/Medical Research Council/United Kingdom ; G-0907/PUK_/Parkinson's UK/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; G1001253/MRC_/Medical Research Council/United Kingdom ; R01 NS073873/NS/NINDS NIH HHS/United States ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-TALBOT/APR14/926-794/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; MR/L023784/2/MRC_/Medical Research Council/United Kingdom ; MRF-060-0003-RG-SMITH/MRF_/MRF_/United Kingdom ; SHAW/NOV14/985-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; },
mesh = {Amyotrophic Lateral Sclerosis/*genetics/metabolism ; Brain/metabolism ; Cholesterol/blood ; Disease Progression ; Female ; *Genome-Wide Association Study ; Glutamine/metabolism ; Humans ; Male ; Mendelian Randomization Analysis ; Microsatellite Repeats ; *Mutation ; Neurodegenerative Diseases/genetics ; Neurons/*metabolism ; Quantitative Trait Loci ; RNA-Seq ; Risk Factors ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.},
}

Amyotrophic Lateral Sclerosis/*genetics/metabolism
Brain/metabolism
Cholesterol/blood
Disease Progression
Female
*Genome-Wide Association Study
Glutamine/metabolism
Humans
Male
Mendelian Randomization Analysis
Microsatellite Repeats
*Mutation
Neurodegenerative Diseases/genetics
Neurons/*metabolism
Quantitative Trait Loci
RNA-Seq
Risk Factors

@article {pmid34390790,
year = {2022},
author = {Xiao, M and Chu, H and Cole, SR and Chen, Y and MacLehose, RF and Richardson, DB and Greenland, S},
title = {Controversy and Debate : Questionable utility of the relative risk in clinical research: Paper 4 :Odds Ratios are far from "portable" - A call to use realistic models for effect variation in meta-analysis.},
journal = {Journal of clinical epidemiology},
volume = {142},
number = {},
pages = {294-304},
pmid = {34390790},
issn = {1878-5921},
support = {R01 LM012607/LM/NLM NIH HHS/United States ; R01 LM012982/LM/NLM NIH HHS/United States ; R01 LM013049/LM/NLM NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; },
mesh = {Bias ; Causality ; Humans ; *Odds Ratio ; Risk ; Systematic Reviews as Topic ; },
abstract = {OBJECTIVE: Recently Doi et al. argued that risk ratios should be replaced with odds ratios in clinical research. We disagreed, and empirically documented the lack of portability of odds ratios, while Doi et al. defended their position. In this response we highlight important errors in their position.

STUDY DESIGN AND SETTING: We counter Doi et al.'s arguments by further examining the correlations of odds ratios, and risk ratios, with baseline risks in 20,198 meta-analyses from the Cochrane Database of Systematic Reviews.

RESULTS: Doi et al.'s claim that odds ratios are portable is invalid because 1) their reasoning is circular: they assume a model under which the odds ratio is constant and show that under such a model the odds ratio is portable; 2) the method they advocate to convert odds ratios to risk ratios is biased; 3) their empirical example is readily-refuted by counter-examples of meta-analyses in which the risk ratio is portable but the odds ratio isn't; and 4) they fail to consider the causal determinants of meta-analytic inclusion criteria: Doi et al. mistakenly claim that variation in odds ratios with different baseline risks in meta-analyses is due to collider bias. Empirical comparison between the correlations of odds ratios, and risk ratios, with baseline risks show that the portability of odds ratios and risk ratios varies across settings.

CONCLUSION: The suggestion to replace risk ratios with odds ratios is based on circular reasoning and a confusion of mathematical and empirical results. It is especially misleading for meta-analyses and clinical guidance. Neither the odds ratio nor the risk ratio is universally portable. To address this lack of portability, we reinforce our suggestion to report variation in effect measures conditioning on modifying factors such as baseline risk; understanding such variation is essential to patient-centered practice.},
}

Bias
Causality
Humans
*Odds Ratio
Risk
Systematic Reviews as Topic

@article {pmid34384876,
year = {2022},
author = {Xiao, M and Chen, Y and Cole, SR and MacLehose, RF and Richardson, DB and Chu, H},
title = {Controversy and Debate: Questionable utility of the relative risk in clinical research: Paper 2: Is the Odds Ratio "portable" in meta-analysis? Time to consider bivariate generalized linear mixed model.},
journal = {Journal of clinical epidemiology},
volume = {142},
number = {},
pages = {280-287},
pmid = {34384876},
issn = {1878-5921},
support = {R01 LM012982/LM/NLM NIH HHS/United States ; UL1 TR002494/TR/NCATS NIH HHS/United States ; R01 LM013049/LM/NLM NIH HHS/United States ; R01 LM012607/LM/NLM NIH HHS/United States ; },
mesh = {Humans ; Linear Models ; *Odds Ratio ; Risk ; Systematic Reviews as Topic ; },
abstract = {OBJECTIVES: A recent paper by Doi et al. advocated completely replacing the relative risk (RR) with the odds ratio (OR) as the effect measure in clinical trials and meta-analyses with binary outcomes. Besides some practical advantages of RR over OR, Doi et al.'s key assumption that the OR is "portable" in the meta-analysis, that is, study-specific ORs are likely not correlated with baseline risks, was not well justified.

STUDY DESIGNS AND SETTINGS: We summarized Spearman's rank correlation coefficient between study-specific ORs and baseline risks in 40,243 meta-analyses from the Cochrane Database of Systematic Reviews.

RESULTS: Study-specific ORs tend to be higher in studies with lower baseline risks of disease for most meta-analyses in Cochrane Database of Systematic Reviews. Using an actual meta-analysis example, we demonstrate that there is a strong negative correlation between OR (RR or RD) with the baseline risk and the conditional effects notably vary with baseline risks.

CONCLUSIONS: Replacing RR or RD with OR is currently unadvisable in clinical trials and meta-analyses. It is possible that no effect measure is "portable" in a meta-analysis. In addition to the overall (or marginal) effect, we suggest presenting the conditional effect based on the baseline risk using a bivariate generalized linear mixed model.},
}

Humans
Linear Models
*Odds Ratio
Risk
Systematic Reviews as Topic

@article {pmid33771206,
year = {2021},
author = {Nabais, MF and Laws, SM and Lin, T and Vallerga, CL and Armstrong, NJ and Blair, IP and Kwok, JB and Mather, KA and Mellick, GD and Sachdev, PS and Wallace, L and Henders, AK and Zwamborn, RAJ and Hop, PJ and Lunnon, K and Pishva, E and Roubroeks, JAY and Soininen, H and Tsolaki, M and Mecocci, P and Lovestone, S and Kłoszewska, I and Vellas, B and , and , and Furlong, S and Garton, FC and Henderson, RD and Mathers, S and McCombe, PA and Needham, M and Ngo, ST and Nicholson, G and Pamphlett, R and Rowe, DB and Steyn, FJ and Williams, KL and Anderson, TJ and Bentley, SR and Dalrymple-Alford, J and Fowder, J and Gratten, J and Halliday, G and Hickie, IB and Kennedy, M and Lewis, SJG and Montgomery, GW and Pearson, J and Pitcher, TL and Silburn, P and Zhang, F and Visscher, PM and Yang, J and Stevenson, AJ and Hillary, RF and Marioni, RE and Harris, SE and Deary, IJ and Jones, AR and Shatunov, A and Iacoangeli, A and van Rheenen, W and van den Berg, LH and Shaw, PJ and Shaw, CE and Morrison, KE and Al-Chalabi, A and Veldink, JH and Hannon, E and Mill, J and Wray, NR and McRae, AF},
title = {Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.},
journal = {Genome biology},
volume = {22},
number = {1},
pages = {90},
pmid = {33771206},
issn = {1474-760X},
support = {U24 AG021886/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; U01 AG024904/AG/NIA NIH HHS/United States ; 108890/Z/15/Z/WT_/Wellcome Trust/United Kingdom ; R01 AG033193/AG/NIA NIH HHS/United States ; 082604/2/07/Z/WT_/Wellcome Trust/United Kingdom ; TURNER/OCT15/972-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; /DH_/Department of Health/United Kingdom ; U01 AG016976/AG/NIA NIH HHS/United States ; R01 HL105756/HL/NHLBI NIH HHS/United States ; 503480/MRC_/Medical Research Council/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; },
mesh = {Alleles ; Biomarkers ; Blood Cells/metabolism ; Case-Control Studies ; *DNA Methylation ; Disease Susceptibility ; *Epigenesis, Genetic ; Gene Expression Profiling ; Genetic Loci ; Genetic Predisposition to Disease ; *Genome-Wide Association Study ; Humans ; Neurodegenerative Diseases/*etiology/metabolism ; },
abstract = {BACKGROUND: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.

RESULTS: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.

CONCLUSIONS: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.},
}

Alleles
Biomarkers
Blood Cells/metabolism
Case-Control Studies
*DNA Methylation
Disease Susceptibility
*Epigenesis, Genetic
Gene Expression Profiling
Genetic Loci
Genetic Predisposition to Disease
*Genome-Wide Association Study
Humans
Neurodegenerative Diseases/*etiology/metabolism

@article {pmid32668255,
year = {2020},
author = {Wan, YW and Al-Ouran, R and Mangleburg, CG and Perumal, TM and Lee, TV and Allison, K and Swarup, V and Funk, CC and Gaiteri, C and Allen, M and Wang, M and Neuner, SM and Kaczorowski, CC and Philip, VM and Howell, GR and Martini-Stoica, H and Zheng, H and Mei, H and Zhong, X and Kim, JW and Dawson, VL and Dawson, TM and Pao, PC and Tsai, LH and Haure-Mirande, JV and Ehrlich, ME and Chakrabarty, P and Levites, Y and Wang, X and Dammer, EB and Srivastava, G and Mukherjee, S and Sieberts, SK and Omberg, L and Dang, KD and Eddy, JA and Snyder, P and Chae, Y and Amberkar, S and Wei, W and Hide, W and Preuss, C and Ergun, A and Ebert, PJ and Airey, DC and Mostafavi, S and Yu, L and Klein, HU and , and Carter, GW and Collier, DA and Golde, TE and Levey, AI and Bennett, DA and Estrada, K and Townsend, TM and Zhang, B and Schadt, E and De Jager, PL and Price, ND and Ertekin-Taner, N and Liu, Z and Shulman, JM and Mangravite, LM and Logsdon, BA},
title = {Meta-Analysis of the Alzheimer's Disease Human Brain Transcriptome and Functional Dissection in Mouse Models.},
journal = {Cell reports},
volume = {32},
number = {2},
pages = {107908},
pmid = {32668255},
issn = {2211-1247},
support = {U01 AG046152/AG/NIA NIH HHS/United States ; R01 AG053960/AG/NIA NIH HHS/United States ; R01 AG017917/AG/NIA NIH HHS/United States ; F31 AG050357/AG/NIA NIH HHS/United States ; RF1 AG051504/AG/NIA NIH HHS/United States ; U01 AG061357/AG/NIA NIH HHS/United States ; P30 AG010161/AG/NIA NIH HHS/United States ; P50 NS038377/NS/NINDS NIH HHS/United States ; R01 AG015473/AG/NIA NIH HHS/United States ; P01 AG017216/AG/NIA NIH HHS/United States ; R01 AG018023/AG/NIA NIH HHS/United States ; R01 AG057339/AG/NIA NIH HHS/United States ; RF1 AG057440/AG/NIA NIH HHS/United States ; P50 AG016574/AG/NIA NIH HHS/United States ; RF1 AG054014/AG/NIA NIH HHS/United States ; U01 AG032984/AG/NIA NIH HHS/United States ; R01 AG050631/AG/NIA NIH HHS/United States ; R01 AG030146/AG/NIA NIH HHS/United States ; U01 AG046170/AG/NIA NIH HHS/United States ; U24 AG061340/AG/NIA NIH HHS/United States ; R01 AG061796/AG/NIA NIH HHS/United States ; P50 AG025688/AG/NIA NIH HHS/United States ; R01 AG032990/AG/NIA NIH HHS/United States ; R01 NS080820/NS/NINDS NIH HHS/United States ; RF1 AG057443/AG/NIA NIH HHS/United States ; RF1 AG057473/AG/NIA NIH HHS/United States ; U01 AG046139/AG/NIA NIH HHS/United States ; P01 AG003949/AG/NIA NIH HHS/United States ; U24 NS072026/NS/NINDS NIH HHS/United States ; U01 AG046161/AG/NIA NIH HHS/United States ; P30 AG019610/AG/NIA NIH HHS/United States ; P50 AG025711/AG/NIA NIH HHS/United States ; U01 AG006786/AG/NIA NIH HHS/United States ; R01 AG036836/AG/NIA NIH HHS/United States ; R01 AG046174/AG/NIA NIH HHS/United States ; R01 AG015819/AG/NIA NIH HHS/United States ; R01 AG057914/AG/NIA NIH HHS/United States ; F31 AG067677/AG/NIA NIH HHS/United States ; },
mesh = {Alzheimer Disease/*genetics ; Animals ; Brain/*metabolism/*pathology ; Case-Control Studies ; Disease Models, Animal ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Gene Regulatory Networks ; Humans ; Male ; Mice ; Sex Characteristics ; Species Specificity ; Transcription, Genetic ; Transcriptome/*genetics ; },
abstract = {We present a consensus atlas of the human brain transcriptome in Alzheimer's disease (AD), based on meta-analysis of differential gene expression in 2,114 postmortem samples. We discover 30 brain coexpression modules from seven regions as the major source of AD transcriptional perturbations. We next examine overlap with 251 brain differentially expressed gene sets from mouse models of AD and other neurodegenerative disorders. Human-mouse overlaps highlight responses to amyloid versus tau pathology and reveal age- and sex-dependent expression signatures for disease progression. Human coexpression modules enriched for neuronal and/or microglial genes broadly overlap with mouse models of AD, Huntington's disease, amyotrophic lateral sclerosis, and aging. Other human coexpression modules, including those implicated in proteostasis, are not activated in AD models but rather following other, unexpected genetic manipulations. Our results comprise a cross-species resource, highlighting transcriptional networks altered by human brain pathophysiology and identifying correspondences with mouse models for AD preclinical studies.},
}

Alzheimer Disease/*genetics
Animals
Brain/*metabolism/*pathology
Case-Control Studies
Disease Models, Animal
Female
Gene Expression Profiling
Gene Expression Regulation
Gene Regulatory Networks
Humans
Male
Mice
Sex Characteristics
Species Specificity
Transcription, Genetic
Transcriptome/*genetics

@article {pmid32594886,
year = {2022},
author = {Duff, K and Hammers, DB},
title = {Practice effects in mild cognitive impairment: A validation of Calamia et al. (2012).},
journal = {The Clinical neuropsychologist},
volume = {36},
number = {3},
pages = {571-583},
pmid = {32594886},
issn = {1744-4144},
support = {R01 AG045163/AG/NIA NIH HHS/United States ; R01 AG055428/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; *Cognitive Dysfunction/diagnosis/psychology ; Humans ; Neuropsychological Tests ; },
abstract = {OBJECTIVE: In a meta-analysis examining practice effects on repeated neuropsychological testing, Calamia et al. (2012) provided information to predict practice effects in healthy and clinical samples across a range of cognitive domains. However, these estimates have not been validated.

METHOD: This study used these prediction estimate calculations to predict follow-up scores across one year on a brief battery of neuropsychological tests in a sample of 93 older adults with amnestic mild cognitive impairment. The predicted follow-up scores were compared to observed follow-up scores.

RESULTS: Using Calamia et al. model's intercept, age, retest interval, clinical status, and specific cognitive tests, three of the seven observed follow-up scores in this cognitive battery were significantly lower than the Calamia et al. predicted follow-up scores. Differences between individual participants' observed and predicted follow-up scores were more striking. For example, on Delayed Recall of the Hopkins Verbal Learning Test - Revised, 40% of the sample had Calamia et al. predicted scores that were one or more standard deviations above their observed scores. These differences were most notable on tests that were not in Calamia et al.'s cognitive battery, suggesting the meta-analysis results may not generalize as well to other tests.

CONCLUSIONS: Although Calamia et al. provided a method for predicting practice effects and follow-up scores, these results raise caution when using them in MCI, especially on cognitive tests that were not in their meta-analysis.},
}

Aged
*Cognitive Dysfunction/diagnosis/psychology
Humans
Neuropsychological Tests

@article {pmid31315673,
year = {2019},
author = {Iacoangeli, A and Al Khleifat, A and Jones, AR and Sproviero, W and Shatunov, A and Opie-Martin, S and , and Morrison, KE and Shaw, PJ and Shaw, CE and Fogh, I and Dobson, RJ and Newhouse, SJ and Al-Chalabi, A},
title = {C9orf72 intermediate expansions of 24-30 repeats are associated with ALS.},
journal = {Acta neuropathologica communications},
volume = {7},
number = {1},
pages = {115},
pmid = {31315673},
issn = {2051-5960},
support = {MC_PC_17214/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; SHAW/APR18/864-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; U01 AG024904/AG/NIA NIH HHS/United States ; G0600974/MRC_/Medical Research Council/United Kingdom ; AL-CHALABI/APR15/844-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; ES/L008238/1//Economic and Social Research Council/International ; MC_PC_17115/MRC_/Medical Research Council/United Kingdom ; SHAW/NOV14/985-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; /WT_/Wellcome Trust/United Kingdom ; MR/R024804/1/MRC_/Medical Research Council/United Kingdom ; 633413//Horizon 2020 Framework Programme/International ; },
mesh = {Aged ; Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/*genetics ; C9orf72 Protein/*genetics ; DNA Repeat Expansion/*genetics ; Databases, Genetic/trends ; Female ; Humans ; Male ; Middle Aged ; White People/*genetics ; Whole Genome Sequencing/methods ; },
abstract = {The expansion of a hexanucleotide repeat GGGGCC in C9orf72 is the most common known cause of ALS accounting for ~ 40% familial cases and ~ 7% sporadic cases in the European population. In most people, the repeat length is 2, but in people with ALS, hundreds to thousands of repeats may be observed. A small proportion of people have an intermediate expansion, of the order of 20 to 30 repeats in size, and it remains unknown whether intermediate expansions confer risk of ALS in the same way that massive expansions do. We investigated the association of this intermediate repeat with ALS by performing a meta-analysis of four previously published studies and a new British/Alzheimer's Disease Neuroimaging Initiative dataset of 1295 cases and 613 controls. The final dataset comprised 5071 cases and 3747 controls. Our meta-analysis showed association between ALS and intermediate C9orf72 repeats of 24 to 30 repeats in size (random-effects model OR = 4.2, 95% CI = 1.23-14.35, p-value = 0.02). Furthermore, we showed a different frequency of the repeat between the northern and southern European populations (Fisher's exact test p-value = 5 × 10[- 3]). Our findings provide evidence for the association between intermediate repeats and ALS (p-value = 2 × 10[- 4]) with direct relevance for research and clinical practice by showing that an expansion of 24 or more repeats should be considered pathogenic.},
}

Aged
Amyotrophic Lateral Sclerosis/diagnosis/epidemiology/*genetics
C9orf72 Protein/*genetics
DNA Repeat Expansion/*genetics
Databases, Genetic/trends
Female
Humans
Male
Middle Aged
White People/*genetics
Whole Genome Sequencing/methods

@article {pmid30620104,
year = {2019},
author = {Pattee, GL and Plowman, EK and Focht Garand, KL and Costello, J and Brooks, BR and Berry, JD and Smith, RA and Atassi, N and Chapin, JL and Yunusova, Y and McIlduff, CE and Young, E and Macklin, EA and Locatelli, ER and Silani, V and Heitzman, D and Wymer, J and Goutman, SA and Gelinas, DF and Perry, B and Nalipinski, P and Stipancic, K and O'Brien, M and Sullivan, SL and Pioro, EP and Gargiulo, G and Green, JR and , },
title = {Provisional best practices guidelines for the evaluation of bulbar dysfunction in amyotrophic lateral sclerosis.},
journal = {Muscle & nerve},
volume = {59},
number = {5},
pages = {531-536},
doi = {10.1002/mus.26408},
pmid = {30620104},
issn = {1097-4598},
support = {R01 DC013547/DC/NIDCD NIH HHS/United States ; },
mesh = {Amyotrophic Lateral Sclerosis/complications/*rehabilitation ; Communication Devices for People with Disabilities ; Deglutition Disorders/diagnosis/etiology/*rehabilitation ; Disease Management ; Humans ; Referral and Consultation ; Speech Disorders/diagnosis/etiology/*rehabilitation ; Speech Therapy ; },
abstract = {INTRODUCTION: Universally established comprehensive clinical bulbar scales objectively assessing disease progression in amyotrophic lateral sclerosis (ALS) are currently lacking. The goal of this working group project is to design a best practice set of provisional bulbar ALS guidelines, available for immediate implementation within all ALS clinics.

METHODS: ALS specialists across multiple related disciplines participated in a series of clinical bulbar symposia, intending to identify and summarize the currently accepted best practices for the assessment and management of bulbar dysfunction in ALS Results: Summary group recommendations for individual speech, Augmentative and Alternative Communication (AAC), and swallowing sections were achieved, focusing on the optimal proposed level of care within each domain.

DISCUSSION: We have identified specific clinical recommendations for each of the 3 domains of bulbar functioning, available for incorporation within all ALS clinics. Future directions will be to establish a formal set of bulbar guidelines through a methodological and evidence-based approach. Muscle Nerve 59:531-531, 2019.},
}

Amyotrophic Lateral Sclerosis/complications/*rehabilitation
Communication Devices for People with Disabilities
Deglutition Disorders/diagnosis/etiology/*rehabilitation
Disease Management
Humans
Referral and Consultation
Speech Disorders/diagnosis/etiology/*rehabilitation
Speech Therapy

@article {pmid30594291,
year = {2019},
author = {Yanagi, KS and Wu, Z and Amaya, J and Chapkis, N and Duffy, AM and Hajdarovic, KH and Held, A and Mathur, AD and Russo, K and Ryan, VH and Steinert, BL and Whitt, JP and Fallon, JR and Fawzi, NL and Lipscombe, D and Reenan, RA and Wharton, KA and Hart, AC},
title = {Meta-analysis of Genetic Modifiers Reveals Candidate Dysregulated Pathways in Amyotrophic Lateral Sclerosis.},
journal = {Neuroscience},
volume = {396},
number = {},
pages = {A3-A20},
pmid = {30594291},
issn = {1873-7544},
support = {T32 MH020068/MH/NIMH NIH HHS/United States ; R01 GM122083/GM/NIGMS NIH HHS/United States ; F31 NS110301/NS/NINDS NIH HHS/United States ; R01 GM118530/GM/NIGMS NIH HHS/United States ; T32 NS062443/NS/NINDS NIH HHS/United States ; P20 GM109035/GM/NIGMS NIH HHS/United States ; },
mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Computational Biology ; Genes, Modifier/*genetics ; Genetic Predisposition to Disease/genetics ; Humans ; Signal Transduction/*genetics ; },
abstract = {Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that has significant overlap with frontotemporal dementia (FTD). Mutations in specific genes have been identified that can cause and/or predispose patients to ALS. However, the clinical variability seen in ALS patients suggests that additional genes impact pathology, susceptibility, severity, and/or progression of the disease. To identify molecular pathways involved in ALS, we undertook a meta-analysis of published genetic modifiers both in patients and in model organisms, and undertook bioinformatic pathway analysis. From 72 published studies, we generated a list of 946 genes whose perturbation (1) impacted ALS in patient populations, (2) altered defects in laboratory models, or (3) modified defects caused by ALS gene ortholog loss of function. Herein, these are all called modifier genes. We found 727 modifier genes that encode proteins with human orthologs. Of these, 43 modifier genes were identified as modifiers of more than one ALS gene/model, consistent with the hypothesis that shared genes and pathways may underlie ALS. Further, we used a gene ontology-based bioinformatic analysis to identify pathways and associated genes that may be important in ALS. To our knowledge this is the first comprehensive survey of ALS modifier genes. This work suggests that shared molecular mechanisms may underlie pathology caused by different ALS disease genes. Surprisingly, few ALS modifier genes have been tested in more than one disease model. Understanding genes that modify ALS-associated defects will help to elucidate the molecular pathways that underlie ALS and provide additional targets for therapeutic intervention.},
}

Amyotrophic Lateral Sclerosis/*genetics
Animals
Computational Biology
Genes, Modifier/*genetics
Genetic Predisposition to Disease/genetics
Humans
Signal Transduction/*genetics

@article {pmid29315334,
year = {2018},
author = {Broce, I and Karch, CM and Wen, N and Fan, CC and Wang, Y and Tan, CH and Kouri, N and Ross, OA and Höglinger, GU and Muller, U and Hardy, J and , and Momeni, P and Hess, CP and Dillon, WP and Miller, ZA and Bonham, LW and Rabinovici, GD and Rosen, HJ and Schellenberg, GD and Franke, A and Karlsen, TH and Veldink, JH and Ferrari, R and Yokoyama, JS and Miller, BL and Andreassen, OA and Dale, AM and Desikan, RS and Sugrue, LP},
title = {Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.},
journal = {PLoS medicine},
volume = {15},
number = {1},
pages = {e1002487},
pmid = {29315334},
issn = {1549-1676},
support = {MC_UU_00024/1/MRC_/Medical Research Council/United Kingdom ; G0900652/MRC_/Medical Research Council/United Kingdom ; G0400074/MRC_/Medical Research Council/United Kingdom ; MC_UU_00024/9/MRC_/Medical Research Council/United Kingdom ; MC_UU_00005/12/MRC_/Medical Research Council/United Kingdom ; K01 AG049152/AG/NIA NIH HHS/United States ; G1100540/MRC_/Medical Research Council/United Kingdom ; MC_U123160657/MRC_/Medical Research Council/United Kingdom ; P01 AG017586/AG/NIA NIH HHS/United States ; MC_U123160651/MRC_/Medical Research Council/United Kingdom ; U24 DA041123/DA/NIDA NIH HHS/United States ; P01 AG003991/AG/NIA NIH HHS/United States ; P50 AG005681/AG/NIA NIH HHS/United States ; P01 AG026276/AG/NIA NIH HHS/United States ; MC_U105597119/MRC_/Medical Research Council/United Kingdom ; K01 AG046374/AG/NIA NIH HHS/United States ; G0502157/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Aged ; Frontotemporal Dementia/*genetics ; Genetic Predisposition to Disease/*genetics ; *Genome-Wide Association Study ; Humans ; Middle Aged ; *Polymorphism, Single Nucleotide ; },
abstract = {BACKGROUND: Converging evidence suggests that immune-mediated dysfunction plays an important role in the pathogenesis of frontotemporal dementia (FTD). Although genetic studies have shown that immune-associated loci are associated with increased FTD risk, a systematic investigation of genetic overlap between immune-mediated diseases and the spectrum of FTD-related disorders has not been performed.

METHODS AND FINDINGS: Using large genome-wide association studies (GWASs) (total n = 192,886 cases and controls) and recently developed tools to quantify genetic overlap/pleiotropy, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with FTD-related disorders-namely, FTD, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS)-and 1 or more immune-mediated diseases including Crohn disease, ulcerative colitis (UC), rheumatoid arthritis (RA), type 1 diabetes (T1D), celiac disease (CeD), and psoriasis. We found up to 270-fold genetic enrichment between FTD and RA, up to 160-fold genetic enrichment between FTD and UC, up to 180-fold genetic enrichment between FTD and T1D, and up to 175-fold genetic enrichment between FTD and CeD. In contrast, for CBD and PSP, only 1 of the 6 immune-mediated diseases produced genetic enrichment comparable to that seen for FTD, with up to 150-fold genetic enrichment between CBD and CeD and up to 180-fold enrichment between PSP and RA. Further, we found minimal enrichment between ALS and the immune-mediated diseases tested, with the highest levels of enrichment between ALS and RA (up to 20-fold). For FTD, at a conjunction false discovery rate < 0.05 and after excluding SNPs in linkage disequilibrium, we found that 8 of the 15 identified loci mapped to the human leukocyte antigen (HLA) region on Chromosome (Chr) 6. We also found novel candidate FTD susceptibility loci within LRRK2 (leucine rich repeat kinase 2), TBKBP1 (TBK1 binding protein 1), and PGBD5 (piggyBac transposable element derived 5). Functionally, we found that the expression of FTD-immune pleiotropic genes (particularly within the HLA region) is altered in postmortem brain tissue from patients with FTD and is enriched in microglia/macrophages compared to other central nervous system cell types. The main study limitation is that the results represent only clinically diagnosed individuals. Also, given the complex interconnectedness of the HLA region, we were not able to define the specific gene or genes on Chr 6 responsible for our pleiotropic signal.

CONCLUSIONS: We show immune-mediated genetic enrichment specifically in FTD, particularly within the HLA region. Our genetic results suggest that for a subset of patients, immune dysfunction may contribute to FTD risk. These findings have potential implications for clinical trials targeting immune dysfunction in patients with FTD.},
}

Aged
Frontotemporal Dementia/*genetics
Genetic Predisposition to Disease/*genetics
*Genome-Wide Association Study
Humans
Middle Aged
*Polymorphism, Single Nucleotide

@article {pmid28017481,
year = {2017},
author = {Sproviero, W and Shatunov, A and Stahl, D and Shoai, M and van Rheenen, W and Jones, AR and Al-Sarraj, S and Andersen, PM and Bonini, NM and Conforti, FL and Van Damme, P and Daoud, H and Del Mar Amador, M and Fogh, I and Forzan, M and Gaastra, B and Gellera, C and Gitler, AD and Hardy, J and Fratta, P and La Bella, V and Le Ber, I and Van Langenhove, T and Lattante, S and Lee, YC and Malaspina, A and Meininger, V and Millecamps, S and Orrell, R and Rademakers, R and Robberecht, W and Rouleau, G and Ross, OA and Salachas, F and Sidle, K and Smith, BN and Soong, BW and Sorarù, G and Stevanin, G and Kabashi, E and Troakes, C and van Broeckhoven, C and Veldink, JH and van den Berg, LH and Shaw, CE and Powell, JF and Al-Chalabi, A},
title = {ATXN2 trinucleotide repeat length correlates with risk of ALS.},
journal = {Neurobiology of aging},
volume = {51},
number = {},
pages = {178.e1-178.e9},
pmid = {28017481},
issn = {1558-1497},
support = {MC_G1000733/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; MALASPINA/APR13/817-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; JONES/OCT15/958-799/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0300329/MRC_/Medical Research Council/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; ALCHALABI-DOBSON/APR14/829-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; AL-CHALABI/APR15/844-791/MNDA_/Motor Neurone Disease Association/United Kingdom ; MR/M008606/1/MRC_/Medical Research Council/United Kingdom ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; FRATTA/JAN15/946-795/MNDA_/Motor Neurone Disease Association/United Kingdom ; G0501573/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; R35 NS097275/NS/NINDS NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; MRF-060-0003-RG-SMITH/MRF_/MRF_/United Kingdom ; SHAW/NOV14/985-797/MNDA_/Motor Neurone Disease Association/United Kingdom ; },
mesh = {Age of Onset ; Alleles ; Amyotrophic Lateral Sclerosis/*genetics ; Ataxin-2/*genetics ; Case-Control Studies ; Female ; *Genetic Association Studies ; Humans ; Male ; Risk ; Trinucleotide Repeat Expansion/*genetics ; Trinucleotide Repeats/*genetics ; },
abstract = {We investigated a CAG trinucleotide repeat expansion in the ATXN2 gene in amyotrophic lateral sclerosis (ALS). Two new case-control studies, a British dataset of 1474 ALS cases and 567 controls, and a Dutch dataset of 1328 ALS cases and 691 controls were analyzed. In addition, to increase power, we systematically searched PubMed for case-control studies published after 1 August 2010 that investigated the association between ATXN2 intermediate repeats and ALS. We conducted a meta-analysis of the new and existing studies for the relative risks of ATXN2 intermediate repeat alleles of between 24 and 34 CAG trinucleotide repeats and ALS. There was an overall increased risk of ALS for those carrying intermediate sized trinucleotide repeat alleles (odds ratio 3.06 [95% confidence interval 2.37-3.94]; p = 6 × 10[-18]), with an exponential relationship between repeat length and ALS risk for alleles of 29-32 repeats (R[2] = 0.91, p = 0.0002). No relationship was seen for repeat length and age of onset or survival. In contrast to trinucleotide repeat diseases, intermediate ATXN2 trinucleotide repeat expansion in ALS does not predict age of onset but does predict disease risk.},
}

Age of Onset
Alleles
Amyotrophic Lateral Sclerosis/*genetics
Ataxin-2/*genetics
Case-Control Studies
Female
*Genetic Association Studies
Humans
Male
Risk
Trinucleotide Repeat Expansion/*genetics
Trinucleotide Repeats/*genetics

@article {pmid26724605,
year = {2016},
author = {Nichols, NL and Mitchell, GS},
title = {Quantitative assessment of integrated phrenic nerve activity.},
journal = {Respiratory physiology & neurobiology},
volume = {226},
number = {},
pages = {81-86},
pmid = {26724605},
issn = {1878-1519},
support = {R00 HL119606/HL/NHLBI NIH HHS/United States ; R01 HL080209/HL/NHLBI NIH HHS/United States ; UL1 TR001427/TR/NCATS NIH HHS/United States ; P01 NS057778/NS/NINDS NIH HHS/United States ; K99 HL119606/HL/NHLBI NIH HHS/United States ; R01 HL069064/HL/NHLBI NIH HHS/United States ; },
mesh = {Amyotrophic Lateral Sclerosis/physiopathology ; Animals ; Chemoreceptor Cells/physiology ; Disease Models, Animal ; Humans ; In Vitro Techniques ; Male ; Microelectrodes ; Phrenic Nerve/*physiology/physiopathology ; Rats, Sprague-Dawley ; Rats, Transgenic ; Reflex/physiology ; Reproducibility of Results ; Respiration ; Species Specificity ; Superoxide Dismutase-1/genetics/metabolism ; },
abstract = {Integrated electrical activity in the phrenic nerve is commonly used to assess within-animal changes in phrenic motor output. Because of concerns regarding the consistency of nerve recordings, activity is most often expressed as a percent change from baseline values. However, absolute values of nerve activity are necessary to assess the impact of neural injury or disease on phrenic motor output. To date, no systematic evaluations of the repeatability/reliability have been made among animals when phrenic recordings are performed by an experienced investigator using standardized methods. We performed a meta-analysis of studies reporting integrated phrenic nerve activity in many rat groups by the same experienced investigator; comparisons were made during baseline and maximal chemoreceptor stimulation in 14 wild-type Harlan and 14 Taconic Sprague Dawley groups, and in 3 pre-symptomatic and 11 end-stage SOD1(G93A) Taconic rat groups (an ALS model). Meta-analysis results indicate: (1) consistent measurements of integrated phrenic activity in each sub-strain of wild-type rats; (2) with bilateral nerve recordings, left-to-right integrated phrenic activity ratios are ∼1.0; and (3) consistently reduced activity in end-stage SOD1(G93A) rats. Thus, with appropriate precautions, integrated phrenic nerve activity enables robust, quantitative comparisons among nerves or experimental groups, including differences caused by neuromuscular disease.},
}

Amyotrophic Lateral Sclerosis/physiopathology
Animals
Chemoreceptor Cells/physiology
Disease Models, Animal
Humans
In Vitro Techniques
Male
Microelectrodes
Phrenic Nerve/*physiology/physiopathology
Rats, Sprague-Dawley
Rats, Transgenic
Reflex/physiology
Reproducibility of Results
Respiration
Species Specificity
Superoxide Dismutase-1/genetics/metabolism

@article {pmid25936935,
year = {2015},
author = {Lill, CM and Rengmark, A and Pihlstrøm, L and Fogh, I and Shatunov, A and Sleiman, PM and Wang, LS and Liu, T and Lassen, CF and Meissner, E and Alexopoulos, P and Calvo, A and Chio, A and Dizdar, N and Faltraco, F and Forsgren, L and Kirchheiner, J and Kurz, A and Larsen, JP and Liebsch, M and Linder, J and Morrison, KE and Nissbrandt, H and Otto, M and Pahnke, J and Partch, A and Restagno, G and Rujescu, D and Schnack, C and Shaw, CE and Shaw, PJ and Tumani, H and Tysnes, OB and Valladares, O and Silani, V and van den Berg, LH and van Rheenen, W and Veldink, JH and Lindenberger, U and Steinhagen-Thiessen, E and , and Teipel, S and Perneczky, R and Hakonarson, H and Hampel, H and von Arnim, CAF and Olsen, JH and Van Deerlin, VM and Al-Chalabi, A and Toft, M and Ritz, B and Bertram, L},
title = {The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {11},
number = {12},
pages = {1407-1416},
pmid = {25936935},
issn = {1552-5279},
support = {089701/WT_/Wellcome Trust/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; MR/L021803/1/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; P30 ES013508/ES/NIEHS NIH HHS/United States ; G0900688/MRC_/Medical Research Council/United Kingdom ; R01ES013717/ES/NIEHS NIH HHS/United States ; R01 ES013717/ES/NIEHS NIH HHS/United States ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; P01 AG017586/AG/NIA NIH HHS/United States ; },
mesh = {Aged ; Alleles ; Alzheimer Disease/*genetics ; Amyotrophic Lateral Sclerosis/genetics ; Case-Control Studies ; Female ; Frontotemporal Lobar Degeneration/genetics ; *Genetic Predisposition to Disease ; Genotype ; Humans ; Male ; Membrane Glycoproteins/*genetics ; Middle Aged ; Neurodegenerative Diseases/*genetics ; Parkinson Disease/genetics ; Quantitative Trait Loci ; Receptors, Immunologic/*genetics ; Risk Factors ; White People ; tau Proteins/cerebrospinal fluid ; },
abstract = {A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.},
}

Aged
Alleles
Alzheimer Disease/*genetics
Amyotrophic Lateral Sclerosis/genetics
Case-Control Studies
Female
Frontotemporal Lobar Degeneration/genetics
*Genetic Predisposition to Disease
Genotype
Humans
Male
Membrane Glycoproteins/*genetics
Middle Aged
Neurodegenerative Diseases/*genetics
Parkinson Disease/genetics
Quantitative Trait Loci
Receptors, Immunologic/*genetics
Risk Factors
White People
tau Proteins/cerebrospinal fluid

@article {pmid25285812,
year = {2014},
author = {Neuenschwander, AG and Thai, KK and Figueroa, KP and Pulst, SM},
title = {Amyotrophic lateral sclerosis risk for spinocerebellar ataxia type 2 ATXN2 CAG repeat alleles: a meta-analysis.},
journal = {JAMA neurology},
volume = {71},
number = {12},
pages = {1529-1534},
pmid = {25285812},
issn = {2168-6157},
support = {R21NS081182/NS/NINDS NIH HHS/United States ; R01NS33123/NS/NINDS NIH HHS/United States ; R21NS079852/NS/NINDS NIH HHS/United States ; R37 NS033123/NS/NINDS NIH HHS/United States ; R01 NS033123/NS/NINDS NIH HHS/United States ; M01 RR000425/RR/NCRR NIH HHS/United States ; R21 NS079852/NS/NINDS NIH HHS/United States ; RC4 NS073009/NS/NINDS NIH HHS/United States ; RC4NS073009/NS/NINDS NIH HHS/United States ; R21 NS081182/NS/NINDS NIH HHS/United States ; R56 NS033123/NS/NINDS NIH HHS/United States ; },
mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Ataxins ; Humans ; Nerve Tissue Proteins/*genetics ; Trinucleotide Repeat Expansion/*genetics ; },
abstract = {IMPORTANCE: Repeats of CAG in the ataxin 2 gene (ATXN2) in the long-normal range (sometimes referred to as intermediate) have been identified as modifiers of amyotrophic lateral sclerosis (ALS) risk. Prior studies have used thresholding considering various cutoffs for ATXN2 repeat length.

OBJECTIVE: To calculate association between ATXN2 CAG repeat alleles and increased risk of ALS across multiple ethnic groups.

DATA SOURCES: The MEDLINE database was searched for studies published by December 29, 2013, reporting ATXN2 CAG repeat length in patients with ALS and controls.

STUDY SELECTION: Studies were included if they reported original data on relative risks or odds ratios (ORs) from ALS and control populations for individual ATXN2 alleles. Review articles that reported no new data were not included in the analysis.

DATA EXTRACTION AND SYNTHESIS: Analysis of allele distribution was performed to ensure that all studies followed identical allele sizing. The ORs, 95% confidence intervals, and population attributable risk percentages were calculated according to standard procedures.

MAIN OUTCOMES AND MEASURES: Occurrence of ALS associated with ATXN2 repeat alleles, expressed as ORs.

RESULTS: Nine studies were analyzed, including 7505 controls and 6151 sporadic ALS cases. The ALS and control cohorts were recruited from different geographical and ethnic regions including the United States, French Canada/Canada, Belgium and the Netherlands, Germany, Italy, mainland China, Turkey, and Flanders-Belgium. The ATXN2 CAG repeat lengths ranged from 13 to 39 in patients with ALS and from 13 to 34 in controls. The ORs were less than 1.00 for alleles with 25 to 28 repeats. The OR was 1.55 for 30 repeats, but this elevation was not statistically significant (95% CI, 0.88-2.73). The ORs were 2.70 (95% CI, 1.47-4.93) for 31 CAG repeats, 11.09 (95% CI, 4.16-29.57) for 32 repeats, and 5.76 (95% CI, 1.79-18.57) for 33 repeats.

CONCLUSIONS AND RELEVANCE: In contrast to prior studies with smaller numbers, risk for ALS associated with long-normal alleles is complex. Alleles with 27 and 28 repeats lower ALS risk slightly. The risk for ALS increases beginning with 29 repeats and reaches a maximum at 32 and 33 repeats. Of note, alleles with repeats of these lengths are known to be predisposed to meiotic expansion to full-penetrance mutant alleles. In patients with ALS, alleles with 31 to 33 repeats may have undergone preferential expansion in motor neurons during mitosis or DNA repair. Our meta-analysis provides a framework for counseling individuals with long-normal ATXN2 repeats.},
}

Amyotrophic Lateral Sclerosis/*genetics
Ataxins
Humans
Nerve Tissue Proteins/*genetics
Trinucleotide Repeat Expansion/*genetics

@article {pmid25233373,
year = {2014},
author = {Simpson, CL and Wojciechowski, R and Oexle, K and Murgia, F and Portas, L and Li, X and Verhoeven, VJ and Vitart, V and Schache, M and Hosseini, SM and Hysi, PG and Raffel, LJ and Cotch, MF and Chew, E and Klein, BE and Klein, R and Wong, TY and van Duijn, CM and Mitchell, P and Saw, SM and Fossarello, M and Wang, JJ and , and Polašek, O and Campbell, H and Rudan, I and Oostra, BA and Uitterlinden, AG and Hofman, A and Rivadeneira, F and Amin, N and Karssen, LC and Vingerling, JR and Döring, A and Bettecken, T and Bencic, G and Gieger, C and Wichmann, HE and Wilson, JF and Venturini, C and Fleck, B and Cumberland, PM and Rahi, JS and Hammond, CJ and Hayward, C and Wright, AF and Paterson, AD and Baird, PN and Klaver, CC and Rotter, JI and Pirastu, M and Meitinger, T and Bailey-Wilson, JE and Stambolian, D},
title = {Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci.},
journal = {PloS one},
volume = {9},
number = {9},
pages = {e107110},
pmid = {25233373},
issn = {1932-6203},
support = {N01 HC095168/HL/NHLBI NIH HHS/United States ; ZIA EY000403/ImNIH/Intramural NIH HHS/United States ; R01 DK077510/DK/NIDDK NIH HHS/United States ; N01-DK-6-2204/DK/NIDDK NIH HHS/United States ; HHSN268200782096C/HG/NHGRI NIH HHS/United States ; N01 HC-95159/HC/NHLBI NIH HHS/United States ; ZIAEY000403//PHS HHS/United States ; N01 HC095166/HL/NHLBI NIH HHS/United States ; MC_U127584475/MRC_/Medical Research Council/United Kingdom ; R01 EY016379/EY/NEI NIH HHS/United States ; N02-HL-6-4278/HL/NHLBI NIH HHS/United States ; UL1 RR033176/RR/NCRR NIH HHS/United States ; CZB/4/710/CSO_/Chief Scientist Office/United Kingdom ; CZB/4/438/CSO_/Chief Scientist Office/United Kingdom ; U01 DK094176/DK/NIDDK NIH HHS/United States ; N01-HC-95162/HC/NHLBI NIH HHS/United States ; UL1RR033176/RR/NCRR NIH HHS/United States ; UL1TR000124/TR/NCATS NIH HHS/United States ; N01 HC095161/HL/NHLBI NIH HHS/United States ; N01 HC095169/HL/NHLBI NIH HHS/United States ; Z99 EY999999/ImNIH/Intramural NIH HHS/United States ; RR-024156/RR/NCRR NIH HHS/United States ; N01-HC-95163/HC/NHLBI NIH HHS/United States ; N01-HC-95168/HC/NHLBI NIH HHS/United States ; Z01 EY000403/ImNIH/Intramural NIH HHS/United States ; UL1 RR024156/RR/NCRR NIH HHS/United States ; N01 HC095167/HL/NHLBI NIH HHS/United States ; R01-DK-077510/DK/NIDDK NIH HHS/United States ; 085475/B/08/Z/WT_/Wellcome Trust/United Kingdom ; K08 EY022943/EY/NEI NIH HHS/United States ; N01-HC-95165/HC/NHLBI NIH HHS/United States ; UL1 TR000114/TR/NCATS NIH HHS/United States ; UL1 TR000124/TR/NCATS NIH HHS/United States ; N01-HC-95169/HC/NHLBI NIH HHS/United States ; R01 EY020483/EY/NEI NIH HHS/United States ; R01EY020483/EY/NEI NIH HHS/United States ; N01-HC-95164/HC/NHLBI NIH HHS/United States ; N01-HC-95160/HC/NHLBI NIH HHS/United States ; MC_PC_U127561128/MRC_/Medical Research Council/United Kingdom ; N01 HC095163/HL/NHLBI NIH HHS/United States ; UL1 TR000142/TR/NCATS NIH HHS/United States ; N01-HC-95161/HC/NHLBI NIH HHS/United States ; /WT_/Wellcome Trust/United Kingdom ; N01 HC095162/HL/NHLBI NIH HHS/United States ; N01-HC-95166/HC/NHLBI NIH HHS/United States ; 085475/08/Z/WT_/Wellcome Trust/United Kingdom ; SRF/01/010/DH_/Department of Health/United Kingdom ; N01 HC095165/HL/NHLBI NIH HHS/United States ; N01 HC095164/HL/NHLBI NIH HHS/United States ; N01 HC095159/HC/NHLBI NIH HHS/United States ; N01-HC-95167/HC/NHLBI NIH HHS/United States ; R01EY016379/EY/NEI NIH HHS/United States ; N01 HC095160/HL/NHLBI NIH HHS/United States ; },
mesh = {Adult ; Age of Onset ; Aged ; Aged, 80 and over ; Alleles ; Eye/*physiopathology ; Female ; Genetic Association Studies ; Genetic Markers/genetics ; Genetic Predisposition to Disease ; Humans ; Hyperopia/*genetics ; Linkage Disequilibrium ; Male ; Middle Aged ; Myopia/*genetics ; Phenotype ; Polymorphism, Single Nucleotide ; White People/genetics ; },
abstract = {Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.},
}

Adult
Age of Onset
Aged
Aged, 80 and over
Alleles
Eye/*physiopathology
Female
Genetic Association Studies
Genetic Markers/genetics
Genetic Predisposition to Disease
Humans
Hyperopia/*genetics
Linkage Disequilibrium
Male
Middle Aged
Myopia/*genetics
Phenotype
Polymorphism, Single Nucleotide
White People/genetics

@article {pmid25187168,
year = {2014},
author = {Li, MD and Burns, TC and Morgan, AA and Khatri, P},
title = {Integrated multi-cohort transcriptional meta-analysis of neurodegenerative diseases.},
journal = {Acta neuropathologica communications},
volume = {2},
number = {},
pages = {93},
pmid = {25187168},
issn = {2051-5960},
support = {U19 AI057229/AI/NIAID NIH HHS/United States ; U19 AI109662/AI/NIAID NIH HHS/United States ; 1U19AI109662/AI/NIAID NIH HHS/United States ; },
mesh = {Central Nervous System/*metabolism ; Cohort Studies ; Female ; Gene Expression Profiling ; *Gene Expression Regulation ; Humans ; Male ; Neurodegenerative Diseases/*pathology ; Oligonucleotide Array Sequence Analysis ; Transcription Factors/genetics/*metabolism ; },
abstract = {INTRODUCTION: Neurodegenerative diseases share common pathologic features including neuroinflammation, mitochondrial dysfunction and protein aggregation, suggesting common underlying mechanisms of neurodegeneration. We undertook a meta-analysis of public gene expression data for neurodegenerative diseases to identify a common transcriptional signature of neurodegeneration.

RESULTS: Using 1,270 post-mortem central nervous system tissue samples from 13 patient cohorts covering four neurodegenerative diseases, we identified 243 differentially expressed genes, which were similarly dysregulated in 15 additional patient cohorts of 205 samples including seven neurodegenerative diseases. This gene signature correlated with histologic disease severity. Metallothioneins featured prominently among differentially expressed genes, and functional pathway analysis identified specific convergent themes of dysregulation. MetaCore network analyses revealed various novel candidate hub genes (e.g. STAU2). Genes associated with M1-polarized macrophages and reactive astrocytes were strongly enriched in the meta-analysis data. Evaluation of genes enriched in neurons revealed 70 down-regulated genes, over half not previously associated with neurodegeneration. Comparison with aging brain data (3 patient cohorts, 221 samples) revealed 53 of these to be unique to neurodegenerative disease, many of which are strong candidates to be important in neuropathogenesis (e.g. NDN, NAP1L2). ENCODE ChIP-seq analysis predicted common upstream transcriptional regulators not associated with normal aging (REST, RBBP5, SIN3A, SP2, YY1, ZNF143, IKZF1). Finally, we removed genes common to neurodegeneration from disease-specific gene signatures, revealing uniquely robust immune response and JAK-STAT signaling in amyotrophic lateral sclerosis.

CONCLUSIONS: Our results implicate pervasive bioenergetic deficits, M1-type microglial activation and gliosis as unifying themes of neurodegeneration, and identify numerous novel genes associated with neurodegenerative processes.},
}

Central Nervous System/*metabolism
Cohort Studies
Female
Gene Expression Profiling
*Gene Expression Regulation
Humans
Male
Neurodegenerative Diseases/*pathology
Oligonucleotide Array Sequence Analysis
Transcription Factors/genetics/*metabolism

@article {pmid25023276,
year = {2014},
author = {Fitzgerald, KC and O'Reilly, ÉJ and Falcone, GJ and McCullough, ML and Park, Y and Kolonel, LN and Ascherio, A},
title = {Dietary ω-3 polyunsaturated fatty acid intake and risk for amyotrophic lateral sclerosis.},
journal = {JAMA neurology},
volume = {71},
number = {9},
pages = {1102-1110},
pmid = {25023276},
issn = {2168-6157},
support = {P01 CA055075/CA/NCI NIH HHS/United States ; P01 CA087969/CA/NCI NIH HHS/United States ; R01 NS045893/NS/NINDS NIH HHS/United States ; P01 CA87969/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*prevention & control ; Dietary Supplements/*statistics & numerical data ; Energy Intake ; Fatty Acids, Omega-3/*pharmacology ; Female ; Humans ; Longitudinal Studies ; Male ; Middle Aged ; Proportional Hazards Models ; Risk ; },
abstract = {IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a severe progressive disease that cannot be prevented or cured. Diet-derived long-chain polyunsaturated fatty acids (PUFAs) are incorporated in brain lipids and modulate oxidative and inflammatory processes and could thus affect ALS risk and progression.

OBJECTIVE: To examine the association between ω-6 and ω-3 PUFA consumption and ALS risk.

Longitudinal analyses based on 1,002,082 participants (479,114 women and 522,968 men) in 5 prospective cohorts: the National Institutes of Health-AARP Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Health Professionals Follow-up Study, the Multiethnic Cohort Study, and the Nurses' Health Study. Diet was assessed via food frequency questionnaire developed or modified for each cohort. Participants were categorized into cohort-specific quintiles of intake of energy-adjusted dietary variables.

MAIN OUTCOMES AND MEASURES: Cohort-specific multivariable-adjusted risk ratios (RRs) of ALS incidence or death estimated by Cox proportional hazards regression and pooled using random-effects methods.

RESULTS: A total of 995 ALS cases were documented during the follow-up. A greater ω-3 PUFA intake was associated with a reduced risk for ALS. The pooled, multivariable-adjusted RR for the highest to the lowest quintile was 0.66 (95% CI, 0.53-0.81; P < .001 for trend). Consumption of both α-linolenic acid (RR, 0.73; 95% CI, 0.59-0.89; P = .003 for trend) and marine ω-3 PUFAs (RR, 0.84; 95% CI, 0.65-1.08; P = .03 for trend) contributed to this inverse association. Intakes of ω-6 PUFA were not associated with ALS risk.

CONCLUSIONS AND RELEVANCE: Consumption of foods high in ω-3 PUFAs may help prevent or delay the onset of ALS.},
}

Adult
Aged
Amyotrophic Lateral Sclerosis/*prevention & control
Dietary Supplements/*statistics & numerical data
Energy Intake
Fatty Acids, Omega-3/*pharmacology
Female
Humans
Longitudinal Studies
Male
Middle Aged
Proportional Hazards Models
Risk

@article {pmid25023141,
year = {2014},
author = {Keller, MF and Ferrucci, L and Singleton, AB and Tienari, PJ and Laaksovirta, H and Restagno, G and Chiò, A and Traynor, BJ and Nalls, MA},
title = {Genome-wide analysis of the heritability of amyotrophic lateral sclerosis.},
journal = {JAMA neurology},
volume = {71},
number = {9},
pages = {1123-1134},
pmid = {25023141},
issn = {2168-6157},
support = {Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; R01 ES013244/ES/NIEHS NIH HHS/United States ; /MRC_/Medical Research Council/United Kingdom ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; ES013244/ES/NIEHS NIH HHS/United States ; Z01AG000949-02/AG/NIA NIH HHS/United States ; },
mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Case-Control Studies ; Cohort Studies ; Female ; Genetic Predisposition to Disease/genetics ; *Genome-Wide Association Study ; Genotype ; Humans ; Male ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; },
abstract = {IMPORTANCE: Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.

OBJECTIVE: To estimate the relative importance of genetic factors in a complex disease such as ALS by accurately quantifying heritability using genome-wide data derived from genome-wide association studies.

We applied the genome-wide complex trait analysis algorithm to 3 genome-wide association study data sets that were generated from ALS case-control cohorts of European ancestry to estimate the heritability of ALS. Cumulatively, these data sets contained genotype data from 1223 cases and 1591 controls that had been previously generated and are publically available on the National Center for Biotechnology Information database of genotypes and phenotypes website (http://www.ncbi.nlm.nih.gov/gap). The cohorts genotyped as part of these genome-wide association study efforts include the InCHIANTI (aging in the Chianti area) Study, the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis, the National Institute of Neurological Disorders and Stroke Repository, and an ALS specialty clinic in Helsinki, Finland.

MAIN OUTCOMES AND MEASURES: A linear mixed model was used to account for all known single-nucleotide polymorphisms simultaneously and to quantify the phenotypic variance present in ostensibly outbred individuals. Variance measures were used to estimate heritability.

RESULTS: With our meta-analysis, which is based on genome-wide genotyping data, we estimated the overall heritability of ALS to be approximately 21.0% (95% CI, 17.1-24.9) (SE = 2.0%), indicating that additional genetic variation influencing risk of ALS loci remains to be identified. Furthermore, we identified 17 regions of the genome that display significantly high heritability estimates. Eleven of these regions represent novel candidate regions for ALS risk.

CONCLUSIONS AND RELEVANCE: We found the heritability of ALS to be significantly higher than previously reported. We also identified multiple, novel genomic regions that we hypothesize may contain causative risk variants that influence susceptibility to ALS.},
}

Amyotrophic Lateral Sclerosis/*genetics
Case-Control Studies
Cohort Studies
Female
Genetic Predisposition to Disease/genetics
*Genome-Wide Association Study
Genotype
Humans
Male
Phenotype
Polymorphism, Single Nucleotide/genetics

@article {pmid24931836,
year = {2014},
author = {Diekstra, FP and Van Deerlin, VM and van Swieten, JC and Al-Chalabi, A and Ludolph, AC and Weishaupt, JH and Hardiman, O and Landers, JE and Brown, RH and van Es, MA and Pasterkamp, RJ and Koppers, M and Andersen, PM and Estrada, K and Rivadeneira, F and Hofman, A and Uitterlinden, AG and van Damme, P and Melki, J and Meininger, V and Shatunov, A and Shaw, CE and Leigh, PN and Shaw, PJ and Morrison, KE and Fogh, I and Chiò, A and Traynor, BJ and Czell, D and Weber, M and Heutink, P and de Bakker, PI and Silani, V and Robberecht, W and van den Berg, LH and Veldink, JH},
title = {C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis.},
journal = {Annals of neurology},
volume = {76},
number = {1},
pages = {120-133},
pmid = {24931836},
issn = {1531-8249},
support = {089701/WT_/Wellcome Trust/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; R01 NS050557/NS/NINDS NIH HHS/United States ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; P01 AG017586/AG/NIA NIH HHS/United States ; R01 NS073873/NS/NINDS NIH HHS/United States ; G1100695/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Amyotrophic Lateral Sclerosis/*genetics ; C9orf72 Protein ; Chromosomes, Human, Pair 19/genetics ; Chromosomes, Human, Pair 9/genetics ; DNA Repeat Expansion/genetics ; Frontotemporal Dementia/*genetics ; Genome-Wide Association Study/*methods/trends ; Humans ; Mutation ; Nerve Tissue Proteins/*genetics ; Polymorphism, Single Nucleotide/genetics ; Proteins/*genetics ; },
abstract = {OBJECTIVE: Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD.

METHODS: We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes.

RESULTS: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 × 10(-12)) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 × 10(-11)) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 × 10(-7)) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 × 10(-7)).

INTERPRETATION: We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.},
}

Amyotrophic Lateral Sclerosis/*genetics
C9orf72 Protein
Chromosomes, Human, Pair 19/genetics
Chromosomes, Human, Pair 9/genetics
DNA Repeat Expansion/genetics
Frontotemporal Dementia/*genetics
Genome-Wide Association Study/*methods/trends
Humans
Mutation
Nerve Tissue Proteins/*genetics
Polymorphism, Single Nucleotide/genetics
Proteins/*genetics

@article {pmid24256812,
year = {2014},
author = {Fogh, I and Ratti, A and Gellera, C and Lin, K and Tiloca, C and Moskvina, V and Corrado, L and Sorarù, G and Cereda, C and Corti, S and Gentilini, D and Calini, D and Castellotti, B and Mazzini, L and Querin, G and Gagliardi, S and Del Bo, R and Conforti, FL and Siciliano, G and Inghilleri, M and Saccà, F and Bongioanni, P and Penco, S and Corbo, M and Sorbi, S and Filosto, M and Ferlini, A and Di Blasio, AM and Signorini, S and Shatunov, A and Jones, A and Shaw, PJ and Morrison, KE and Farmer, AE and Van Damme, P and Robberecht, W and Chiò, A and Traynor, BJ and Sendtner, M and Melki, J and Meininger, V and Hardiman, O and Andersen, PM and Leigh, NP and Glass, JD and Overste, D and Diekstra, FP and Veldink, JH and van Es, MA and Shaw, CE and Weale, ME and Lewis, CM and Williams, J and Brown, RH and Landers, JE and Ticozzi, N and Ceroni, M and Pegoraro, E and Comi, GP and D'Alfonso, S and van den Berg, LH and Taroni, F and Al-Chalabi, A and Powell, J and Silani, V and , },
title = {A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis.},
journal = {Human molecular genetics},
volume = {23},
number = {8},
pages = {2220-2231},
pmid = {24256812},
issn = {1460-2083},
support = {MR/K013041/1/MRC_/Medical Research Council/United Kingdom ; 089701/WT_/Wellcome Trust/United Kingdom ; G0900635/MRC_/Medical Research Council/United Kingdom ; MR/L501529/1/MRC_/Medical Research Council/United Kingdom ; RC2 NS070342/NS/NINDS NIH HHS/United States ; MR/J006742/1/MRC_/Medical Research Council/United Kingdom ; G0902227/MRC_/Medical Research Council/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; R01 NS050557/NS/NINDS NIH HHS/United States ; MR/L010305/1/MRC_/Medical Research Council/United Kingdom ; 1R01NS073873/NS/NINDS NIH HHS/United States ; G0701420/MRC_/Medical Research Council/United Kingdom ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; MR/K01417X/1/MRC_/Medical Research Council/United Kingdom ; R01 NS073873/NS/NINDS NIH HHS/United States ; MR/L501517/1/MRC_/Medical Research Council/United Kingdom ; G1100695/MRC_/Medical Research Council/United Kingdom ; G0501573/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; 070122/A/02/Z/WT_/Wellcome Trust/United Kingdom ; RC2-NS070-342/NS/NINDS NIH HHS/United States ; GTB12001/TI_/Telethon/Italy ; },
mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Case-Control Studies ; Chromosomes, Human, Pair 17/*genetics ; *Genome-Wide Association Study ; Humans ; Prognosis ; },
abstract = {Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (∼90%) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P = 1.11 × 10(-8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P = 8.62 × 10(-9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P = 7.69 × 10(-9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as ∼12% using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.},
}

Amyotrophic Lateral Sclerosis/*genetics
Case-Control Studies
Chromosomes, Human, Pair 17/*genetics
*Genome-Wide Association Study
Humans
Prognosis

@article {pmid24234648,
year = {2014},
author = {Goris, A and van Setten, J and Diekstra, F and Ripke, S and Patsopoulos, NA and Sawcer, SJ and , and van Es, M and , and Andersen, PM and Melki, J and Meininger, V and Hardiman, O and Landers, JE and Brown, RH and Shatunov, A and Leigh, N and Al-Chalabi, A and Shaw, CE and Traynor, BJ and Chiò, A and Restagno, G and Mora, G and Ophoff, RA and Oksenberg, JR and Van Damme, P and Compston, A and Robberecht, W and Dubois, B and van den Berg, LH and De Jager, PL and Veldink, JH and de Bakker, PI},
title = {No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis.},
journal = {Human molecular genetics},
volume = {23},
number = {7},
pages = {1916-1922},
pmid = {24234648},
issn = {1460-2083},
support = {G0900635/MRC_/Medical Research Council/United Kingdom ; Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; MC_G1000733/MRC_/Medical Research Council/United Kingdom ; R01 NS049477/NS/NINDS NIH HHS/United States ; G0600974/MRC_/Medical Research Council/United Kingdom ; R01 NS050557/NS/NINDS NIH HHS/United States ; 089701/WT_/Wellcome Trust/United Kingdom ; NS050557/NS/NINDS NIH HHS/United States ; R01 NS073873/NS/NINDS NIH HHS/United States ; G1100695/MRC_/Medical Research Council/United Kingdom ; G0501573/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; G0900688/MRC_/Medical Research Council/United Kingdom ; Z01-AG000949-02/AG/NIA NIH HHS/United States ; },
mesh = {Amyotrophic Lateral Sclerosis/*epidemiology/*genetics ; Comorbidity ; Genetic Predisposition to Disease ; Humans ; Multiple Sclerosis/*epidemiology/*genetics ; Polymorphism, Single Nucleotide ; },
abstract = {Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS.},
}

Amyotrophic Lateral Sclerosis/*epidemiology/*genetics
Comorbidity
Genetic Predisposition to Disease
Humans
Multiple Sclerosis/*epidemiology/*genetics
Polymorphism, Single Nucleotide

@article {pmid24092916,
year = {2015},
author = {Scammacca, NK and Roberts, G and Vaughn, S and Stuebing, KK},
title = {A Meta-Analysis of Interventions for Struggling Readers in Grades 4-12: 1980-2011.},
journal = {Journal of learning disabilities},
volume = {48},
number = {4},
pages = {369-390},
pmid = {24092916},
issn = {1538-4780},
support = {P50 HD052117/HD/NICHD NIH HHS/United States ; },
mesh = {Adolescent ; Child ; Dyslexia/*rehabilitation ; Education, Special/*statistics & numerical data ; Humans ; Outcome Assessment, Health Care/*statistics & numerical data ; },
abstract = {This meta-analysis synthesizes the literature on interventions for struggling readers in Grades 4 through 12 published between 1980 and 2011. It updates Scammacca et al.'s analysis of studies published between 1980 and 2004. The combined corpus of 82 study-wise effect sizes was meta-analyzed to determine (a) the overall effectiveness of reading interventions studied over the past 30 years, (b) how the magnitude of the effect varies based on student, intervention, and research design characteristics, and (c) what differences in effectiveness exist between more recent interventions and older ones. The analysis yielded a mean effect of 0.49, considerably smaller than the 0.95 mean effect reported in 2007. The mean effect for standardized measures was 0.21, also much smaller than the 0.42 mean effect reported in 2007. The mean effects for reading comprehension measures were similarly diminished. Results indicated that the mean effects for the 1980-2004 and 2005-2011 groups of studies were different to a statistically significant degree. The decline in effect sizes over time is attributed at least in part to increased use of standardized measures, more rigorous and complex research designs, differences in participant characteristics, and improvements in the school's "business-as-usual" instruction that often serves as the comparison condition in intervention studies.},
}

Adolescent
Child
Dyslexia/*rehabilitation
Education, Special/*statistics & numerical data
Humans
Outcome Assessment, Health Care/*statistics & numerical data

@article {pmid23362045,
year = {2013},
author = {Fitzgerald, KC and O'Reilly, ÉJ and Fondell, E and Falcone, GJ and McCullough, ML and Park, Y and Kolonel, LN and Ascherio, A},
title = {Intakes of vitamin C and carotenoids and risk of amyotrophic lateral sclerosis: pooled results from 5 cohort studies.},
journal = {Annals of neurology},
volume = {73},
number = {2},
pages = {236-245},
pmid = {23362045},
issn = {1531-8249},
support = {P01 CA087969/CA/NCI NIH HHS/United States ; P01 CA055075/CA/NCI NIH HHS/United States ; R37 CA54281/CA/NCI NIH HHS/United States ; P01 CA87969/CA/NCI NIH HHS/United States ; R01 NS045893/NS/NINDS NIH HHS/United States ; R37 CA054281/CA/NCI NIH HHS/United States ; },
mesh = {Adult ; Aged ; Amyotrophic Lateral Sclerosis/*epidemiology/*metabolism ; Antioxidants/*administration & dosage ; Ascorbic Acid/*administration & dosage ; Carotenoids/*administration & dosage ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Oxidative Stress/drug effects ; Proportional Hazards Models ; Prospective Studies ; Risk Factors ; },
abstract = {OBJECTIVE: Prior research has suggested the possible role of oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS). Prospective data examining dietary antioxidants such carotenoids and vitamin C are limited.

METHODS: Risk of ALS associated with carotenoid and vitamin C intake was investigated in 5 prospective cohorts: the National Institutes of Health-Association of American Retired Persons Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, the Health Professionals Follow-up Study (HPFS), and the Nurses Health Study (NHS). ALS deaths were documented using the National Death Index, and confirmed nonfatal ALS cases were included from HPFS and NHS. A total of 1,153 ALS deaths occurred among 1,100,910 participants (562,942 men; 537,968 women). Participants were categorized into cohort-specific quintiles of intake for dietary variables. We applied Cox proportional hazards regression to calculate cohort-specific risk ratios (RRs), and pooled results using random-effects methods.

RESULTS: A greater total major carotenoids intake was associated with a reduced risk of ALS (pooled, multivariate-adjusted RR for the highest to the lowest quintile = 0.75, 95% confidence interval [CI] = 0.61-0.91, p for trend = 0.004). Individually, higher dietary intakes of β-carotene and lutein were inversely associated with ALS risk. The pooled multivariate RRs comparing the highest to the lowest quintile for β-carotene and lutein were 0.85 (95% CI = 0.64-1.13, p for trend = 0.03) and 0.79 (95% CI = 0.64-0.96, p for trend = 0.01), respectively. Lycopene, β-cryptoxanthin, and vitamin C were not associated with reduced risk of ALS.

INTERPRETATION: Consumption of foods high in carotenoids may help prevent or delay onset of ALS.},
}

Adult
Aged
Amyotrophic Lateral Sclerosis/*epidemiology/*metabolism
Antioxidants/*administration & dosage
Ascorbic Acid/*administration & dosage
Carotenoids/*administration & dosage
Female
Follow-Up Studies
Humans
Male
Middle Aged
Oxidative Stress/drug effects
Proportional Hazards Models
Prospective Studies
Risk Factors

@article {pmid23253611,
year = {2012},
author = {Teng, YD and Benn, SC and Kalkanis, SN and Shefner, JM and Onario, RC and Cheng, B and Lachyankar, MB and Marconi, M and Li, J and Yu, D and Han, I and Maragakis, NJ and Lládo, J and Erkmen, K and Redmond, DE and Sidman, RL and Przedborski, S and Rothstein, JD and Brown, RH and Snyder, EY},
title = {Multimodal actions of neural stem cells in a mouse model of ALS: a meta-analysis.},
journal = {Science translational medicine},
volume = {4},
number = {165},
pages = {165ra164},
doi = {10.1126/scitranslmed.3004579},
pmid = {23253611},
issn = {1946-6242},
support = {1RC1NS068391-01/NS/NINDS NIH HHS/United States ; 1RC2NS070342-01/NS/NINDS NIH HHS/United States ; R01-NS34247/NS/NINDS NIH HHS/United States ; R01NS050557-05/NS/NINDS NIH HHS/United States ; R21NS053935/NS/NINDS NIH HHS/United States ; U01NS05225-03/NS/NINDS NIH HHS/United States ; },
mesh = {Amyotrophic Lateral Sclerosis/*pathology ; Animals ; Cell Differentiation ; Disease Models, Animal ; Mice ; Mice, Transgenic ; Neural Stem Cells/*cytology ; Superoxide Dismutase/genetics ; Superoxide Dismutase-1 ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by the unremitting degeneration of motor neurons. Multiple processes involving motor neurons and other cell types have been implicated in its pathogenesis. Neural stem cells (NSCs) perform multiple actions within the nervous system to fulfill their functions of organogenesis and homeostasis. We test the hypothesis that transplanted, undifferentiated multipotent migratory NSCs may help to ameliorate an array of pathological mechanisms in the SOD1(G93A) transgenic mouse model of ALS. On the basis of a meta-analysis of 11 independent studies performed by a consortium of ALS investigators, we propose that transplanted NSCs (both mouse and human) can slow both the onset and the progression of clinical signs and prolong survival in ALS mice, particularly if regions sustaining vital functions such as respiration are rendered chimeric. The beneficial effects of transplanted NSCs seem to be mediated by a number of actions including their ability to produce trophic factors, preserve neuromuscular function, and reduce astrogliosis and inflammation. We conclude that the widespread, pleiotropic, modulatory actions exerted by transplanted NSCs may represent an accessible therapeutic application of stem cells for treating ALS and other untreatable degenerative diseases.},
}

Amyotrophic Lateral Sclerosis/*pathology
Animals
Cell Differentiation
Disease Models, Animal
Mice
Mice, Transgenic
Neural Stem Cells/*cytology
Superoxide Dismutase/genetics
Superoxide Dismutase-1

@article {pmid22749050,
year = {2012},
author = {Foerster, BR and Dwamena, BA and Petrou, M and Carlos, RC and Callaghan, BC and Pomper, MG},
title = {Diagnostic accuracy using diffusion tensor imaging in the diagnosis of ALS: a meta-analysis.},
journal = {Academic radiology},
volume = {19},
number = {9},
pages = {1075-1086},
pmid = {22749050},
issn = {1878-4046},
support = {P30 CA006973/CA/NCI NIH HHS/United States ; },
mesh = {Amyotrophic Lateral Sclerosis/*diagnosis/pathology ; Anisotropy ; Diffusion Tensor Imaging/*methods ; Humans ; Monte Carlo Method ; ROC Curve ; Sensitivity and Specificity ; },
abstract = {RATIONALE AND OBJECTIVES: A number of studies have reported decreases in fractional anistropy (FA) in amyotrophic lateral sclerosis using diffusion tensor imaging (DTI). The purpose of this study was to perform a meta-analysis in order to estimate the diagnostic test accuracy measures of DTI for the diagnosis of amyotrophic lateral sclerosis (ALS).

MATERIALS AND METHODS: We searched MEDLINE (1966-April 2011), EMBASE (1999-April 2011), CINAHL (1999-April 2011), and Cochrane (2005-April 2011) databases to identify studies that measured FA in ALS subjects. Human, single-center studies using a DTI region of interest (ROI) or tractography techniques were used to compare FA values along the brain corticospinal tracts between ALS subjects and healthy controls. There were no language restrictions. Independent extraction of articles by 2 authors using predefined data fields including study quality indicators. We identified 30 case-control studies that used region of interest or tractography DTI techniques. We applied binormal receiver operative characteristic (ROC) curve analysis to assign specificity and sensitivity for each study. We applied the bivariate mixed-effects regression model using the Markov Chain Monte Carlo Simulation to calculate summary estimates for the sensitivity and specificity. We used the metan module in Stata, version 11.0, to calculate the area under the ROC curve, diagnostic odds ratio and the test effectiveness summary estimates.

RESULTS: The pooled sensitivity was 0.65 (95% CI 0.61-0.69); the pooled specificity, 0.67 (95% CI 0.63-0.72); the pooled diagnostic odds ratio, 1.88 (95% CI 1.46-2.30); the pooled test effectiveness, 1.04 (95% CI 0.81-1.27); and the pooled area under the ROC curve, 0.76 (95% CI 0.71-0.81). Subanalyses comparing magnetic resonance imaging (MRI) field strength (1.5T vs. 3.0T) and brain location (corticospinal tract average vs. internal capsule) revealed no significant differences in the test accuracy measures. Reference standard used for the diagnosis of ALS was the El Escorial criteria. There was at least moderate heterogeneity between the studies. True study quality is uncertain.

CONCLUSION: The discriminatory capability of DTI to make a diagnosis of ALS is only modest. There were no significant differences in the diagnostic test accuracy summary estimates with respect to MRI field strength or brain location.},
}

Amyotrophic Lateral Sclerosis/*diagnosis/pathology
Anisotropy
Diffusion Tensor Imaging/*methods
Humans
Monte Carlo Method
ROC Curve
Sensitivity and Specificity

@article {pmid22082213,
year = {2012},
author = {Slattery, TJ and Staub, A and Rayner, K},
title = {Saccade launch site as a predictor of fixation durations in reading: comments on Hand, Miellet, O'Donnell, and Sereno (2010).},
journal = {Journal of experimental psychology. Human perception and performance},
volume = {38},
number = {1},
pages = {251-261},
doi = {10.1037/a0025980},
pmid = {22082213},
issn = {1939-1277},
support = {HD 26765/HD/NICHD NIH HHS/United States ; },
mesh = {Analysis of Variance ; *Data Interpretation, Statistical ; Fixation, Ocular/*physiology ; Humans ; Linear Models ; Psycholinguistics/*methods ; *Reading ; Saccades/*physiology ; Time Factors ; },
abstract = {An important question in research on eye movements in reading is whether word frequency and word predictability have additive or interactive effects on fixation durations. A fair number of studies have reported only additive effects of the frequency and predictability of a target word on reading times on that word, failing to show significant interactions. Recently, however, Hand, Miellet, O'Donnell, and Sereno (see record 2010-19099-001) reported interactive effects in a study that included the distance of the prior fixation from the target word (launch site). They reported that when the saccade into the target word was launched from very near to the word (within 3 characters), the predictability effect was larger for low frequency words, but when the saccade was launched from a medium distance (4-6 characters from the word) the predictability effect was larger for high frequency words. Hand et al. argued for the importance of including launch site in analyses of target word fixation durations. Here we describe several problems with Hand et al.'s use of analyses of variance in which launch site is divided into distinct ordinal levels. We describe a more appropriate way to analyze such data-linear mixed-effect models-and we use this method to show that launch site does not modulate the interaction between frequency and predictability in two other data sets.},
}

Analysis of Variance
*Data Interpretation, Statistical
Fixation, Ocular/*physiology
Humans
Linear Models
Psycholinguistics/*methods
*Reading
Saccades/*physiology
Time Factors

@article {pmid19321847,
year = {2009},
author = {Wills, AM and Cronin, S and Slowik, A and Kasperaviciute, D and Van Es, MA and Morahan, JM and Valdmanis, PN and Meininger, V and Melki, J and Shaw, CE and Rouleau, GA and Fisher, EM and Shaw, PJ and Morrison, KE and Pamphlett, R and Van den Berg, LH and Figlewicz, DA and Andersen, PM and Al-Chalabi, A and Hardiman, O and Purcell, S and Landers, JE and Brown, RH},
title = {A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS.},
journal = {Neurology},
volume = {73},
number = {1},
pages = {16-24},
pmid = {19321847},
issn = {1526-632X},
support = {089701/WT_/Wellcome Trust/United Kingdom ; G0600974/MRC_/Medical Research Council/United Kingdom ; G0500289/MRC_/Medical Research Council/United Kingdom ; R01 ES013482-01/ES/NIEHS NIH HHS/United States ; G0900688/MRC_/Medical Research Council/United Kingdom ; G0400149/MRC_/Medical Research Council/United Kingdom ; },
mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Aryldialkylphosphatase/*genetics ; Bias ; Chromosome Mapping/methods ; DNA Mutational Analysis/methods/statistics & numerical data ; Data Interpretation, Statistical ; Genetic Markers/genetics ; Genetic Predisposition to Disease/*genetics ; Genetic Testing/methods/statistics & numerical data ; Genome-Wide Association Study/methods/statistics & numerical data ; Genotype ; Humans ; Odds Ratio ; Polymorphism, Single Nucleotide/*genetics ; Reproducibility of Results ; },
abstract = {BACKGROUND: Six candidate gene studies report a genetic association of DNA variants within the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). However, several other large studies, including five genome-wide association studies, have not duplicated this finding.

METHODS: We conducted a meta-analysis of 10 published studies and one unpublished study of the paraoxonase locus, encompassing 4,037 ALS cases and 4,609 controls, including genome-wide association data from 2,018 ALS cases and 2,425 controls.

RESULTS: The combined fixed effects odds ratio (OR) for rs662 (PON1 Q192R) was 1.09 (95% confidence interval [CI], 1.02-1.16, p = 0.01); the genotypic OR for RR homozygotes at Q192R was 1.25 (95% CI, 1.07-1.45, p = 0.0004); the combined OR for rs854560 (PON1 L55M) was 0.97 (95% CI, 0.86-1.10, p = 0.62); the OR for rs10487132 (PON2) was 1.08 (95% CI, 0.92-1.27, p = 0.35). Although the rs662 polymorphism reached a nominal level of significance, no polymorphism was significant after multiple testing correction. In the subanalysis of samples with genome-wide data from which population outliers were removed, rs662 had an OR of 1.06 (95% CI, 0.97-1.16, p = 0.22).

CONCLUSIONS: In contrast to previous positive smaller studies, our genetic meta-analysis showed no significant association of amyotrophic lateral sclerosis (ALS) with the PON locus. This is the largest meta-analysis of a candidate gene in ALS to date and the first ALS meta-analysis to include data from whole genome association studies. The findings reinforce the need for much larger and more collaborative investigations of the genetic determinants of ALS.},
}

Amyotrophic Lateral Sclerosis/*genetics
Aryldialkylphosphatase/*genetics
Bias
Chromosome Mapping/methods
DNA Mutational Analysis/methods/statistics & numerical data
Data Interpretation, Statistical
Genetic Markers/genetics
Genetic Predisposition to Disease/*genetics
Genetic Testing/methods/statistics & numerical data
Genome-Wide Association Study/methods/statistics & numerical data
Genotype
Humans
Odds Ratio
Polymorphism, Single Nucleotide/*genetics
Reproducibility of Results

@article {pmid18234791,
year = {2008},
author = {Worobey, M},
title = {Phylogenetic evidence against evolutionary stasis and natural abiotic reservoirs of influenza A virus.},
journal = {Journal of virology},
volume = {82},
number = {7},
pages = {3769-3774},
pmid = {18234791},
issn = {1098-5514},
support = {R21 AI065371/AI/NIAID NIH HHS/United States ; },
mesh = {Animals ; Disease Reservoirs/*virology ; Humans ; Influenza A virus/*genetics ; Phylogeny ; RNA, Viral/*genetics ; Sequence Analysis, DNA ; Siberia ; Water Microbiology ; },
abstract = {Zhang et al. (G. Zhang, D. Shoham, D. Gilichinsky, S. Davydov, J. D. Castello, and S. O. Rogers, J. Virol. 80:12229-12235, 2006) have claimed to have recovered influenza A virus RNA from Siberian lake ice, postulating that ice might represent an important abiotic reservoir for the persistence and reemergence of this medically important pathogen. A rigorous phylogenetic analysis of these influenza A virus hemagglutinin gene sequences, however, indicates that they originated from a laboratory reference strain derived from the earliest human influenza A virus isolate, WS/33. Contrary to Zhang et al.'s assertions that the Siberian "ice viruses" are most closely related either to avian influenza virus or to human influenza virus strains from Asia from the 1960s (Zhang et al., J. Virol. 81:2538 [erratum], 2007), they are clearly contaminants from the WS/33 positive control used in their laboratory. There is thus no credible evidence that environmental ice acts as a biologically relevant reservoir for influenza viruses. Several additional cases with findings that seem at odds with the biology of influenza virus, including modern-looking avian influenza virus RNA sequences from an archival goose specimen collected in 1917 (T. G. Fanning, R. D. Slemons, A. H. Reid, T. A. Janczewski, J. Dean, and J. K. Taubenberger, J. Virol. 76:7860-7862, 2002), can also be explained by laboratory contamination or other experimental errors. Many putative examples of evolutionary stasis in influenza A virus appear to be due to laboratory artifacts.},
}

Animals
Disease Reservoirs/*virology
Humans
Influenza A virus/*genetics
Phylogeny
RNA, Viral/*genetics
Sequence Analysis, DNA
Siberia
Water Microbiology

@article {pmid17908587,
year = {2007},
author = {Cong, X and Cox, DD and Cantor, SB},
title = {Bayesian meta-analysis of Papanicolaou smear accuracy.},
journal = {Gynecologic oncology},
volume = {107},
number = {1 Suppl 1},
pages = {S133-7},
pmid = {17908587},
issn = {0090-8258},
support = {P01 CA082710/CA/NCI NIH HHS/United States ; CA82710/CA/NCI NIH HHS/United States ; },
mesh = {Bayes Theorem ; Female ; Humans ; *Papanicolaou Test ; Sensitivity and Specificity ; Uterine Cervical Neoplasms/diagnosis/*pathology ; Vaginal Smears/*standards ; },
abstract = {OBJECTIVE: To perform a Bayesian analysis of data from a previous meta-analysis of Papanicolaou (Pap) smear accuracy (Fahey et al. Am J Epidemiol 1995; 141:680-689) and compare the results.

METHODS: We considered two Bayesian models for the same data set used in the Fahey et al. study. Model I was a beta-binomial model which considered the number of true positives and false negatives as independent binomial random variables with probability parameters beta (sensitivity) and alpha (one minus specificity), respectively. We assumed that beta and alpha are independent, each following a beta distribution with exponential priors. Model II considered sensitivity and specificity jointly through a bivariate normal distribution on the logits of the sensitivity and specificity. We performed sensitivity analysis to examine the effect of prior selection on the parameter estimates.

RESULTS: We compared the estimates of average sensitivity and specificity from the Bayesian models with those from Fahey et al.'s summary receiver operating characteristics (SROC) approach. Model I produced results similar to those of the SROC approach. Model II produced point estimates higher than those of the SROC approach, although the credible intervals overlapped and were wider. Sensitivity analysis showed that the Bayesian models are somewhat sensitive to the variance of the prior distribution, but their point estimates are more robust than those of the SROC approach.

CONCLUSIONS: The Bayesian approach has advantages over the SROC approach in that it accounts for between-study variation and allows for estimating the sensitivity and specificity for a particular trial, taking into consideration the results of other trials, i.e., "borrowing strength" from other trials.},
}

Bayes Theorem
Female
Humans
*Papanicolaou Test
Sensitivity and Specificity
Uterine Cervical Neoplasms/diagnosis/*pathology
Vaginal Smears/*standards

@article {pmid17641152,
year = {2007},
author = {Chen, H and Richard, M and Sandler, DP and Umbach, DM and Kamel, F},
title = {Head injury and amyotrophic lateral sclerosis.},
journal = {American journal of epidemiology},
volume = {166},
number = {7},
pages = {810-816},
pmid = {17641152},
issn = {0002-9262},
support = {Z01 ES049005/ImNIH/Intramural NIH HHS/United States ; },
mesh = {Adult ; Aged ; Aged, 80 and over ; Amyotrophic Lateral Sclerosis/*epidemiology/etiology ; Case-Control Studies ; Confidence Intervals ; Craniocerebral Trauma/complications/*epidemiology ; Female ; Humans ; Life Style ; Male ; Middle Aged ; New England/epidemiology ; Odds Ratio ; Risk Assessment ; Risk Factors ; Soccer/*injuries ; },
abstract = {Recent data showed that soccer players in Italy had an unusually high risk of amyotrophic lateral sclerosis (ALS) and that repeated head trauma might have contributed to this increase. The authors examined whether head injury was related to ALS risk in a case-control study of 109 New England ALS cases diagnosed in 1993-1996 and 255 matched controls. They also conducted a meta-analysis of the published literature. Overall, ever having experienced a head injury was nonsignificantly associated with a higher ALS risk. When compared with persons without a head injury, a statistically significant ALS risk elevation was found for participants with more than one head injury (odds ratio (OR) = 3.1, 95 percent confidence interval (CI): 1.2, 8.1) and patients who had had a head injury during the past 10 years (OR = 3.2, 95 percent CI: 1.0, 10.2). For participants who had had multiple head injuries with the latest occurring in the past 10 years, risk was elevated more than 11-fold. The meta-analysis also indicated a moderately elevated risk of ALS among persons with previous head injuries (OR = 1.7, 95 percent CI: 1.3, 2.2). In this study population, physical injuries to other body parts, including the trunk, arms, or legs, were not related to ALS risk. These data support the notion that head injury may increase the risk of ALS.},
}

Adult
Aged
Aged, 80 and over
Amyotrophic Lateral Sclerosis/*epidemiology/etiology
Case-Control Studies
Confidence Intervals
Craniocerebral Trauma/complications/*epidemiology
Female
Humans
Life Style
Male
Middle Aged
New England/epidemiology
Odds Ratio
Risk Assessment
Risk Factors
Soccer/*injuries

@article {pmid17261678,
year = {2007},
author = {Hirtz, D and Thurman, DJ and Gwinn-Hardy, K and Mohamed, M and Chaudhuri, AR and Zalutsky, R},
title = {How common are the "common" neurologic disorders?.},
journal = {Neurology},
volume = {68},
number = {5},
pages = {326-337},
doi = {10.1212/01.wnl.0000252807.38124.a3},
pmid = {17261678},
issn = {1526-632X},
mesh = {Bias ; Data Interpretation, Statistical ; Developed Countries/statistics & numerical data ; Humans ; Incidence ; Nervous System Diseases/*epidemiology ; Prevalence ; *Proportional Hazards Models ; Reproducibility of Results ; Risk Assessment/*methods ; Risk Factors ; Sample Size ; United States/epidemiology ; },
abstract = {OBJECTIVE: To estimate the current incidence and prevalence in the United States of 12 neurologic disorders.

METHODS: We summarize the strongest evidence available, using data from the United States or from other developed countries when US data were insufficient.

RESULTS: For some disorders, prevalence is a better descriptor of impact; for others, incidence is preferable. Per 1,000 children, estimated prevalence was 5.8 for autism spectrum disorder and 2.4 for cerebral palsy; for Tourette syndrome, the data were insufficient. In the general population, per 1,000, the 1-year prevalence for migraine was 121, 7.1 for epilepsy, and 0.9 for multiple sclerosis. Among the elderly, the prevalence of Alzheimer disease was 67 and that of Parkinson disease was 9.5. For diseases best described by annual incidence per 100,000, the rate for stroke was 183, 101 for major traumatic brain injury, 4.5 for spinal cord injury, and 1.6 for ALS.

CONCLUSIONS: Using the best available data, our survey of a limited number of disorders shows that the burden of neurologic illness affects many millions of people in the United States.},
}

Bias
Data Interpretation, Statistical
Developed Countries/statistics & numerical data
Humans
Incidence
Nervous System Diseases/*epidemiology
Prevalence
*Proportional Hazards Models
Reproducibility of Results
Risk Assessment/*methods
Risk Factors
Sample Size
United States/epidemiology

@article {pmid8644956,
year = {1996},
author = {Nichol, G and Detsky, AS and Stiell, IG and O'Rourke, K and Wells, G and Laupacis, A},
title = {Effectiveness of emergency medical services for victims of out-of-hospital cardiac arrest: a metaanalysis.},
journal = {Annals of emergency medicine},
volume = {27},
number = {6},
pages = {700-710},
doi = {10.1016/s0196-0644(96)70187-7},
pmid = {8644956},
issn = {0196-0644},
support = {U01 HL077885/HL/NHLBI NIH HHS/United States ; },
mesh = {Cardiopulmonary Resuscitation ; *Emergency Medical Services/organization & administration/standards ; Heart Arrest/mortality/*therapy ; Humans ; Life Support Care ; Reaction Time ; Survival Analysis ; },
abstract = {STUDY OBJECTIVE: To determine the relative effectiveness of differences in response time interval, proportion of bystander CPR, and type and tier of emergency medical services (EMS) system on survival after out of hospital cardiac arrest.

METHODS: We performed a comprehensive literature search, excluding EMS systems other than those of interest (systems of interest were those comprising one tier with providers of basic life support [BLS] or advanced life support [ALS] and those comprising two tiers with providers of BLS or BLS-defibrillation followed by ALS), patient population of fewer than 100 cardiac arrests, studies in which we could not determine the total number of arrests of presumed cardiac origin, and studies lacking data on survival to hospital discharge. Metaanalysis using generalized linear model with dispersion estimation for random effects was then performed.

RESULTS: Increased survival to hospital discharge was significantly associated with tier (P < .01), response time interval (P < .01), and bystander CPR (P = .04). A significant interaction was detected between response time interval and bystander CPR (P = .02). For the studies analyzed, survival was 5.2% in a one-tier EMS system or 10.5% in a two-tier EMS system. A 1-minute decrease in mean response time interval was associated with absolute increases in survival rates of .4% and .7% in a one-tier and two-tier EMS systems, respectively.

CONCLUSION: Increased survival to hospital discharge may be associated with decreased response time interval and with the use of a two-tier EMS system as opposed to a one-tier system. The data available for this analysis were suboptimal. Policymakers need more methodologically rigorous research to have more reliable and valid estimates of the effectiveness of different EMS systems.},
}

Cardiopulmonary Resuscitation
*Emergency Medical Services/organization & administration/standards
Heart Arrest/mortality/*therapy
Humans
Life Support Care
Reaction Time
Survival Analysis

@article {pmid41530593,
year = {2026},
author = {Muneer, MA and Tariq, I and Zulfiqar, E and Saaki, SS and Gupta, I and Bokhari, SMNA and Verma, A and Mehta, R and Sah, R and Ahmed, SI},
title = {Efficacy and safety of dextromethorphan/quinidine in treating pseudobulbar affect in neurological disorders: A systematic review and dose-classified network meta-analysis.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {47},
number = {1},
pages = {159},
pmid = {41530593},
issn = {1590-3478},
mesh = {Humans ; *Dextromethorphan/administration & dosage/adverse effects/pharmacology/therapeutic use ; *Quinidine/administration & dosage/adverse effects/pharmacology/therapeutic use ; *Pseudobulbar Palsy/drug therapy ; Network Meta-Analysis as Topic ; Drug Combinations ; *Nervous System Diseases/drug therapy/complications ; Randomized Controlled Trials as Topic ; },
abstract = {BACKGROUND: Pseudobulbar affect (PBA) is a disabling neuropsychiatric condition characterized by sudden, involuntary episodes of crying or laughing incongruent with mood. It occurs in several neurological disorders, including amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), stroke, and traumatic brain injury (TBI). Dextromethorphan/quinidine (DM/Q) is the only Food and Drug Administration (FDA)-approved therapy for PBA, but optimal dosing and safety profiles remain uncertain.

OBJECTIVE: To evaluate the efficacy and safety of different DM/Q dosing regimens for treating PBA through a systematic review and network meta-analysis.

METHODS: A comprehensive search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov was conducted through March 2025. Randomized controlled trials reporting outcomes on the Center for Neurologic Study-Lability Scale (CNS-LS), Visual Analog Scale-Quality of Life (VAS-QOL), Visual Analog Scale-Quality of Recovery (VAS-QOR), and adverse events were included. Analyses were performed using R (netmeta package), and bias was assessed with the Cochrane RoB 2.0 tool.

RESULTS: Five randomized controlled trials comprising 605 participants were analyzed. DM/Q 20/10 mg and 30/10 mg significantly improved CNS-LS scores (mean difference [MD] - 2.52 and - 2.45, respectively), while DM/Q 30/30 mg produced greater gains in VAS-QOL (MD 17.20) and VAS-QOR (MD 14.90). Dizziness was the only statistically significant, dose-related adverse event.

CONCLUSION: DM/Q combination therapy provides effective symptom control for PBA, with favorable tolerability. Both 20/10 mg and 30/10 mg doses improve emotional lability, while 30/30 mg yields additional quality-of-life benefits. Further studies should assess long-term safety and disorder-specific dosing optimization.},
}

Humans
*Dextromethorphan/administration & dosage/adverse effects/pharmacology/therapeutic use
*Quinidine/administration & dosage/adverse effects/pharmacology/therapeutic use
*Pseudobulbar Palsy/drug therapy
Network Meta-Analysis as Topic
Drug Combinations
*Nervous System Diseases/drug therapy/complications
Randomized Controlled Trials as Topic

@article {pmid41527739,
year = {2026},
author = {Le, J and Hu, X and Jiang, Y and Wang, Q and Ma, Q and Cui, W},
title = {Insights into phosphoproteomic studies and prospects of phosphoproteins as biomarkers for brain disorders.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251411546},
doi = {10.1177/13872877251411546},
pmid = {41527739},
issn = {1875-8908},
abstract = {The dysregulation of phosphorylation networks plays a critical role in the pathogenesis of a wide spectrum of brain disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, ischemic stroke, drug abuse, major depressive disorder, and schizophrenia. Notably, phosphorylated isoforms of microtubule-associated protein tau and neurofilament heavy polypeptide are already utilized in clinical diagnostics, highlighting the promise of protein phosphorylation signatures as biomarkers for prediction, diagnosis, prognosis, and treatment monitoring. Recent advances in deep phosphoproteomic technologies now facilitate the comprehensive mapping of phosphorylation alterations across diverse biological samples and disease stages. This review summarizes current phosphoproteomic studies aimed at identifying biomarkers for brain disorders and elaborates on the promising application of phosphorylated proteins in this context.},
}

@article {pmid41422050,
year = {2025},
author = {Valletta, M and Briel, N and Yuksekel, I and Barboure, M and Coward, A and De Houwer, JFH and Fawad, A and González-Mayoral, A and Iaccarino, G and Martínez-Dubarbie, F and Moukaled, S and Andreasson, U and Gobom, J and Brinkmalm, A and Tijms, B and Zetterberg, H and Blennow, K and Suárez-Calvet, M and Schöll, M and Paterson, RW and Montoliu-Gaya, L and Sogorb-Esteve, A},
title = {Fluid biomarkers for neurodegenerative diseases: a comprehensive update.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {12},
pmid = {41422050},
issn = {1758-9193},
abstract = {UNLABELLED: Fluid biomarkers are revolutionizing the diagnosis and management of neurodegenerative diseases by enabling earlier diagnosis and disease monitoring. In particular, blood-based biomarkers have emerged as a minimally invasive and scalable alternative to cerebrospinal fluid analysis. Recent advances in blood-based tau biomarkers have shown high diagnostic accuracy for Alzheimer’s disease (AD). Other neurodegenerative diseases—such as synucleinopathies, frontotemporal lobar degeneration, limbic-predominant age-related TDP-43 encephalopathy (LATE), and amyotrophic lateral sclerosis—pose substantial challenges due to their heterogeneous clinical presentations and the current absence of robust biomarkers for hallmark pathologies. Nonetheless, promising candidate markers are emerging for improved disease characterization and staging. Technological innovations, including single-molecule arrays (Simoa), advanced mass spectrometry workflows and nucleic acid linked immune-sandwich assay (NULISA) have markedly enhanced the sensitivity and precision of biomarker quantification from low-concentration biological matrices. More recently, the development of fully automated platforms shows great promise for routine measurement of blood-based biomarkers in clinical settings. Despite this progress key challenges remain, including the need for improved assay reproducibility, standardization, and the optimization of clinical workflows. In this review, we provide a comprehensive update on recent progress in fluid biomarker research across AD and major neurodegenerative diseases, highlight technological advances in detection methods, and discuss current challenges and opportunities for clinical translation.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-025-01919-z.},
}

@article {pmid41380476,
year = {2026},
author = {Gu, Y and Chen, Y and Tang, X and Guo, J and Hu, J and Yang, W and Li, J and Chen, X and Fan, D and Chen, GB and He, J and Ren, Y and Dong, Y and Sato, C and Chen, Y and Zinman, L and Rogaeva, E and Zhang, M},
title = {Multi-omics analyses identify potential epigenetic loci associated with survival in amyotrophic lateral sclerosis across diverse populations.},
journal = {EBioMedicine},
volume = {123},
number = {},
pages = {106071},
pmid = {41380476},
issn = {2352-3964},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/mortality ; DNA Methylation ; *Epigenesis, Genetic ; Polymorphism, Single Nucleotide ; Male ; Female ; Middle Aged ; CpG Islands ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; *Genetic Loci ; Aged ; Genotype ; Epigenomics/methods ; Whole Genome Sequencing ; Multiomics ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with highly diverse survival time. However, genetic and epigenetic factors influencing ALS survival across diverse populations remain unclear.

METHODS: We performed whole-genome sequencing (WGS) and DNA methylome array in blood DNA of patients with ALS. For survival analysis, we used Cox proportional hazards model for genetic variants, DNA methylation (DNAm) of CpG sites or CpG-SNPs in Chinese and Canadian cohorts, followed by meta-analysis. We performed pathway enrichment analysis for candidate genes inferred from DNAm events associated with survival. In paired genome and methylome data, we analysed the effect of the candidate CpG-SNP genotypes on DNAm status.

FINDINGS: Genome-wide cross-population meta-analysis of common variants in 511 patients with ALS showed a suggestive association of CAV1/CAV2 rs117002347 genotypes with survival. Epigenome-wide cross-population meta-analysis in 459 patients revealed that ALS survival was significantly linked to DNAm of 88 CpGs on 40 genes, and highlighted the AMPK and cytoskeleton pathways. Epigenome-wide cross-population meta-analysis of CpG-SNPs in 459 patients identified 8 loci on 4 genes, including BAG6 (cg27014438/rs28732154), which was further validated in another 204 patients with ALS. Moreover, analysis of paired genome/epigenome data (n = 454) indicated that BAG6 rs28732154 genotypes may modulate cg27014438 methylation, which is also a cis-eQTM of BAG6 expression in blood.

INTERPRETATION: Our study identified BAG6 cg27014438 methylation as a potential epigenetic modifier of ALS survival. BAG6 cg27014438 methylation is modulated by rs28732154 genotypes, and linked to BAG6 expression. Our findings extended our understanding of epigenetic modifiers in ALS survival.

FUNDING: This work was supported by the National Natural Science Foundation of China (82071430, 82371878) (MZ), Shanghai Municipal Natural Science Foundation General Program (22ZR1466400) (MZ), the Fundamental Research Funds for the Central Universities (MZ), the G. Harry Sheppard Memorial Research Fund, and Canadian Consortium on Neurodegeneration in Aging (ER).},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/mortality
DNA Methylation
*Epigenesis, Genetic
Polymorphism, Single Nucleotide
Male
Female
Middle Aged
CpG Islands
Genome-Wide Association Study
Genetic Predisposition to Disease
*Genetic Loci
Aged
Genotype
Epigenomics/methods
Whole Genome Sequencing
Multiomics

@article {pmid41028808,
year = {2025},
author = {Rawat, A and Khurana, S and Verma, S and Dhawan, U and Gourie-Devi, M and Ganguly, NK and Taneja, V},
title = {Insights from meta-analysis and experimental validation identify exosomal miR-146a-5p as a potential biomarker for sporadic amyotrophic lateral sclerosis.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {33846},
pmid = {41028808},
issn = {2045-2322},
support = {2020-2641/CMB/ADHOC-BMS//Indian Council of Medical Research/ ; 3/1/2/151/Neuro/2021-NCD-I//Indian Council of Medical Research/ ; 420804-07627//Research Development Program, Sir Ganga Ram Hospital/ ; },
mesh = {*Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood/mortality ; Humans ; *MicroRNAs/genetics/blood/metabolism ; Biomarkers/blood/metabolism ; *Exosomes/genetics/metabolism ; Male ; Female ; Gene Expression Profiling ; Middle Aged ; },
abstract = {MicroRNAs (miRNAs) have emerged as key regulators in the pathogenesis of amyotrophic lateral sclerosis (ALS). Despite growing evidence that miRNAs exhibit altered expression profiles in ALS, their utility as a biomarker remains limited. To address this, we conducted a meta-analysis using the Robust Rank Aggregation package, incorporating 20 differential miRNA profiling studies. Among these, miR-146a-5p emerged as the most dysregulated and significant miRNA in ALS (P = 0.0000142, P-adj = 0.0096), particularly in extracellular vesicle-derived studies. To evaluate its diagnostic accuracy, we validated miR-146a-5p expression in serum-derived exosomes and observed a significant increase in sporadic ALS (sALS) patients (n = 22) as compared to healthy controls (n = 18). Moreover, higher levels of miR-146a-5p were strongly associated with longer survival (≥ 5 years) (P = 0.0135), with a positive correlation between miR-146a-5p expression and survival duration (P = 0.0313) in sALS patients. Further, gene set enrichment analysis of miR-146a-5p target genes highlighted critical involvement of the Immune system and NF-kappa B signaling pathways in ALS pathophysiology. These findings highlight miR-146a-5p as a potential biomarker for ALS.},
}

*Amyotrophic Lateral Sclerosis/genetics/diagnosis/blood/mortality
Humans
*MicroRNAs/genetics/blood/metabolism
Biomarkers/blood/metabolism
*Exosomes/genetics/metabolism
Male
Female
Gene Expression Profiling
Middle Aged

@article {pmid40180646,
year = {2025},
author = {Temiz, K and Gul, A and Gov, E},
title = {5-Repurposed Drug Candidates Identified in Motor Neurons and Muscle Tissues with Amyotrophic Lateral Sclerosis by Network Biology and Machine Learning Based on Gene Expression.},
journal = {Neuromolecular medicine},
volume = {27},
number = {1},
pages = {24},
pmid = {40180646},
issn = {1559-1174},
mesh = {*Amyotrophic Lateral Sclerosis/drug therapy/genetics ; Humans ; *Machine Learning ; *Motor Neurons/metabolism/drug effects ; *Drug Repositioning/methods ; Transcriptome ; Gene Expression Profiling ; *Muscle, Skeletal/metabolism ; Gene Regulatory Networks ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that leads to motor neuron degeneration, muscle weakness, and respiratory failure. Despite ongoing research, effective treatments for ALS are limited. This study aimed to apply network biology and machine learning (ML) techniques to identify novel repurposed drug candidates for ALS. In this study, we conducted a meta-analysis using 4 transcriptome data in ALS patients (including motor neuron and muscle tissue) and healthy controls. Through this analysis, we uncovered common shared differentially expressed genes (DEGs) separately for motor neurons and muscle tissue. Using common DEGs as proxies, we identified two distinct clusters of highly clustered differential co-expressed cluster genes: the 'Muscle Tissue Cluster' for muscle tissue and the 'Motor Neuron Cluster' for motor neurons. We then evaluated the performance of the nodes of these two modules to distinguish between diseased and healthy states with ML algorithms: KNN, SVM, and Random Forest. Furthermore, we performed drug repurposing analysis and text-mining analyses, employing the nodes of clusters as drug targets to identify novel drug candidates for ALS. The potential impact of the drug candidates on the expression of cluster genes was predicted using linear regression, SVR, Random Forest, Gradient Boosting, and neural network algorithms. As a result, we identified five novel drug candidates for the treatment of ALS: Nilotinib, Trovafloxacin, Apratoxin A, Carboplatin, and Clinafloxacin. These findings highlight the potential of drug repurposing in ALS treatment and suggest that further validation through experimental studies could lead to new therapeutic avenues.},
}

*Amyotrophic Lateral Sclerosis/drug therapy/genetics
Humans
*Machine Learning
*Motor Neurons/metabolism/drug effects
*Drug Repositioning/methods
Transcriptome
Gene Expression Profiling
*Muscle, Skeletal/metabolism
Gene Regulatory Networks

@article {pmid33814477,
year = {2021},
author = {Su, CL and Tam, KW and Fang, TP and Chiang, LL and Chen, HC},
title = {Effects of pulmonary rehabilitation program on amyotrophic lateral sclerosis: A meta-analysis of randomized controlled trials.},
journal = {NeuroRehabilitation},
volume = {48},
number = {3},
pages = {255-265},
doi = {10.3233/NRE-210052},
pmid = {33814477},
issn = {1878-6448},
mesh = {Amyotrophic Lateral Sclerosis/*rehabilitation ; Humans ; Muscle Weakness ; Randomized Controlled Trials as Topic ; Resistance Training/*methods ; *Respiration ; },
abstract = {BACKGROUND: Patients with amyotrophic lateral sclerosis (ALS) develop respiratory failure and progressive muscle weakness. The effects of pulmonary rehabilitation on the lung function of patients with ALS are unclear.

OBJECTIVE: Through this meta-analysis of randomized controlled trials (RCTs), we evaluated the effects of pulmonary rehabilitation, such as type of treatment, on patients with ALS and compared the effectiveness of this treatment.

METHODS: PubMed, EMBASE, Web of Science, and Cochrane databases were searched until December 2020. The methodological quality of each study was assessed using the updated Cochrane Risk of Bias tool (RoB 2.0). Data were analyzed using Review Manager version 5.4 (Cochrane Collaboration, Oxford, England), and the meta-analysis was performed in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines.

RESULTS: Of 2168 articles, 10 trials were reviewed; among these trials, two focused on respiratory training and eight on physical exercise, three of which involved a combination of aerobic and resistance training. Our meta-analysis demonstrated no difference in the ALSFRS-R score and % FVC among patients with ALS.

CONCLUSIONS: Respiratory training or physical exercise did not significantly affect the ALSFRS-R score and % FVC of patients with ALS. At 12 months after intervention, the ALSFRS-R score in the physical exercise group was higher than that in the usual care group. Further clinical trials are warranted to develop approaches for improving the lung function of patients with ALS.},
}

Amyotrophic Lateral Sclerosis/*rehabilitation
Humans
Muscle Weakness
Randomized Controlled Trials as Topic
Resistance Training/*methods
*Respiration

@article {pmid21925771,
year = {2012},
author = {Mok, K and Traynor, BJ and Schymick, J and Tienari, PJ and Laaksovirta, H and Peuralinna, T and Myllykangas, L and Chiò, A and Shatunov, A and Boeve, BF and Boxer, AL and DeJesus-Hernandez, M and Mackenzie, IR and Waite, A and Williams, N and Morris, HR and Simón-Sánchez, J and van Swieten, JC and Heutink, P and Restagno, G and Mora, G and Morrison, KE and Shaw, PJ and Rollinson, PS and Al-Chalabi, A and Rademakers, R and Pickering-Brown, S and Orrell, RW and Nalls, MA and Hardy, J},
title = {Chromosome 9 ALS and FTD locus is probably derived from a single founder.},
journal = {Neurobiology of aging},
volume = {33},
number = {1},
pages = {209.e3-8},
pmid = {21925771},
issn = {1558-1497},
support = {R01 AG26251/AG/NIA NIH HHS/United States ; 089701/WT_/Wellcome Trust/United Kingdom ; G0701075/MRC_/Medical Research Council/United Kingdom ; R01 AG038791/AG/NIA NIH HHS/United States ; R01AG031278/AG/NIA NIH HHS/United States ; MC_G1000735/MRC_/Medical Research Council/United Kingdom ; 089698/WT_/Wellcome Trust/United Kingdom ; G0701441/MRC_/Medical Research Council/United Kingdom ; R01AG038791/AG/NIA NIH HHS/United States ; R01 AG026251/AG/NIA NIH HHS/United States ; ZIA AG000933/ImNIH/Intramural NIH HHS/United States ; G0700943/MRC_/Medical Research Council/United Kingdom ; Z01 AG000949/ImNIH/Intramural NIH HHS/United States ; R01 AG031278/AG/NIA NIH HHS/United States ; },
mesh = {Amyotrophic Lateral Sclerosis/*genetics ; Chromosomes, Human, Pair 9/*genetics ; Finland ; Frontotemporal Dementia/*genetics ; Genetic Linkage ; *Genome-Wide Association Study ; Haplotypes ; Humans ; *Polymorphism, Single Nucleotide ; },
abstract = {We and others have recently reported an association between amyotrophic lateral sclerosis (ALS) and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data are that there is a single founder for this form of disease.},
}

Amyotrophic Lateral Sclerosis/*genetics
Chromosomes, Human, Pair 9/*genetics
Finland
Frontotemporal Dementia/*genetics
Genetic Linkage
*Genome-Wide Association Study
Haplotypes
Humans
*Polymorphism, Single Nucleotide

@article {pmid41525888,
year = {2026},
author = {Tessitore, S and Torazza, C and Bonifacino, T and Bacchetti, F and Roselli, F and Raiteri, L and Milanese, M and Bonanno, G},
title = {Focus on the excitatory and inhibitory neurotransmission imbalance in amyotrophic lateral sclerosis: a harmful disease player or a potential therapeutic opportunity?.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107272},
doi = {10.1016/j.nbd.2026.107272},
pmid = {41525888},
issn = {1095-953X},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. Evidence indicates that ALS is a "multifactorial" and "multicellular" disease; however, the causes of ALS remain elusive, as the mechanisms underlying the disease have not yet been completely clarified. One major proposed mechanism, first described in 1990, is the glutamate excitotoxicity theory. This theory suggests that excessive glutamatergic neurotransmission, combined with impaired glutamate clearance, significantly contributes to motor neuron degeneration. Aberrant glutamate neurotransmission may lead to precocious motor neuron hyperexcitability in the brain cortex and spinal cord, which can be later followed by hypoexcitability phases. Accumulating evidence suggests that impairment in inhibitory neurotransmission is relevant for excitation/inhibition imbalance, leading to excitotoxicity, a critical feature of ALS. Gamma-aminobutyric acid (GABA) and glycine are the primary inhibitory neurotransmitters that modulate neuronal excitability, including that of motor neurons. In ALS, dysfunction of inhibitory processes and loss of cortical and spinal inhibitory interneurons are observed. Renshaw cells, which mediate recurrent inhibition in the spinal cord, seem particularly vulnerable. The interactions among neurotransmitters, including glutamate, GABA, and glycine, play pivotal roles in regulating the excitation/inhibition balance. Auto- or hetero-receptor-mediated interactions are crucial, but auto- or hetero-transporter-mediated neurotransmission control, as well as other molecular mechanisms that regulate neuronal interplay, are also relevant, as they can be altered in pathological conditions such as ALS. To facilitate the search for new effective therapies for ALS, attention toward the impairment of inhibitory neurotransmission is essential to determine the role of excitation/inhibition imbalance on excitotoxicity. Different pharmacological agents are being used to treat other pathologies in which the excitation/inhibition ratio is impaired. Among these, we highlighted the potential of novel glycine and GABA receptor ligands and transporter inhibitors, as stand-alone interventions or in combination with other treatments. The present review aims to elucidate the complex interplay between excitatory and inhibitory neurotransmission in ALS, exploring the potential to target this imbalance for therapeutic purposes.},
}

@article {pmid41525811,
year = {2026},
author = {Pradhan, LK and Das, SK},
title = {Zebrafish neural regeneration: mechanistic insights into human nervous system repair.},
journal = {Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.neuroscience.2026.01.009},
pmid = {41525811},
issn = {1873-7544},
abstract = {The zebrafish (Danio rerio) is a powerful vertebrate model for studying neurodegenerative diseases and regenerative medicine due to its genetic similarity to humans and its unique ability to regenerate the central nervous system (CNS). This review synthesizes key findings on zebrafish neural regeneration across the retina, spinal cord, and brain, emphasizing translational relevance. Zebrafish effectively model disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, stroke, epilepsy, autism spectrum disorders, and CNS injuries. Unlike mammals, they restore damaged axons and recover function through a permissive extracellular matrix, transient inflammation, and glial plasticity. In the retina, Müller glia reprograms after injury to generate progenitors that replace lost neurons, regulated by Wnt/β-catenin, Shh, EGF, Hippo/YAP, and ROCK signaling. In the spinal cord, ependymo-radial glia forms a laminin- and fibronectin-rich "glial bridge," guided by FGF and CTGF signaling, supporting axon regrowth. In the brain, GFAP- and Olig2-positive radial glia drive neurogenesis within ventricular niches, integrating new neurons while maintaining circuit integrity. Regeneration involves transient Notch suppression, context-specific Wnt and FGF activation, and immune modulation without fibrosis. Advances in single-cell RNA sequencing, CRISPR-Cas9, lineage tracing, and multi-omics have identified injury-induced progenitor states, regulators (ascl1a, lin28, sox2, stat3), and epigenetic programs enabling regeneration. Emerging research on bioelectric signaling, microbiota-brain interactions, and lipid mediators further expands systemic understanding. Overall, zebrafish provide a unified model for decoding vertebrate CNS regeneration and guiding therapeutic strategies to restore neural repair in humans.},
}

@article {pmid41524979,
year = {2026},
author = {Sun, Y and Huang, C and Pan, Y and He, X and Zhang, H},
title = {Muscle Fibrosis in Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Diagnostic Advances, and Therapeutic Strategies.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {357},
pmid = {41524979},
issn = {1559-1182},
support = {2021KY727//Health Commission of Zhejiang Province, Medical and health project/ ; A20210510//Hangzhou Municipal Health Commission, Medical and health science project/ ; },
mesh = {Animals ; Humans ; *Amyotrophic Lateral Sclerosis/therapy/pathology/diagnosis/metabolism/complications ; Fibrosis ; *Muscle, Skeletal/pathology/metabolism ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily characterized by the degeneration of motor neurons. However, the pathological process of ALS extends beyond the central nervous system, with dynamic changes in skeletal muscle playing a crucial role in the progression of the disease. Recent research has shown that muscle fibrosis, marked by the abnormal accumulation of extracellular matrix (ECM), leads to reduced muscle elasticity, compromised contractile function, and impaired regeneration of neuromuscular junctions (NMJs). This condition represents not only the final stage of muscle atrophy in ALS but also a significant factor accelerating disease progression through "neuromuscular interactions." We conducted a systematic review of the molecular mechanisms of muscle fibrosis in ALS. This included examining the dysregulation of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF/CCN2), and the Wnt/β-catenin signaling pathways. We also considered key cellular contributors, such as fibro-adipogenic precursor cells and macrophages. The review also covers the use of non-invasive imaging techniques, such as MRI and muscle ultrasound, for early detection and monitoring. We also evaluate potential therapeutic approaches, ranging from anti-fibrotic drugs and gene therapy to physical interventions. In summary, muscle fibrosis is a promising therapeutic target that could complement strategies focused on motor neurons, ultimately improving functional outcomes in patients with amyotrophic lateral sclerosis.},
}

Animals
Humans
*Amyotrophic Lateral Sclerosis/therapy/pathology/diagnosis/metabolism/complications
Fibrosis
*Muscle, Skeletal/pathology/metabolism

@article {pmid41518742,
year = {2026},
author = {Milella, G and Carlone, S and Luisi, F and Velucci, V and Defazio, G},
title = {Facial-onset SOD1 amyotrophic lateral sclerosis: A case report and systematic review.},
journal = {Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia},
volume = {145},
number = {},
pages = {111856},
doi = {10.1016/j.jocn.2026.111856},
pmid = {41518742},
issn = {1532-2653},
abstract = {BACKGROUND: Facial-onset weakness is an exceptionally rare presentation of SOD1-associated amyotrophic lateral sclerosis (ALS), and its natural history, anatomical spread, and prognostic implications remain unclear.

METHODS: We report a woman carrying a heterozygous SOD1 A5T variant who presented with isolated, rapidly progressive bilateral facial palsy, and we performed a PRISMA-compliant systematic review of MEDLINE, Scopus, and Web of Science to identify genetically confirmed SOD1-positive ALS with facial-onset weakness. Case-level demographic, genetic, clinical, neurophysiological, and outcome data were extracted and synthesised descriptively.

RESULTS: Eleven patients were included (7 men, 4 women; mean age at onset 52.3 years). Seven SOD1 variants were represented, predominantly associated with short survival (e.g. A5V, C7G, A5T). Facial weakness was initially confined to the lower face in 5/11 patients, while 6/11 had combined upper and lower facial involvement. Disease spread followed a stereotyped pattern: early contralateral facial recruitment (mean 3.6 months), rapid bulbar involvement (4.2 months), and later extension to the upper limbs (9.2 months), frequently with side-concordance between facial and arm involvement. Lower motor neuron (LMN) signs predominated in the early phases of the disease. Survival was short (median 16 months), lower than reported for unselected SOD1-ALS cohorts with the same genotypes. Three patients received tofersen, with heterogeneous outcomes.

CONCLUSIONS: Facial-onset SOD1 ALS defines a distinctive phenotype characterised by LMN-predominant facial palsy in early phases, near-neighbour spread, and an aggressive course exceeding genotype-based expectations. Prompt recognition and genetic testing in progressive facial palsy unresponsive to immunotherapy are essential to ensure access to gene-targeted treatments.},
}

@article {pmid41518572,
year = {2026},
author = {Zhang, Z and Zhang, M and Cao, Z and Zhao, H and Li, X and Luo, P},
title = {Fibrillarin: bridging ribosome biogenesis and apoptosis in cellular stress and disease.},
journal = {Apoptosis : an international journal on programmed cell death},
volume = {31},
number = {1},
pages = {11},
pmid = {41518572},
issn = {1573-675X},
support = {82171363//National Natural Science Foundation of China/ ; },
mesh = {Humans ; *Apoptosis/genetics ; *Ribosomes/metabolism/genetics ; *Neoplasms/genetics/metabolism/pathology ; *Stress, Physiological ; Animals ; Tumor Suppressor Protein p53/metabolism/genetics ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; Cell Nucleolus/metabolism ; Signal Transduction ; Chromosomal Proteins, Non-Histone ; },
abstract = {Nucleolar stress has emerged as a critical regulatory mechanism linking ribosome biogenesis defects to apoptotic cell death in various pathological conditions. Fibrillarin (FBL), the catalytic component of box C/D small nucleolar ribonucleoproteins, participates in multiple forms of programmed cell death through both p53-dependent and p53-independent pathways across diverse disease contexts including cancer and neurodegeneration. In malignancies including breast cancer, colorectal cancer, and hepatocellular carcinoma, FBL overexpression promotes apoptosis resistance, whereas in Alzheimer's disease and ALS/FTD, FBL dysfunction contributes to pathological neuronal death. Dysregulation of FBL can lead to excessive apoptosis or apoptosis resistance depending on cellular context and disease state. Various cellular stressors trigger aberrant FBL function, disrupting rRNA processing and ribosome assembly, which then activates nucleolar stress responses that culminate in cell death through ribosomal protein-MDM2-p53 axis activation or selective translational control of survival factors in a context-dependent manner. Therefore, targeting FBL-mediated apoptotic pathways is considered an important avenue for the treatment of various cancers and neurodegenerative diseases. In this review, we summarize the major and recent findings focusing on the mechanisms of FBL-regulated apoptosis in disease pathogenesis and provide a systematic overview of current therapeutic strategies targeting nucleolar stress pathways, including RNA polymerase I inhibitors and precision medicine approaches based on p53 status, which may provide important therapeutic targets that merit further investigation.},
}

Humans
*Apoptosis/genetics
*Ribosomes/metabolism/genetics
*Neoplasms/genetics/metabolism/pathology
*Stress, Physiological
Animals
Tumor Suppressor Protein p53/metabolism/genetics
*Neurodegenerative Diseases/genetics/metabolism/pathology
Cell Nucleolus/metabolism
Signal Transduction
Chromosomal Proteins, Non-Histone

@article {pmid41517697,
year = {2026},
author = {Wang, Z and Yao, L and Tu, M},
title = {Evaluating the causal connections between sleep duration and disease prevalence: A comprehensive systematic review and meta-analysis of Mendelian randomization studies.},
journal = {Medicine},
volume = {105},
number = {2},
pages = {e45225},
doi = {10.1097/MD.0000000000045225},
pmid = {41517697},
issn = {1536-5964},
mesh = {Humans ; Mendelian Randomization Analysis ; *Sleep/genetics/physiology ; Prevalence ; Genetic Predisposition to Disease ; Sleep Duration ; },
abstract = {BACKGROUND: The causal link between sleep duration and diverse health conditions remains unconfirmed. This meta-analysis aimed to clarify these relationships by synthesizing Mendelian randomization (MR) study evidence.

METHODS: PubMed was systematically searched up to February 15, 2024, for MR studies exploring genetic predispositions to sleep duration/insomnia (short/long/overall sleep duration, insomnia) and associations with circulatory, digestive, neurodegenerative, metabolic diseases, and cancers. Eligible effect estimates were meta-analyzed.

RESULTS: Fifty-one MR studies were included. Genetic variations in sleep traits were strongly linked to elevated risk of 12 cardiovascular diseases, obesity-related metrics (Type 2 diabetes, fasting glucose/insulin, HbA1c), neurological disorders (Alzheimer, amyotrophic lateral sclerosis, Parkinson disease), mental health conditions (attention-deficit/hyperactivity disorder, autism, bipolar disorder, major depressive disorder, schizophrenia), inflammatory bowel disease, and lung cancer.

CONCLUSION: Genetic evidence confirms causal associations between sleep characteristics and multiple diseases, emphasizing sleep's key role in health promotion and supporting personalized sleep management to reduce disease risk.},
}

Humans
Mendelian Randomization Analysis
*Sleep/genetics/physiology
Prevalence
Genetic Predisposition to Disease
Sleep Duration

@article {pmid41517538,
year = {2025},
author = {Dziadkowiak, E and Marschollek, K and Kwaśniak-Nowakowska, A and Zimny, A and Rałowska-Gmoch, W and Boroń, M and Koszewicz, M},
title = {Establishing Diagnostic and Differential Diagnostic Criteria for Amyotrophic Lateral Sclerosis.},
journal = {Journal of clinical medicine},
volume = {15},
number = {1},
pages = {},
pmid = {41517538},
issn = {2077-0383},
abstract = {Motor neuron disease (MND) represents a broad and heterogeneous group of disorders involving the upper or lower motor neurons, represented mainly by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and progressive bulbar palsy (PBP). Primary motor neuronopathies are characterized by progressive degenerative loss of anterior horn cell motoneurons (lower motor neurons) or loss of giant pyramidal Betz cells (upper motor neurons). Rare atypical variants of MND-ALS include flail arm syndrome (FA), flail leg syndrome (FL), facial-onset sensory and motor neuronopathy (FOSMN), finger extension weakness and downbeat nystagmus motor neuron disease (FEWDON-MND) and long-standing and juvenile MND-ALS. In this article, we present a review of diagnostic criteria and the differential diagnosis for MND, focusing on ALS.},
}

@article {pmid41512846,
year = {2026},
author = {Zou, C and Li, P and Li, B and Sparwasser, T and Yuan, J},
title = {Next steps in regulatory T cells: Biology and clinical application.},
journal = {Cell},
volume = {189},
number = {1},
pages = {6-22},
doi = {10.1016/j.cell.2025.11.035},
pmid = {41512846},
issn = {1097-4172},
mesh = {Humans ; *T-Lymphocytes, Regulatory/immunology/cytology ; Animals ; Interleukin-2/therapeutic use ; Graft vs Host Disease/immunology/prevention & control/therapy ; Immune Tolerance ; Amyotrophic Lateral Sclerosis/therapy/immunology ; },
abstract = {Recent advances in regulatory T cell (Treg) biology and clinical application of Treg-based treatments show promise as a new generation of transforming therapeutics for immune-related disorders, positioning Tregs as a "living drug" to rebuild immune tolerance and repair damaged tissues simultaneously. This perspective summarizes the key knowledge on Treg biology and highlights the recent important discoveries in the development of clinical applications based on Treg biology, from low-dose interleukin-2 therapy showing promising results in trials for ALS and adoptive Treg transfer demonstrating efficacy in preventing GVHD to early pilot studies of CAR Tregs. Drawing on these advances, we provide perspectives on key research priorities and translational challenges and set forth a roadmap that integrates basic and clinical insights into developing next-generation therapies focusing on precision tolerance strategies.},
}

Humans
*T-Lymphocytes, Regulatory/immunology/cytology
Animals
Interleukin-2/therapeutic use
Graft vs Host Disease/immunology/prevention & control/therapy
Immune Tolerance
Amyotrophic Lateral Sclerosis/therapy/immunology

@article {pmid41511321,
year = {2025},
author = {Borgheai, SB and Achorn, BE and Zisk, AH and Hosni, SM and Richter, KEG and Menniti, FS and Shahriari, Y},
title = {A Comprehensive Overview of Neurophysiological Correlates of Cognitive Impairment in Amyotrophic Lateral Sclerosis.},
journal = {Cells},
volume = {15},
number = {1},
pages = {},
pmid = {41511321},
issn = {2073-4409},
support = {NSF-1913492//U.S. National Science Foundation/ ; NSF-2006012//U.S. National Science Foundation/ ; P20GM103430//Institutional Development Award (IDeA) Network for Biomedical Research Excellence/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/physiopathology/complications/genetics ; *Cognitive Dysfunction/physiopathology ; Brain/physiopathology ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that leads to the gradual loss of motor control, typically resulting in paralysis and death within 3 to 5 years of diagnosis. ALS shares neuropathological and genetic associations with fronto-temporal dementia (FTD), a neurodegenerative condition primarily impacting cognitive functions. These two conditions are increasingly viewed as manifestations of a single molecular disease process that affects distinct brain systems, impacting motor neuronal pathways in ALS and fronto-cortical functions in FTD. However, this simple dichotomy belies the complexity of these conditions. In particular, patients with primary motor ALS can also experience significant cognitive deficits. Investigating the pathobiological and neurophysiological underpinnings of these impairments is essential for a comprehensive understanding of ALS and may open avenues for targeted therapies to alleviate these debilitating symptoms. Moreover, the biophysical correlates of cognitive deficits in ALS may serve as sensitive biomarkers for evaluating potential therapeutics. In this narrative review, we begin with an overview of the clinical features and genetics of ALS, followed by a review of the associated cognitive deficits that are adjunctive to motor decline. We then highlight neuroimaging studies from our laboratory and the broader literature, using EEG and other modalities that are beginning to uncover systems-level brain disruptions potentially underlying cognitive impairment in motor-dominant ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/physiopathology/complications/genetics
*Cognitive Dysfunction/physiopathology
Brain/physiopathology

@article {pmid41504939,
year = {2026},
author = {Evola, V and Parmar, MS},
title = {Targeting neuroinflammation in neurodegenerative disorders: the emerging potential of semaglutide.},
journal = {Inflammation research : official journal of the European Histamine Research Society ... [et al.]},
volume = {75},
number = {1},
pages = {13},
pmid = {41504939},
issn = {1420-908X},
mesh = {Humans ; *Neurodegenerative Diseases/drug therapy/immunology ; *Glucagon-Like Peptides/therapeutic use/pharmacology ; Animals ; *Neuroprotective Agents/therapeutic use ; *Neuroinflammatory Diseases/drug therapy ; *Anti-Inflammatory Agents/therapeutic use ; Glucagon-Like Peptide-1 Receptor Agonists ; Glucagon-Like Peptide 1 ; },
abstract = {BACKGROUND: Chronic neuroinflammation is increasingly recognized not as a secondary effect but as a primary driver of neurodegenerative disease progression. In conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD), and Lewy body dementia (LBD), dysregulated glial activity, marked by sustained microglial and astrocytic activation, initiates a cascade of cytokine release, oxidative stress, and impaired neuronal support. This review synthesizes recent advances in understanding these shared inflammatory processes, emphasizing how glia-centric pathology shapes disease-specific trajectories and therapeutic responses.

FINDINGS: Within this framework, we evaluate the therapeutic potential of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) with emerging neuroprotective properties. Preclinical studies suggest that semaglutide can suppress pro-inflammatory signaling, mitigate oxidative injury, and enhance key anti-inflammatory and neuroprotective pathways that restore trophic support and cellular resilience. We also examine real-world evidence and emerging human clinical trial data, which recently demonstrated that semaglutide rapidly modulates AD pathology by significantly reducing cerebrospinal fluid (CSF) levels of p-tau, t-tau, and neurogranin, and promoting a less inflammatory CD8[+]T-cell signature. In addition to reduction in neuroinflammation marker, YKL-40. While subsequent large-scale Phase 3 trials in early AD did not meet primary cognitive endpoints (CDR-SB) despite favorable biomarker modulation.

CONCLUSION: Positioning semaglutide as a therapeutic option targeting neuroinflammation-mediated neuropathology, this review underscores its potential for repurposing as a disease-modifying therapy across diverse neurodegenerative disorders and highlights the urgent need for targeted trials in MS, ALS, FTD, HD, and LBD-conditions that remain without effective immunomodulatory treatments despite clear inflammatory origins. However, while direct CSF measurements confirm limited but measurable BBB penetration, the clinical translation of its effects remains a key challenge.},
}

Humans
*Neurodegenerative Diseases/drug therapy/immunology
*Glucagon-Like Peptides/therapeutic use/pharmacology
Animals
*Neuroprotective Agents/therapeutic use
*Neuroinflammatory Diseases/drug therapy
*Anti-Inflammatory Agents/therapeutic use
Glucagon-Like Peptide-1 Receptor Agonists
Glucagon-Like Peptide 1

@article {pmid41504202,
year = {2025},
author = {Wu, JY and Ye, S and Yin, TL and Zhang, S and Zheng, DF and Fu, JY and Ma, GW and Fan, DS},
title = {Amyotrophic Lateral Sclerosis With Concurrent LHON-associated m.14484T>C Mutation: A Case Report and Literature Review.},
journal = {Revista de neurologia},
volume = {80},
number = {11},
pages = {44110},
pmid = {41504202},
issn = {1576-6578},
support = {81873784//National Natural Sciences Foundation of China/ ; 82071426//National Natural Sciences Foundation of China/ ; BYSYDL2019002//Clinical Cohort Construction Program of Peking University Third Hospital/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics ; Male ; *Mutation ; Adult ; Female ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease that mostly presents as sporadic cases. Currently, no mitochondrial-related gene mutations have been identified as the cause of ALS. Mitochondrial gene mutations cause rare hereditary diseases, and the symptoms of pure muscle weakness and muscle atrophy are rarely observed.

CASE REPORT: We report the case of a young patient clinically diagnosed with ALS concurrently associated with a pathogenic mutation in the mitochondrially encoded nicotinamide adenine dinucleotide: ubiquinone oxidoreductase core subunit 6 (MT-ND6) gene. However, the pathogenic relationship between the MT-ND6 gene and ALS has not been confirmed.

CONCLUSION: We provide a case report and a literature review aimed at increasing the understanding of the connection between the two. It is essential to consider the potential modifying role of mitochondrial pathogenic genes in ALS.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics
Male
*Mutation
Adult
Female

@article {pmid41504056,
year = {2025},
author = {Lymperopoulos, A and M'Sadoques, AJ and Stoicovy, RA and Altsman, VL},
title = {Why Is Epinephrine Preferred for Cardiac Arrest? The Answer May Lie in β2-Adrenergic Receptor Activation.},
journal = {Frontiers in bioscience (Landmark edition)},
volume = {30},
number = {12},
pages = {47927},
doi = {10.31083/FBL47927},
pmid = {41504056},
issn = {2768-6698},
support = {R01 #HL155718-01//National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) grant/ ; #333609-2025//American Foundation for Pharmaceutical Education (AFPE) Gateway to Research Scholarship/ ; },
mesh = {*Epinephrine/therapeutic use/pharmacology ; Humans ; *Heart Arrest/drug therapy ; *Receptors, Adrenergic, beta-2/metabolism ; *Vasoconstrictor Agents/therapeutic use/pharmacology ; Cardiopulmonary Resuscitation/methods ; Animals ; },
abstract = {Epinephrine (Epi, adrenaline) is routinely used during cardiopulmonary resuscitation (CPR) for cardiac arrest and is a first line treatment according to the international advanced life support (ALS) guidelines, which recommend 1 mg Epi be administered every 3-5 minutes during CPR. However, specific pharmacological factors that may distinguish Epi from other vasopressor agents used during CPR are unclear. This opinion article argues that one such factor, perhaps even the most important, is the activation of the β2-adrenergic receptor (AR) subtype, which only Epi, among all vasopressor hormones, can induce. β2AR activation equips Epi with more robust capabilities for pulse generation in the pacemaker cells (sinoatrial node) for the heart and of restoring contractile function in ischemic/hypoxic cardiomyocytes via sodium/potassium pump activation, compared to all other vasopressor hormones, including the closely related catecholamine norepinephrine (NE, noradrenaline). These additional actions of Epi via the β2AR, which are probably not shared by NE or other vasopressor agents, may make it particularly useful in situations where simple blood pressure elevation is insufficient, such as cardiac arrest.},
}

*Epinephrine/therapeutic use/pharmacology
Humans
*Heart Arrest/drug therapy
*Receptors, Adrenergic, beta-2/metabolism
*Vasoconstrictor Agents/therapeutic use/pharmacology
Cardiopulmonary Resuscitation/methods
Animals

@article {pmid41503832,
year = {2026},
author = {Tuli, S and Patel, P and Shethji, A and Gau, D},
title = {Mitochondria and the Actin Cytoskeleton in Neurodegeneration.},
journal = {Cytoskeleton (Hoboken, N.J.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/cm.70095},
pmid = {41503832},
issn = {1949-3592},
support = {CA267180/NH/NIH HHS/United States ; TL1 TR001858/NH/NIH HHS/United States ; },
abstract = {Mitochondrial dysfunction and cytoskeletal disorganization are widely recognized hallmarks of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Although these disorders differ in clinical presentation and etiology, accumulating evidence points to a shared cellular vulnerability at the intersection of mitochondrial dynamics and actin cytoskeletal regulation. In this review, we examine the emerging role of actin-mitochondria crosstalk as a convergent mechanism in neurodegeneration. We discuss how disruptions in actin filament remodeling, mitochondrial fission and fusion, organelle transport, and mitophagy contribute to neuronal dysfunction and loss across these diseases. Particular attention is given to disease-specific pathways, including cofilin-actin rod formation in AD, α-synuclein-driven actin disruption in PD, mutant huntingtin's effects on mitochondrial fragmentation in HD, and profilin-1-associated mitochondrial defects in ALS. By synthesizing findings from diverse models, we highlight how perturbations in the cytoskeleton-mitochondria interface may act as an upstream trigger and amplifier of neurodegenerative cascades. We also outline key knowledge gaps and propose future directions for research, with an emphasis on targeting actin-mitochondrial interactions as a potential therapeutic strategy across multiple neurodegenerative conditions.},
}

@article {pmid41499987,
year = {2026},
author = {Poulidou, V and Tseriotis, VS and Bombaci, A and Vucic, S and Pavey, N and Papagiannopoulos, S and Kimiskidis, VK and Arnaoutoglou, M},
title = {The split elbow sign in amyotrophic lateral sclerosis: A systematic review and meta-analysis.},
journal = {Neurophysiologie clinique = Clinical neurophysiology},
volume = {56},
number = {2},
pages = {103134},
doi = {10.1016/j.neucli.2025.103134},
pmid = {41499987},
issn = {1769-7131},
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) patients can exhibit split phenomena, with preferential weakness of specific muscle groups. The aim of this review is to investigate the split elbow (SE) phenomenon (different weakness/wasting pattern between biceps and triceps) as a potential clinical and neurophysiological feature in ALS.

METHODS: Our study was reported according to the PRISMA statement and registered in PROSPERO (CRD42024528359). MEDLINE, SCOPUS, Web of Science, and grey literature sources were searched using the terms "split elbow" and "amyotrophic lateral sclerosis" up to April 2025. English-written peer-reviewed, randomized, non-randomized, observational, diagnostic accuracy, and case-control studies were included. Study quality was assessed using Joanna Briggs Institute critical appraisal tool. Regarding muscle strength, we pooled the standardized mean difference of normalized Medical Research Council (MRC) scores using random effects. We used a bivariate random-effects model to evaluate SE index (SEICMAP, compound muscle action potential of biceps/triceps) in distinguishing ALS from controls.

RESULTS: Seven studies with 1941 ALS patients (61.8 % male) met inclusion criteria. Pooled standardized mean difference (triceps - biceps MRC scores) was -0.17 [95 % CI, -1.03 to 0.69], p = 0.63, indicating no significant difference in muscle strength between elbow flexion and extension. Between-study heterogeneity was high (I[2] = 97.1 % [95.5 %; 98.2 %], p < 0.0001). The SEICMAP demonstrated only moderate accuracy in distinguishing ALS from controls (pooled sensitivity, specificity, and AUC of 0.789 [0.655-0.880], 0.580 [0.487-0.668], and 0.661, respectively).

CONCLUSIONS: Current evidence does not support a consistent SE pattern in ALS. Methodological variability and small sample sizes limit the generalizability of available findings, indicating that the SE is unlikely to provide meaningful diagnostic utility in routine clinical practice.},
}

@article {pmid41498587,
year = {2026},
author = {Maskell, KG and Cook, AL and King, AE and Dickson, TC and Blizzard, CA},
title = {Modeling amyotrophic lateral sclerosis (ALS) in vitro: from mechanistic studies to translatable drug discovery.},
journal = {Lab on a chip},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5lc00577a},
pmid = {41498587},
issn = {1473-0189},
abstract = {Amyotrophic lateral sclerosis is a rapidly progressing, fatal neurodegenerative disease that causes selective degeneration of the corticomotor system. Currently, ALS remains incurable, and the available treatment options offer little in the way of extending life or improving quality of life. This is due, at least in part, to a lack of representative disease models. In vitro modeling offers rapid, experimentally accessible platforms for mechanistic discovery research and drug screening, but modeling the complexity of ALS - a multicellular, multisystem disease - in a dish, is not without its challenges. Here, we review the current landscape of in vitro pre-clinical ALS research, with emphasis on the development of compartmentalised culture and the promise this holds for translatable modeling of ALS.},
}

@article {pmid41498352,
year = {2026},
author = {Hewitt-Dean, J and Tebbutt, J and Hobson, E},
title = {The impact of motor neurone disease on oral health: a scoping review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-7},
doi = {10.1080/21678421.2025.2603312},
pmid = {41498352},
issn = {2167-9223},
abstract = {OBJECTIVE: To identify current evidence on oral health-related quality of life in people with Motor Neurone Disease (MND), as well as identify barriers to oral health and care, and establish priorities for future research.

METHODS: A scoping review was conducted. Electronic databases and grey literature sources were searched from 2000 to 2024. Articles discussing oral health in adults with MND were included. Findings were supplemented by stakeholder consultation with people with MND, caregivers, clinicians, and researchers.

RESULTS: Fourteen articles met inclusion criteria, comprising eight cross-sectional studies, one prospective quality improvement project, one single center observational and four review articles. Five key themes emerged: dental status and oral hygiene activities, orofacial function, secretion management, service delivery and Oral health-related quality of life (OHRQoL). Studies indicated that MND negatively impacts oral health through impaired ability to perform oral hygiene and altered orofacial functioning. Only one study examined oral health-related quality of life. Stakeholder consultation highlighted additional concerns including challenges with service access, the impact of MND on oral health, and difficulties maintaining oral hygiene due to physical limitations.

CONCLUSIONS: Oral health remains an under-researched area in MND care despite its potential impact on quality of life and overall wellbeing. Future research priorities should include investigating relationships between oral health and MND outcomes, improving service delivery models, and increasing dental professional awareness. Active involvement of people with MND in research design and implementation is essential for developing effective interventions.},
}

@article {pmid41498289,
year = {2025},
author = {Ram, J and Glickman, MH},
title = {The many faces of p97/Cdc48 in mitochondrial homeostasis.},
journal = {Essays in biochemistry},
volume = {69},
number = {5},
pages = {},
doi = {10.1042/EBC20253045},
pmid = {41498289},
issn = {1744-1358},
mesh = {Humans ; *Valosin Containing Protein/metabolism/genetics ; *Mitochondria/metabolism ; *Homeostasis ; Animals ; *Adenosine Triphosphatases/metabolism/genetics ; Nuclear Proteins ; },
abstract = {Through its various roles in protein quality control, membrane dynamics, and cellular survival pathways, the AAA+ ATPase p97/valosin-containing protein emerges as a significant regulator of mitochondrial homeosta sis. This review comprehensively examines the multifaceted functions of p97 in mitochondrial biology, spanning from mitochondria-associated degradation to newly discovered functions in organellar cross-talk and disease pathogenesis. Underlying its cellular importance, p97 mutations are found in amyotrophic lateral sclerosis and frontotemporal dementia. To elucidate its mechanistic contribution to these processes, we provide a detailed table (Table 1) listing all known mitochondrial Cdc48/p97 substrates and associ ated proteins, categorized by their respective pathways. Recruitment to most of these substrates occurs by specialized adaptors, including Doa1/phospholipase A-2-activating protein, UBXD8, and UBXN1. p97 orchestrates the extraction and proteasomal degradation of outer mitochondrial membrane proteins, which are essential for maintaining mitochondrial integrity. For example, by controlling the turnover of fusion factors MFN1/2 and fission machinery, p97 regulates mitochondrial dynamics. p97 also governs apoptotic signaling through the regulated degradation of anti-apoptotic factors, such as myeloid cell leukemia-1 and VDAC, thereby modulating mitochondrial permeability. In mitophagy, p97 enables the clearance of damaged organelles by extracting ubiquitinated substrates and recruiting autophagy machinery. Beyond proteolysis, p97 facilitates recycling of endoplasmic reticulum-mitochondria contact sites through regulation of UBXD8-dependent lipid metabolism. Recent discoveries have revealed p97's involvement in pathogen host interactions and circular RNA-mediated regulation, thereby expanding our understanding of its cellular functions. The emerging picture positions p97 as an integrative hub co-ordinating mitochondrial protein homeostasis, organellar dynamics, and cell fate decisions, with therapeutic potential for metabolic and neurodegenerative disorders.},
}

Humans
*Valosin Containing Protein/metabolism/genetics
*Mitochondria/metabolism
*Homeostasis
Animals
*Adenosine Triphosphatases/metabolism/genetics
Nuclear Proteins

@article {pmid41498281,
year = {2026},
author = {Santamaria, MP and Mathias-Santamaria, IF and Tavelli, L and Barootchi, S and Prato, GPP},
title = {An updated evidence-based recommendation for the treatment of gingival recession associated with non-carious cervical lesions.},
journal = {Journal of periodontology},
volume = {},
number = {},
pages = {},
doi = {10.1002/jper.70049},
pmid = {41498281},
issn = {1943-3670},
abstract = {BACKGROUND: Approximately 50% of the gingival recessions (GRs) are associated with non-carious cervical lesions (NCCLs), forming what are known as combined defects (CDs), which often require specific treatment protocols that differ from those used for GRs on teeth with an intact and sound surface. This narrative review aims to evaluate the current and relevant literature on the treatment of CDs and update the latest decision-making process with the new literature.

METHODS: Medline/PubMed, Embase, BIREME, and Google Scholar databases were searched. The NCCL portion of the CDs was classified according to Pini-Prato et al.'s classification (2010). The GR portion of the CDs was classified according to Cairo et al.'s classification (2011) and gingival phenotype. Based on these, a decision tree, supported by the current literature, was proposed.

RESULTS: Several approaches associating different surgical techniques/graft materials with different NCCL restoration protocols and materials are available. When A-, A+, and B- NCCL are present, only a surgical procedure for root coverage is needed based on GR characteristics. When either B+ or V-shaped NCCL is present, a composite restorative protocol and a root coverage procedure should be considered.

CONCLUSIONS: CDs are characterized by the coexistence of gingival recession and a non-carious cervical lesion. This updated decision-making process incorporated current literature, including new evidence on soft tissue grafts, which can guide clinicians in the treatment of CDs.

PLAIN LANGUAGE SUMMARY: Gum recession often occurs alongside defects in the tooth that are not caused by cavities. These two conditions can appear on the same tooth in about half of the cases. When that happens, treatment becomes more complex and requires careful planning. Choosing the best approach depends on the shape and severity of the tooth defect. This recommendation helps dentists and patients understand how to manage these combined problems. Most cases fall into mild categories (A-, A+, and B-; i.e., shallow tooth defects) and can be treated with standard procedures for gum recession alone. However, about 25% of cases have a more advanced defect (B+; i.e., deep tooth defects), which requires both a tooth restoration and gum surgery. The way gum recession is treated also depends on how thick the gum tissue is. If the tissue is thin, using the patient's own tissue for a graft usually gives the best results. If the tissue is already thick, a graft may not be necessary. In moderate cases, a graft using either patient tissue or commercial materials can improve long-term success. This recommendation summarizes the latest research and provides practical guidance to improve treatment outcomes for both patients and clinicians.},
}

@article {pmid41496184,
year = {2026},
author = {Portaro, S and Latella, D and Manuli, A and Calderone, A and Calabrò, RS},
title = {Bridging the gap in sexuality and neuromuscular disorders: a scoping review of an overlooked but crucial topic.},
journal = {Sexual medicine reviews},
volume = {14},
number = {1},
pages = {},
doi = {10.1093/sxmrev/qeaf076},
pmid = {41496184},
issn = {2050-0521},
support = {//Current Research Funds 2024-2025/ ; //Ministry of Health, Italy/ ; },
mesh = {Humans ; *Neuromuscular Diseases/psychology ; *Quality of Life/psychology ; *Sexuality/psychology ; *Sexual Dysfunction, Physiological/psychology ; Social Stigma ; Female ; *Sexual Health ; },
abstract = {INTRODUCTION: Neuromuscular disorders (NMDs) comprise a group of conditions affecting the muscles and/or the nerves controlling them, resulting in progressive muscle weakness. Beyond the physical limitations, NMDs can significantly impact quality of life (QoL), including sexuality. Sexuality, as defined by the World Health Organization, encompasses physical, psychological, and social dimensions. However, research exploring the multifaceted impact of NMDs on sexual well-being remains limited, despite the potential influence of physical impairments, psychological distress, and social stigma.

OBJECTIVES: This scoping review aims to synthesize the existing literature on sexuality in individuals with NMDs, identifying the interplay of physical, psychological, and social factors affecting sexual QoL, highlighting research gaps, and informing future research and clinical practice.

METHODS: A scoping review was conducted using PubMed, Web of Science, Cochrane Library, Embase, and Scopus databases (up to May 15, 2025) to identify studies examining sexuality in individuals with NMDs. Studies addressing physical, psychological, and social factors influencing sexual health in NMD patients were included. Data were extracted using a standardized form and synthesized narratively. The review was registered on Open OSF (DOI https://doi.org/10.17605/OSF.IO/RP9U2).

RESULTS: Fourteen studies with various conditions such as Duchenne muscular dystrophy, amyotrophic lateral sclerosis (ALS), myotonic dystrophy type 1, myasthenia gravis, and Charcot-Marie-Tooth disease were included, from interviews to surveys. One key theme that emerged was the extent to which personal narratives reveal the emotional weight of stigma, the struggle with body image, and how intimacy is peripheral in medical institutions. In surveys, many said their sexual activity had declined, particularly among people with progressive diseases like ALS and myotonic dystrophy. Many of these studies also pointed to how sexual health was directly associated with QoL, a good reminder that it's an important aspect of well-being that we need to pay more attention to in care and support.

CONCLUSION: This scoping review highlights a significant gap in research regarding sexuality in individuals with NMDs. The limited number of studies identified underscores the need for further research to understand the complex interplay of physical, psychosocial, and social factors affecting sexual well-being in this population.},
}

Humans
*Neuromuscular Diseases/psychology
*Quality of Life/psychology
*Sexuality/psychology
*Sexual Dysfunction, Physiological/psychology
Social Stigma
Female
*Sexual Health

@article {pmid41493706,
year = {2026},
author = {Hashemi, M and Shafiei Asheghabadi, P and Moassesfar, M and Mashhadikhan, S and Nasirzade, S and Vasheghani Farahani, A and Mehdizadeh, S and Minaei, S and Rahmani, M and Jamshidian, F and Farahani, N and Reiter, RJ and Taheriazam, A and Hasani Sadi, F and Hushmandi, K and Alimohammadi, M and Rahimzadeh, P and Entezari, M},
title = {MicroRNAs and Long Non-Coding RNAs Affect the Mechanisms Involved in Age-Related Neurodegeneration in a Manner Depending on RNA-Binding Proteins.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {343},
pmid = {41493706},
issn = {1559-1182},
mesh = {Humans ; *RNA, Long Noncoding/metabolism/genetics ; *MicroRNAs/genetics/metabolism ; Animals ; *RNA-Binding Proteins/metabolism/genetics ; *Aging/genetics/pathology/metabolism ; *Neurodegenerative Diseases/genetics/metabolism/pathology ; },
abstract = {Neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD), are marked by progressive neuronal loss and aberrant protein aggregation, presenting substantial global healthcare challenges. Recent research has illuminated the pivotal roles of RNA-binding proteins (RBPs) and non-coding RNAs (ncRNAs), notably microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in the molecular pathogenesis of age-related neurodegeneration. RBPs orchestrate RNA metabolism and engage extensively with miRNAs and lncRNAs to modulate gene expression at the post-transcriptional level. Dysregulation of these interactions precipitates pathological phenomena such as protein misfolding, stress granule formation, and disrupted RNA processing, thereby exacerbating neuronal dysfunction and death. Specific miRNAs have been implicated in regulating key neurodegenerative biomarkers, including tau and amyloid-β in AD, motor neuron maintenance in ALS, and survival pathways in HD. Elucidating the intricate interplay between RBPs and ncRNAs holds significant promise for the development of therapeutic strategies aimed at ameliorating RNA-mediated mechanisms in neurodegenerative disorders.},
}

Humans
*RNA, Long Noncoding/metabolism/genetics
*MicroRNAs/genetics/metabolism
Animals
*RNA-Binding Proteins/metabolism/genetics
*Aging/genetics/pathology/metabolism
*Neurodegenerative Diseases/genetics/metabolism/pathology

@article {pmid41488323,
year = {2025},
author = {Lotlikar, MS and Zellmer, JC and Bhattacharyya, R},
title = {Sigma receptors and mitochondria-associated ER membranes are converging therapeutic targets for Alzheimer's disease.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1733659},
pmid = {41488323},
issn = {1662-4548},
abstract = {Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.},
}

@article {pmid41481411,
year = {2026},
author = {Ortholand, J and Gensollen, N and Durrleman, S and Du Montcel, ST},
title = {Joint model with latent disease age: Overcoming the need for reference time.},
journal = {Statistical methods in medical research},
volume = {},
number = {},
pages = {9622802251399917},
doi = {10.1177/09622802251399917},
pmid = {41481411},
issn = {1477-0334},
abstract = {Heterogeneity of the progression of neurodegenerative diseases is one of the main challenges faced in developing therapies. Thanks to the increasing number of clinical databases, progression models have allowed a better understanding of this heterogeneity. Joint models have proven their effectiveness by combining longitudinal and survival data. Nevertheless, they require a reference time, which is ill-defined for neurodegenerative diseases, where biological underlying processes start before the first symptoms. In this work, we propose a joint non-linear mixed-effect model with a latent disease age, to overcome this need for a precise reference time. We used a longitudinal model with a latent disease age as a longitudinal sub-model. We associated it with a survival sub-model that estimates a Weibull distribution from the latent disease age. We validated our model on simulated data and benchmarked it with a state-of-the-art joint model on data from patients with Amyotrophic Lateral Sclerosis (ALS). Finally, we showed how the model could be used to describe ALS heterogeneity. Our model got significantly better results than the state-of-the-art joint model for absolute bias on ALS functional rating scale revised score (4.21(SD 4.41) versus 4.24(SD 4.14)(p-value=1.4×10-17)), and mean-cumulative-AUC for right-censored events on death (0.67(0.07) versus 0.61(0.09)(p-value=1.7×10-03)). To conclude, we propose a new model better suited in the context of unreliable reference time.},
}

@article {pmid41480618,
year = {2025},
author = {Hu, G and Gogzheyan, C and Panja, S and Sil, S and Gendelman, HE},
title = {Extracellular vesicle-based therapies for neurodegenerative diseases.},
journal = {NeuroImmune pharmacology and therapeutics},
volume = {4},
number = {4},
pages = {377-390},
pmid = {41480618},
issn = {2750-6665},
abstract = {Extracellular vesicles (EVs) are mediators of neurodegeneration and emerging therapeutic tools for central nervous system disorders. On the one hand, they help spread beta amyloid, tau, α-synuclein, TDP-43, and mutant SOD1, contributing to the signs and symptoms of Alzheimer's, Parkinson's, Amyotrophic lateral sclerosis, and Huntington's Diseases. By activating glial cells, they promote chronic neuroinflammation through carrying cytokines, inflammasomes, and chemokines. On the other hand, EVs' ability to transport neuroregulatory products and cross the blood-brain barrier makes them ideal vehicles for drug delivery. Their function can be surface-modified to deliver targeted therapies, including anti-inflammatory and neuroprotective regulatory RNAs, proteins, and lipids, as well as factors that help maintain neural homeostasis. Notably, we suggest that colostrum-derived EVs, enriched with growth factors and immune-regulatory microRNAs, offer a natural, scalable, and biocompatible source for neuroprotective treatment. Although EVs can act as "Janus-faced" entities - serving both as disease initiators and versatile therapeutic vehicles - controlling their activity can enable immune-based therapeutics for neurodegenerative diseases.},
}

@article {pmid41479097,
year = {2026},
author = {Stamatelopoulos, D and Papakonstantinou, E and Bacopoulou, F and Vlachakis, D},
title = {Polyphenols from Olive Oil: A Promising Therapeutic Approach for Neurodegenerative Diseases.},
journal = {Advances in experimental medicine and biology},
volume = {1490},
number = {},
pages = {343-349},
pmid = {41479097},
issn = {0065-2598},
mesh = {*Olive Oil/chemistry/therapeutic use ; Humans ; *Polyphenols/therapeutic use/pharmacology ; *Neurodegenerative Diseases/drug therapy/metabolism/pathology ; *Neuroprotective Agents/therapeutic use ; Animals ; Oxidative Stress/drug effects ; Antioxidants/therapeutic use ; Diet, Mediterranean ; Anti-Inflammatory Agents/therapeutic use ; },
abstract = {Neurodegenerative diseases such as Alzheimer's, Parkinson's, ALS, and Huntington's disease pose a growing global health challenge due to their prevalence in aging populations and their devastating impact on cognitive and motor functions. Current treatments focus on symptom management, with no options available to reverse neuronal damage. Emerging evidence highlights the potential role of extra virgin olive oil (EVOO) polyphenols in neuroprotection, particularly in the context of the Mediterranean diet, which is associated with lower rates of neurodegenerative disorders. EVOO's rich polyphenolic compounds, including hydroxytyrosol, oleuropein, tyrosol, and oleocanthal, exhibit potent antioxidant, anti-inflammatory, and neuroprotective properties. These bioactive molecules have shown potential in modulating disease-specific pathways, such as reducing oxidative stress, inhibiting abnormal protein aggregation, and regulating neuroinflammation. This paper explores the therapeutic potential of olive oil polyphenols for neurodegenerative diseases, detailing their mechanisms of action across different conditions. Our findings suggest that incorporating EVOO into dietary and medical interventions could serve as a promising strategy for mitigating neurodegenerative disease progression and enhancing cognitive health.},
}

*Olive Oil/chemistry/therapeutic use
Humans
*Polyphenols/therapeutic use/pharmacology
*Neurodegenerative Diseases/drug therapy/metabolism/pathology
*Neuroprotective Agents/therapeutic use
Animals
Oxidative Stress/drug effects
Antioxidants/therapeutic use
Diet, Mediterranean
Anti-Inflammatory Agents/therapeutic use

@article {pmid40990470,
year = {2026},
author = {Siu, MC and Selinopoulou, M and Abarca Salazar, S and Sturgeon, JP and Huynh, J and Basu Roy, R},
title = {Diagnostic Performance of Host-based Gene Expression Diagnostics in Children With Extrapulmonary Tuberculosis: A Systematic Review.},
journal = {The Pediatric infectious disease journal},
volume = {45},
number = {2},
pages = {140-146},
doi = {10.1097/INF.0000000000004998},
pmid = {40990470},
issn = {1532-0987},
mesh = {Humans ; Child ; *Tuberculosis/diagnosis/genetics ; Child, Preschool ; Adolescent ; Sensitivity and Specificity ; Infant ; Mycobacterium tuberculosis/genetics ; *Gene Expression Profiling ; Infant, Newborn ; Tuberculosis, Extrapulmonary ; },
abstract = {BACKGROUND: Diagnosing extrapulmonary tuberculosis (EPTB) in children is challenging due to nonspecific presentations and poor diagnostic yield from conventional microbiologic tests. Host gene expression signatures offer a non-sputum-based diagnostic alternative. This systematic review evaluates their diagnostic performance in pediatric EPTB.

METHODS: We systematically reviewed host-based gene expression diagnostics for pediatric EPTB. PubMed, Embase and Cochrane Library (January 1965-May 2025) were searched for studies in children (0-18 years) with EPTB. Exclusions were adult-only studies, mixed data on pulmonary TB and EPTB without disaggregation, pulmonary TB-only studies, reviews and abstracts. Two reviewers screened data, resolving disagreements by discussion.

RESULTS: Of 830 records, 2 studies met the inclusion criteria: Pan et al. (2017) and Olbrich et al. (2024), both in low and middle-income countries, enrolling a total of 891 children under 15 years. Olbrich et al.'s 3-gene MTB-HR prototype showed 59.8% sensitivity against a strict culture-confirmed reference standard and 50.0% in isolated EPTB with a low risk of bias. Using a microbiologic, clinical and radiologic composite standard, Pan et al.'s miRNA-29a assay achieved 67.2% sensitivity, 88.5% specificity in peripheral blood mononuclear cells; 81.1% sensitivity, 90.0% specificity in cerebrospinal fluid; 84.4% sensitivity, 95.4% specificity in combined peripheral blood mononuclear cell/cerebrospinal fluid with a high risk of bias.

CONCLUSIONS: Evidence for host gene expression diagnostics in pediatric EPTB is limited by few studies, small sample sizes, bias and lack of disaggregated data, with accuracy falling short of the World Health Organization targets.},
}

Humans
Child
*Tuberculosis/diagnosis/genetics
Child, Preschool
Adolescent
Sensitivity and Specificity
Infant
Mycobacterium tuberculosis/genetics
*Gene Expression Profiling
Infant, Newborn
Tuberculosis, Extrapulmonary

@article {pmid40631493,
year = {2026},
author = {Li, W and Gillies, RM and Sun, H and Khan, A},
title = {Career indecision among medical students: A scoping review of contributing sources, associated factors, and support strategies.},
journal = {Medical teacher},
volume = {48},
number = {1},
pages = {42-60},
doi = {10.1080/0142159X.2025.2520927},
pmid = {40631493},
issn = {1466-187X},
mesh = {Humans ; *Students, Medical/psychology ; *Career Choice ; *Decision Making ; Self Efficacy ; Adaptation, Psychological ; },
abstract = {BACKGROUND: While career indecision is well-studied in vocational psychology, its application in medical education remains limited. This scoping review examined sources of indecision, associated factors, and strategies to support medical students' career decision-making.

METHODS: A systematic search of PubMed, Scopus, CINAHL, and ERIC identified relevant studies published from January 2014 to December 2024. Two reviewers independently screened articles and data were charted. Eligible articles were synthesised using directed qualitative content analysis with inductive expansion, guided by Kulcsár et al.'s career decision-making taxonomy.

RESULTS: Ninety-three studies were included. Most studies focused on the career aspect of specialty selection. Career decision-making difficulties were categorised into Readiness (dysfunctional beliefs, career decision-making self-efficacy, willingness, general indecisiveness), Lack of Information (about self, about world of work, about how to make career decisions) and Use of Information (unreliable information, internal conflicts, external conflicts). Personal coping strategies and institutional support recommendations were identified. Influencing factors included demographics, personal traits, educational experiences, attitudes, and macro-level disruptions.

CONCLUSIONS: This review maps medical students' career decision-making difficulties to a structured framework and outlines support strategies and influencing factors. Findings underscore the value of integrating career psychology into medical education and addressing structural barriers to better support students' career development.},
}

Humans
*Students, Medical/psychology
*Career Choice
*Decision Making
Self Efficacy
Adaptation, Psychological

@article {pmid39871563,
year = {2025},
author = {Guo, J and Liu, XY and Yang, SS and Li, Q and Duan, Y and Zhu, SS and Zhou, K and Yan, YZ and Zeng, P},
title = {Roles of C/EBPβ/AEP in Neurodegenerative Diseases.},
journal = {Current topics in medicinal chemistry},
volume = {25},
number = {20},
pages = {2440-2452},
pmid = {39871563},
issn = {1873-4294},
support = {82301506//National Natural Science Foundation of China/ ; 220XQD090//Research Foundation of Scientific Research Program of University of South China/ ; 2023JJ40560//Provincial Natural Science Foundation of Hunan/ ; S202410555234, S202410555259, S202410555262//Science and Technology Innovation Project for College Students/ ; },
mesh = {Humans ; *Neurodegenerative Diseases/metabolism/drug therapy/pathology ; *CCAAT-Enhancer-Binding Protein-beta/metabolism/antagonists & inhibitors/chemistry ; Animals ; Small Molecule Libraries/chemistry/pharmacology ; },
abstract = {In recent years, an increasing number of studies have shown that increased activation of aspartic endopeptidases (AEPs) is a common symptom in neurodegenerative diseases (NDDs). AEP cleaves amyloid precursor protein (APP), tau (microtubule-associated protein tau), α- synuclein (α-syn), SET (a 39-KDa phosphoprotein widely expressed in various tissues and localizes predominantly in the nucleus), and TAR DNA-binding protein 43 (TDP-43), and promotes their aggregation, contributing to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) pathogenesis. Abundant evidence supports the notion that CCAAT/enhancer-binding protein β (C/EBPβ)/AEP may play an important role in NDDs. Developing its small molecule inhibitors is a promising treatment of NDDs. However, current research suggests that the pathophysiological mechanism of the C/EBPβ/AEP pathway is very complex in NDDs. This review summarizes the structure of C/EBPβ and AEP, their major physiological functions, potential pathogenesis, their small molecule inhibitors, and how C/EBPβ/AEP offers a novel pathway for the treatment of NDDs.},
}

Humans
*Neurodegenerative Diseases/metabolism/drug therapy/pathology
*CCAAT-Enhancer-Binding Protein-beta/metabolism/antagonists & inhibitors/chemistry
Animals
Small Molecule Libraries/chemistry/pharmacology

@article {pmid41477139,
year = {2025},
author = {Syamal, M},
title = {Treatment of Neurogenic Voice Disorders.},
journal = {World journal of otorhinolaryngology - head and neck surgery},
volume = {11},
number = {4},
pages = {541-547},
pmid = {41477139},
issn = {2589-1081},
abstract = {This overview serves as a foundational resource for clinicians caring for neurologically complex patients presenting with voice complaints. Neurogenic voice disorders are diverse in their clinical presentations and therapeutic approaches. A thorough medical history, including family history, detailed laryngeal examination, voice assessments, and neuroimaging, are imperative, as well as a multidisciplinary, collaborative approach with neurologists, speech language pathologists, and patient caregivers. Disorders such as amyotrophic lateral sclerosis (ALS), cerebrovascular accidents (strokes), Huntington's disease, myasthenia gravis (MG), Parkinson's disease (PD), and voice tremor should be understood by otolaryngologists. Each condition presents unique challenges and requires tailored treatment strategies ranging from supportive therapies and pharmacological interventions to surgery. Voice management techniques, including the use of botulinum toxin for hyperkinetic disorders and deep brain stimulation for refractory cases, are highlighted as promising interventions.},
}

@article {pmid41476438,
year = {2025},
author = {Oza, R},
title = {Physical Activity as an Intervention for Frailty Syndrome: A Narrative Review.},
journal = {Cureus},
volume = {17},
number = {12},
pages = {e100293},
pmid = {41476438},
issn = {2168-8184},
abstract = {Frailty is a geriatric syndrome characterised by a decline in functional reserves as the body ages, resulting in increased disability, comorbidity, and mortality. With trends towards ageing populations, frailty syndrome becomes more clinically relevant, highlighting the importance of appropriately preventing and managing the characteristics of frailty syndrome. Risk factor modification is recommended to delay or prevent the onset of frailty, including physical activity alongside other modifiable behaviours such as diet. Ageing is associated with chronic low-grade inflammation, resulting in reduced muscle protein synthesis and increased resistance to insulin, which both contribute to sarcopenia. Sarcopenia underpins key characteristics of frailty, including weakness and slow speed. Physical activity stimulates anabolic pathways and improves insulin resistance, reducing sarcopenia. Moreover, aerobic exercise is responsible for increasing the VO2 peak, whilst resistance exercise improves muscle strength, both of which are known to decrease in frail elders. This narrative review primarily explored the effectiveness of physical activity in reducing the risk of the onset of frailty syndrome through a narrative review of the relevant literature concerning this subject. A secondary focus of this narrative review is to compare the success of alternative interventions for preventing frailty, relative to physical activity. Physical activity interventions have been shown to improve components of frailty scoring and selected biological markers of frailty, with evidence suggesting physical activity is an effective single-domain intervention for frailty; however, multidomain approaches may result in a greater overall improvement in frailty prevention. Further research is required to identify the types of exercise that modify specific aspects of Fried et al.'s frailty criteria (FFC), as well as what interventions can be used alongside physical activity, to holistically treat all characteristics of frailty syndrome.},
}

@article {pmid37827930,
year = {2023},
author = {Cassereau, J and Bernard, E and Genestet, S and Chebbah, M and Le Clanche, S and Verschueren, A and Couratier, P},
title = {Management of amyotrophic lateral sclerosis in clinical practice: Results of the expert consensus using the Delphi methodology.},
journal = {Revue neurologique},
volume = {179},
number = {10},
pages = {1134-1144},
doi = {10.1016/j.neurol.2023.07.011},
pmid = {37827930},
issn = {0035-3787},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnosis/therapy ; Riluzole/therapeutic use ; Motor Neurons ; Diagnosis, Differential ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a rare disease characterized by a progressive and irreversible degeneration of upper and lower motor neurons leading to death. In France, limited data exist describing the criteria used in clinical practice for diagnosis and follow-up, and how novel therapies may fit in. The objective of this Delphi panel was to obtain an overview of current French practices in ALS diagnosis, management, and follow-up by determining the scales and criteria used in clinical practice outside of clinical trials, as well as the place of a future treatment like AMX0035, acting on endoplasmic reticulum (ER) stress and mitochondrial dysfunction, in the current therapeutic strategies. A questionnaire was administered to 24 ALS healthcare providers practicing in ALS centers in France. Two rounds of remote voting were organized, before proposition of final consensus statements. Consensus was considered reached when at least 66% of the voters agreed. Consensus were obtained to define the new Gold Coast criteria as the ones used in clinical practice to establish the diagnosis of ALS, thus replacing the revised El Escorial criteria, considered too complex and now mainly used to characterize the patient populations to be included in clinical trials. The clinical factors considered to establish ALS diagnosis are mainly the demonstration of progression of the motor deficit and elimination of differential diagnoses. The ALSFRS-R scale is used in daily clinical practice to assess patient's functional impairment in terms of number of points lost, with the bulbar, respiratory, and fine motor subscores being the most important to evaluate independently. A critical medical need was identified regarding the provision of new therapeutic alternatives in ALS. The panel members would support the earliest management of patients. In this landscape, based on data from a very encouraging phase II (Centaur trial), AMX0035 represents a new tool of choice in current treatment strategies for all patients for whom experts are confident in the diagnosis of ALS, in combination with riluzole. These results will need to be confirmed by the ongoing phase III trial (Phoenix trial).},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnosis/therapy
Riluzole/therapeutic use
Motor Neurons
Diagnosis, Differential

@article {pmid41471389,
year = {2025},
author = {Gershoni Emek, N and Tan, AM and Geva, M and Fekete, A and Abate, C and Hayden, MR},
title = {Pridopidine, a Potent and Selective Therapeutic Sigma-1 Receptor (S1R) Agonist for Treating Neurodegenerative Diseases.},
journal = {Pharmaceuticals (Basel, Switzerland)},
volume = {18},
number = {12},
pages = {},
pmid = {41471389},
issn = {1424-8247},
abstract = {Pridopidine is a highly selective sigma-1 receptor (S1R) agonist in clinical development for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). The S1R is a ubiquitous chaperone protein enriched in the central nervous system and regulates multiple pathways critical for neuronal cell function and survival, including cellular stress responses, mitochondrial function, calcium signaling, protein folding, and autophagy. S1R has a crucial role in the ER mitochondria-associated membrane (MAM), whose dysfunction is implicated in several neurodegenerative diseases. By activating the S1R, pridopidine corrects multiple cellular pathways necessary to the cell's ability to respond to stress, which are disrupted in neurodegenerative diseases. Pridopidine restores MAM integrity; rescues Ca[2+] homeostasis and autophagy; mitigates ER stress, mitochondrial dysfunction, and oxidative damage; and enhances brain-derived neurotrophic factor (BDNF) axonal transport and secretion, synaptic plasticity, and dendritic spine density. Pridopidine demonstrates neuroprotective effects in in vivo models of neurodegenerative diseases (NDDs). Importantly, pridopidine demonstrates the biphasic dose response characteristic of S1R agonists. In clinical trials in HD and ALS, pridopidine has shown benefits across multiple endpoints. Pridopidine's mechanism of action, modulating core cellular survival pathways, positions it as a promising candidate for disease modification for different nervous system disorders. Its broad therapeutic potential includes neurodevelopmental disorders, and rare diseases including Wolfram syndrome, Rett syndrome, and Vanishing White Matter Disease. Here, we review the experimental data demonstrating pridopidine's S1R-mediated neuroprotective effects. These findings underscore the therapeutic relevance of S1R activation and support further investigation of pridopidine for the treatment of different neurodegenerative diseases including ALS and HD.},
}

@article {pmid41468784,
year = {2025},
author = {Palanivel, V and Salkar, A and Shenoy, A and Eva, TA and Perera, R and Chitranshi, N and Gupta, V and You, Y and Mirzaei, M and Graham, SL and Gupta, V and Basavarajappa, D},
title = {Neuropeptide Y at the crossroads of neurodegeneration: Mechanistic insights and emerging therapeutic strategies.},
journal = {Neuropeptides},
volume = {115},
number = {},
pages = {102583},
doi = {10.1016/j.npep.2025.102583},
pmid = {41468784},
issn = {1532-2785},
abstract = {Neuropeptide Y (NPY), a widely distributed and highly conserved neuropeptide, plays a central role in the regulation of diverse physiological processes, including stress responses, energy homeostasis, vascular tone, and immune modulation, via activation of its receptor subtypes. Beyond its physiological roles, the dysregulation of NPY expression has been documented in several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Machado-Joseph disease, and retinal disorders such as diabetic retinopathy and glaucoma. These alterations in NPY levels and receptor activity highlight its potential not only as a biomarker for disease progression but also as a promising therapeutic target. Previous evidence revealed that NPY exerts neuroprotection by alleviating excitotoxicity, oxidative stress, mitochondrial dysfunction, and neuroinflammation while concurrently facilitating neurogenesis, synaptic plasticity, and cellular resilience. NPY activates receptor-mediated intracellular signaling cascades like PI3K/Akt, MAPK/ERK, and p38K, that control cellular survival, proteostasis, and inflammation and thereby influence disease trajectories. Understanding NPY operation with these mechanisms can unveil new avenues for targeted therapy. Current insights into the complex roles of NPY in neurodegeneration are discussed in this review, and their implications in diagnostic and treatment strategies are addressed.},
}

@article {pmid41465514,
year = {2025},
author = {Riku, Y and Brion, JP and Ando, K and Uchihara, T and Iwasaki, Y},
title = {The Determinant of Tau Spreading in Alzheimer's Disease: Dependent on Senile Plaque, Neural Circuits, or Spatial Proximity?.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
pmid = {41465514},
issn = {1422-0067},
support = {JPMH23FC1008//MHLW Research on rare and intractable diseases Program/ ; 23K06935, 25K22597, and 25K10781//JSPS-KAKENHI/ ; },
mesh = {Humans ; *Alzheimer Disease/metabolism/pathology ; *tau Proteins/metabolism ; *Plaque, Amyloid/metabolism/pathology ; Animals ; Neurofibrillary Tangles/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Brain/metabolism/pathology ; },
abstract = {Alzheimer's disease (AD) is neuropathologically characterized by tau-immunopositive neurofibrillary tangles (NFTs) and amyloid-β (Aβ)-immunopositive senile plaques. According to the widely accepted amyloid cascade hypothesis, Aβ pathology represents the upstream event in AD pathophysiology and induces tau aggregation. However, numerous studies have suggested that tau aggregates correlate more closely with neuronal loss and regional brain atrophy than with Aβ depositions. Tau aggregation in AD demonstrates a hierarchical spreading pattern beginning in the transentorhinal cortex, but the mechanisms underlying this spreading manner of lesions remain to be elucidated. This review aims to address current controversies regarding tau pathology in AD from the perspectives of both the 'amyloid cascade' and 'tauopathy' hypotheses. From the 'amyloid cascade' viewpoint, Aβ deposition prominently involves distal axon and axon terminals, and in some regions, there are anatomical correspondences between axonal Aβ pathology and cytoplasmic tau aggregations (e.g., a close relationship between senile plaques in the molecular layer of the hippocampal dentate gyrus and NFTs in the transentorhinal cortex). Nevertheless, this model cannot explain the whole body of hierarchical spreading of tau aggregation because notable spaciotemporal discrepancies also exist in many regions. From the 'tauopathy' perspective, the distribution of tau aggregates in AD involves key nodes within the memory circuits. Also, experimental studies have suggested that patient-derived tau exhibits seeding and neuron-to-neuron propagation properties. Interestingly, tau aggregation in AD appears to spread laterally in a proximity-dependent, cortico-cortical fashion rather than along long-range memory circuits. This contrasts with the system-selective, poly-nodal degenerations seen in four-repeat tauopathies, amyotrophic lateral sclerosis, or spinocerebellar degenerations. Moreover, the proportions of three-repeat and four-repeat isoforms shift during the maturation of NFTs in AD. Overall, spreading patterns of tau-pathology in AD cannot be fully explained by Aβ pathology and also differ from the system degeneration seen in other tauopathies.},
}

Humans
*Alzheimer Disease/metabolism/pathology
*tau Proteins/metabolism
*Plaque, Amyloid/metabolism/pathology
Animals
Neurofibrillary Tangles/metabolism/pathology
Amyloid beta-Peptides/metabolism
Brain/metabolism/pathology

@article {pmid41065069,
year = {2026},
author = {Shan, Y and Jing, W and Zhang, H and Liu, Y and Wei, S and Wu, F and Pan, W},
title = {Amyotrophic lateral sclerosis rehabilitation management and non-pharmacological symptomatic treatment: A review.},
journal = {International journal of clinical pharmacology and therapeutics},
volume = {64},
number = {1},
pages = {38-46},
doi = {10.5414/CP204744},
pmid = {41065069},
issn = {0946-1965},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology/diagnosis/psychology/therapy ; Quality of Life ; Treatment Outcome ; },
abstract = {Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that lacks effective treatment options for the prevention of progression. Relieving swallowing difficulties, reducing breathing difficulties, and alleviating muscle spasms are essential to improving the quality of life in patients with ALS. Many symptoms can be treated clinically with medication; however, the evidence level of related research is relatively low. Rehabilitation management can aid in improving various functional impairments and enhancing quality of life. This review introduces and describes the relevant evaluations of rehabilitation and nonpharmacological symptomatic treatment methods for functional disorders from the perspectives of motor and nonmotor symptoms. This review may promote the popularization of ALS rehabilitation management and provide an additional reference for ALS treatment.},
}

Humans
*Amyotrophic Lateral Sclerosis/rehabilitation/physiopathology/diagnosis/psychology/therapy
Quality of Life
Treatment Outcome

@article {pmid41465278,
year = {2025},
author = {Marzetti, E and Di Lorenzo, R and Calvani, R and Coelho-Júnior, HJ and Landi, F and Pesce, V and Picca, A},
title = {Linking Cell Architecture to Mitochondrial Signaling in Neurodegeneration: The Role of Intermediate Filaments.},
journal = {International journal of molecular sciences},
volume = {26},
number = {24},
pages = {},
pmid = {41465278},
issn = {1422-0067},
support = {D1.2024//Università Cattolica del Sacro Cuore/ ; D1.2025//Università Cattolica del Sacro Cuore/ ; Ricerca Corrente 2025//Italian Ministry of Health/ ; DM 1557 11.10.2022//European Commission/ ; 2022YNENP3//Italian Ministry of University and Research/ ; },
mesh = {Humans ; *Mitochondria/metabolism/pathology ; Animals ; *Neurodegenerative Diseases/metabolism/pathology ; *Intermediate Filaments/metabolism/pathology ; *Signal Transduction ; Neurons/metabolism/pathology ; },
abstract = {Mitochondrial dysfunction is a pivotal contributor to neurodegeneration. Neurons heavily rely on mitochondrial oxidative metabolism and therefore need highly efficient quality control mechanisms, including proteostasis, mitochondrial biogenesis, fusion-fission dynamics, and mitophagy, to sustain bioenergetics and synaptic function. With aging, deterioration of mitochondrial quality control pathways leads to impaired oxidative phosphorylation, excessive reactive oxygen species generation, calcium imbalance, and defective clearance of damaged organelles, ultimately compromising neuronal viability. Pathological protein aggregates, such as α-synuclein in Parkinson's disease, β-amyloid and tau in Alzheimer's disease, and misfolded superoxide dismutase 1 and transactive response DNA-binding protein 43 in amyotrophic lateral sclerosis, further aggravate mitochondrial stress, establishing self-perpetuating cycles of neurotoxicity. Such mitochondrial defects underscore mitochondria as a convergent pathogenic hub and a promising therapeutic target for neuroprotection. Intermediate filaments (IFs), traditionally viewed as passive structural elements, have recently gained attention for their roles in cytoplasmic organization, mitochondrial positioning, and energy regulation. Emerging evidence indicates that IF-mitochondria interactions critically influence organelle morphology and function in neurons. This review highlights the multifaceted involvement of mitochondrial dysfunction and IF dynamics in neurodegeneration, emphasizing their potential as targets for novel therapeutic strategies.},
}

Humans
*Mitochondria/metabolism/pathology
Animals
*Neurodegenerative Diseases/metabolism/pathology
*Intermediate Filaments/metabolism/pathology
*Signal Transduction
Neurons/metabolism/pathology

@article {pmid41464650,
year = {2025},
author = {Sonaglioni, A and Nicolosi, GL and Lombardo, M and Baravelli, M and Muti, P},
title = {Comparative Meta-Analysis of Left Ventricular Mechanics in Takotsubo Syndrome and Anterior STEMI Due to Left Anterior Descending Artery Occlusion.},
journal = {Journal of clinical medicine},
volume = {14},
number = {24},
pages = {},
pmid = {41464650},
issn = {2077-0383},
support = {N/A//Ministero della Salute/ ; },
abstract = {Background: Takotsubo syndrome (TTS) often mimics anterior ST-elevation myocardial infarction (STEMI) caused by left anterior descending (LAD) occlusion, yet the two entities differ fundamentally in pathophysiology and mechanical behavior. Two-dimensional speckle-tracking echocardiography (2D-STE) enables detailed assessment of left ventricular (LV) deformation beyond conventional ejection fraction (LVEF). This meta-analysis compared global and regional LV strain patterns in TTS versus LAD-related anterior STEMI during the acute phase. Methods: A systematic search of PubMed, Embase, and Scopus through October 2025 identified observational case-control studies directly comparing TTS and angiographically confirmed anterior STEMI, with LV mechanics assessed by 2D-STE. Random-effects models were used to pool standardized mean differences (SMDs) for LVEF; global longitudinal strain (GLS); apical, mid-ventricular, and basal longitudinal strain (ALS, MLS, BLS); and global radial strain (GRS). Heterogeneity (I[2]), publication bias (funnel plots, Egger's test), meta-regression, and leave-one-out sensitivity analyses were performed. Results: Six studies comprising 221 TTS and 290 anterior STEMI patients met the inclusion criteria. TTS patients were older, predominantly female, and had fewer metabolic risk factors, while LV size was comparable. LVEF was significantly lower in TTS (SMD -1.149; 95% CI -2.20 to -0.10; p = 0.032), with stable findings across sensitivity analyses and no evidence of publication bias. GLS, ALS, MLS, and BLS showed only a non-significant trend toward greater impairment in TTS, and these comparisons were limited by marked inter-study heterogeneity. In contrast, GRS was significantly and consistently more reduced in TTS (SMD -1.284; 95% CI -1.59 to -0.98; p < 0.001), indicating more profound global radial dysfunction. Meta-regression showed no significant influence of demographic factors or vendor-specific software on LVEF or GLS differences. Conclusions: Compared with LAD-related anterior STEMI, TTS is associated with more severely depressed LVEF and markedly impaired radial strain, while longitudinal strain differences remain inconclusive and suggest only a potential trend toward greater dysfunction, reflecting the limited and heterogeneous evidence. These findings are consistent with diffuse, stress-induced myocardial stunning in TTS and suggest that 2D-STE may aid differentiation between stress cardiomyopathy and ischemic infarction in the acute setting, although longitudinal strain parameters should be interpreted cautiously and regarded as hypothesis-generating.},
}

@article {pmid41464612,
year = {2025},
author = {Klumb, S and Haley, L and Hathaway, C and Irby, J and Cheng, J and Rumley, J},
title = {Degenerative Cervical Myelopathy Diagnosis and Its Differentiation from Neurological Mimics, MS and ALS: A Literature Review.},
journal = {Journal of clinical medicine},
volume = {14},
number = {24},
pages = {},
doi = {10.3390/jcm14248711},
pmid = {41464612},
issn = {2077-0383},
abstract = {Multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and degenerative cervical myelopathy (DCM) share features that may confound diagnosis. DCM is caused by degenerative changes in the cervical spine leading to spinal cord compression and injury, resulting in significant disability. Misdiagnosis of DCM for a similar neurological condition can lead to further spinal cord damage from delayed surgical treatment. Here we review the diagnostic criteria, clinical signs and symptoms, and imaging typical for DCM, and two of its clinical mimics, MS and ALS. Shared motor symptoms of all three conditions can make diagnosis difficult, especially early in disease course. Noteworthy differences include neck and shoulder pain in DCM, visual disturbances in MS, and bulbar symptoms and the absence of sensory deficits in ALS. In DCM and MS, MRI is used to support the diagnosis, with specific findings on MRI that differentiate DCM versus MS. In ALS, MRI is used to rule out differential diagnoses. Applying the diagnostic criteria for MS and ALS, as well as understanding the typical presentation and MRI findings of DCM, is crucial. Through discussion of these conditions, this review aims to help limit misdiagnosis rates, allowing for early management, which can improve long-term patient outcomes.},
}

@article {pmid41463333,
year = {2025},
author = {Tendero-Lopez, D and Dominguez, M and Aguilar-Aragon, M},
title = {Modelling Neural Disorders with the D. melanogaster Larval Peripheral and Adult Dopaminergic Systems.},
journal = {Biomolecules},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/biom15121677},
pmid = {41463333},
issn = {2218-273X},
mesh = {Animals ; *Drosophila melanogaster/metabolism ; Larva/metabolism ; *Disease Models, Animal ; Humans ; *Dopamine/metabolism ; *Dopaminergic Neurons/metabolism/pathology ; *Nervous System Diseases/metabolism ; Parkinson Disease/metabolism ; },
abstract = {The increasing prevalence of neurological disorders highlights the need for disease animal models to elucidate the underlying biomolecular and cellular mechanisms of disease and to facilitate studies aimed at developing effective treatments. The fruit fly Drosophila melanogaster, at both larval and adult stages, can serve as an effective model for different human-relevant neurological diseases. Larvae are particularly suited for studying peripheral nervous system disorders, such as Charcot-Marie-Tooth and amyotrophic lateral sclerosis, while adults enable investigations of higher-order cognitive functions and age-related conditions, including Parkinson's disease and depression-like behaviours. Combining larval and adult models offers a complementary framework to dissect the biomolecular pathways of neurological disorders and accelerate preclinical research.},
}

Animals
*Drosophila melanogaster/metabolism
Larva/metabolism
*Disease Models, Animal
Humans
*Dopamine/metabolism
*Dopaminergic Neurons/metabolism/pathology
*Nervous System Diseases/metabolism
Parkinson Disease/metabolism

@article {pmid41462890,
year = {2025},
author = {Fajkić, A and Belančić, A and Lam, YW and Rački, V and Pilipović, K and Janković, T and Mežnarić, S and Mršić-Pelčić, J and Vitezić, D},
title = {Novel Translational Concept: Axon-to-Muscle Exosomal Signaling as an Emerging Therapeutic Target in Spinal Muscular Atrophy.},
journal = {Biomedicines},
volume = {13},
number = {12},
pages = {},
doi = {10.3390/biomedicines13122876},
pmid = {41462890},
issn = {2227-9059},
abstract = {Spinal muscular atrophy (SMA) has transitioned from a uniformly fatal disease to a treatable condition, yet incomplete neuromuscular recovery underscores the limits of current SMN-restorative therapies. Emerging data implicate disrupted axon-to-muscle exosomal signaling as an important, overlooked driver of residual dysfunction. Exosomes, nanovesicles mediating bidirectional neuronal-muscular communication, carry synaptic organizers, trophic factors, and microRNAs essential for neuromuscular junction integrity. SMN deficiency alters exosomal biogenesis and cargo, leading to loss of agrin-MuSK signaling, impaired β-actin transport, and muscle atrophy. Comparative insights from amyotrophic lateral sclerosis and muscular dystrophy reveal that stem-cell-derived or engineered exosomes restore synaptic stability, enhance regeneration, and cross biological barriers safely. Thus, we speculate herein on a translational model integrating exosome-based therapies with existing genetic interventions to achieve durable, systems-level recovery in SMA. Exosomal profiling may further yield minimally invasive biomarkers for disease monitoring and treatment optimization, establishing vesicle-mediated communication as a novel therapeutic axis in neuromuscular medicine.},
}

@article {pmid41459056,
year = {2025},
author = {Auclair-Ouellet, N and Kassem, O and Bronner, S and Oula, ML and Binda, S},
title = {Leveraging microbiome-based interventions to improve the management of neurodegenerative diseases: evidence for effects along the microbiota-gut-brain axis.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1699884},
pmid = {41459056},
issn = {2296-861X},
abstract = {The microbiota-gut-brain axis (MGBA) has recently emerged as a useful model for the understanding of the onset and progression of neurodegenerative diseases (NDDs). Microbiome-based interventions using biotic supplements (probiotics, prebiotics, synbiotics, postbiotics) can modulate the MGBA and constitute relevant solutions to help reduce the risk of neurological changes associated with NDDs and manage symptoms. This narrative review provides a summary of the functioning of the MGBA and of its interactions with disease processes involved in the onset and progression of NDDs. Microbiome-based interventions and their mechanisms of action are reviewed, and important considerations for the design of interventions are discussed. Next, preclinical and clinical studies on the potential of microbiome-based interventions in Alzheimer's disease (AD), Parkinson's disease (PD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are reviewed. Evidence related to biomarkers of pathology (e.g., beta-amyloid or alpha-synuclein protein depositions), neuroinflammation, and metabolic activity is summarized, along with emerging evidence for the improvement of clinical symptoms and disease trajectories. Overall, preclinical studies show that microbiome-based supplements have significant positive effects on mechanisms and pathways involved in the pathophysiology of NDDs. Clinical studies show that these interventions provide important benefits both in terms of biomarkers and clinical symptoms. However, evidence is limited in some key clinical areas, such as mental wellbeing in AD and cognition in PD, and for the management of clinical symptoms in ALS and HD overall. Gaps in knowledge and open questions as well as perspectives for future research are discussed.},
}

@article {pmid41458376,
year = {2025},
author = {Qian, G and Ding, L and Tan, C and Wang, L and Long, C},
title = {Mucosal immune response modulated by secreted and membrane-bound hydrolases of Candida albicans in vulvovaginal candidiasis.},
journal = {Frontiers in fungal biology},
volume = {6},
number = {},
pages = {1692795},
pmid = {41458376},
issn = {2673-6128},
abstract = {Vulvovaginal candidiasis (VVC) affects the physical and mental health of millions of women worldwide. The leading cause of VVC, Candida albicans, can induce a strong mucosal inflammatory reaction during the VVC infection, where secreted and membrane-bound adhesion and hydrolases seem to be the key virulent factors to promote the mucosal antifungal immunity and immunopathology. Several hydrolases, such as Saps, Als, candidalysin, lipases, and phospholipases, have been identified in vaginal secretions isolated from VVC patients; however, the immune impacts of some hydrolases have not been well documented. In this review, we focus on the literature that addresses the immunopathogenic roles of the Als adhesin family or proteinase, such as Sap and candidalysin, in VVC. Our goal is to expand our knowledge of VVC pathogenesis in order to provide new strategies for VVC treatment.},
}