@article {pmid41448826,
year = {2025},
author = {Chenette, DM and McCaughey, S and Reinecker, R and Milliard, CF and Chow, TW and Dacks, PA},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e107543},
doi = {10.1002/alz70858_107543},
pmid = {41448826},
issn = {1552-5279},
mesh = {Humans ; *Frontotemporal Dementia/genetics/psychology/diagnosis ; Male ; Female ; Middle Aged ; Genetic Testing/statistics & numerical data ; Aged ; C9orf72 Protein/genetics ; Canada ; tau Proteins/genetics ; United Kingdom ; },
abstract = {BACKGROUND: Frontotemporal dementia (FTD) is a heterogenous disorder characterized by early age of onset and changes in behavior or language. It is estimated that approximately 20% of patients have an autosomal dominant presentation. Mutations in the GRN, MAPT, or C9orf72 genes account for the majority of genetic FTD.

METHOD: The FTD Insights Survey was developed and executed by the Association for Frontotemporal Degeneration (AFTD) and the FTD Disorders Registry. This dataset contains 1,800 responses (US, UK, Canada) and is available to researchers. Responses to "Have you been tested to see if you carry a specific gene for FTD" were analyzed. Data was assessed for 1) FTD patients who selected "I am diagnosed with FTD" and 2) relatives who selected "I have a close biological relative with FTD" and didn't select "I am diagnosed with FTD".

RESULT: Twenty-three percent (23.3%, n = 51) of 219 patients received genetic testing. Individuals diagnosed with FTD with ALS (n = 9) reported the highest rates of genetic testing (88.9%, n = 8). A greater percentage of patients who completed genetic testing reported having at least one biological relative diagnosed with FTD compared to those who did not receive genetic testing (44.2% vs.12% respectively). Twelve percent (12.4%, n = 61) of 492 biological relatives received genetic testing. Relatives of individuals diagnosed with FTD with ALS (n = 39) reported the highest rates of genetic testing (25.6%, n = 10). Of relatives who responded yes (n = 95) to the question, "Does your family carry a gene for FTD", 49.5% (n = 47) received genetic testing.

CONCLUSION: Less than a quarter of FTD patients received genetic testing despite genetic forms comprising a notable percentage of all FTD cases. Highest rates were reported for individuals diagnosed with FTD with ALS, and rates were higher with known family history. Low rates of genetic testing may exacerbate challenges facing families impacted by FTD such as assessing familial risk of developing FTD and determining eligibility for investigational drugs in development for genetic forms of FTD. Additional research is needed to better understand the accessibility of genetic testing and counseling. Taken together, these findings highlight the need to further raise awareness of genetic FTD with healthcare providers, patients, and biological relatives.},
}

Humans
*Frontotemporal Dementia/genetics/psychology/diagnosis
Male
Female
Middle Aged
Genetic Testing/statistics & numerical data
Aged
C9orf72 Protein/genetics
Canada
tau Proteins/genetics
United Kingdom

@article {pmid41448825,
year = {2025},
author = {Shigematsu, K and Komori, N and Yamagishi, H},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e102343},
doi = {10.1002/alz70859_102343},
pmid = {41448825},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; Prospective Studies ; *Hand Strength/physiology ; Aged, 80 and over ; *Mesenchymal Stem Cell Transplantation/methods ; *Drug Development ; Parkinson Disease/therapy ; Alzheimer Disease/therapy ; *Cholinesterases/blood ; Amyotrophic Lateral Sclerosis/therapy ; Supranuclear Palsy, Progressive/therapy ; },
abstract = {BACKGROUND: Immediate improvements in subjective and objective symptoms can sometimes be observed following the administration of adipose-derived mesenchymal stem cells (ADSCs). This rapid improvement was surprising, as we had assumed that regenerative medicine would require several days or more to show effects. Therefore, we measured grip strength and cholinesterase values before and after treatment. ADSCs have gained attention in regenerative medicine due to their multipotent nature and potential therapeutic effects.

METHOD: We conducted a prospective observational study on 21 patients who received ADSC treatment. Informed consent was obtained from all participants. Serum cholinesterase levels and grip strength were measured immediately before and after ADSC administration. Grip strength was measured on the non-infusion side, maintaining the same posture for both pre- and post-treatment measurements.

RESULT: The study included patients with various conditions: Parkinson's disease (PD, n=9), Amyotrophic Lateral Sclerosis (ALS, n=4), Alzheimer's disease (n=2), Chronic Obstructive Pulmonary Disease (COPD, n=4), and Progressive Supranuclear Palsy (PSP, n=1). The mean age was 67.5 years (range: 53-81), with 14 males and 7 females. A paired samples t-test revealed a statistically significant decrease in cholinesterase levels after ADSC administration (mean difference: -21.905 U/L, p < 0.001). Although not statistically significant, there was a trend towards improvement in grip strength (mean difference: 1.0619 kg, p = 0.119).

CONCLUSION: Our findings demonstrate a significant immediate decrease in serum cholinesterase levels following ADSC administration. The observed decrease in cholinesterase levels might indicate an enhancement of acetylcholine activity, potentially explaining the trend towards improved grip strength. The immediate effects observed in this study are intriguing, as they suggest that ADSCs may have rapid neuromodulatory effects beyond their known regenerative properties. Previous studies have shown that ADSCs can differentiate into various cell types, including neural cells, and secrete neurotrophic factors. The trend towards improved grip strength, although not statistically significant, is noteworthy. Grip strength is a reliable indicator of overall muscle strength and has been associated with various health outcomes. The potential improvement in grip strength immediately after ADSC administration warrants further investigation, as it could have implications for patients with neuromuscular disorders.},
}

Humans
Male
Female
Aged
Middle Aged
Prospective Studies
*Hand Strength/physiology
Aged, 80 and over
*Mesenchymal Stem Cell Transplantation/methods
*Drug Development
Parkinson Disease/therapy
Alzheimer Disease/therapy
*Cholinesterases/blood
Amyotrophic Lateral Sclerosis/therapy
Supranuclear Palsy, Progressive/therapy

@article {pmid41447225,
year = {2025},
author = {Shenouda, M and Robertson, J},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e099984},
doi = {10.1002/alz70859_099984},
pmid = {41447225},
issn = {1552-5279},
mesh = {Animals ; Mice ; *Drug Development ; *DNA-Binding Proteins/metabolism/drug effects ; Humans ; Neurons/drug effects/metabolism ; Disease Models, Animal ; Amyotrophic Lateral Sclerosis ; Frontotemporal Dementia ; },
abstract = {BACKGROUND: Nuclear depletion and neuronal cytoplasmic aggregation of the transactive response DNA-binding protein 43 (TDP-43) is observed in up to 95% amyotrophic lateral sclerosis (ALS) cases, 70% of Alzheimer's Disease (AD) cases, and 50% of frontotemporal dementia (FTD) cases. The cytoplasmic aggregation of TDP-43 has been correlated with inducing neuronal loss. As such, preventing TDP-43 aggregation could have therapeutic potential for ALS/FTD and associated diseases. It has been shown that aggregation of TDP-43 can be attenuated by chaperone proteins. Herein, we have identificatied and validated a new small molecule 'JRMS' as potent binder of {IP-protein}
which upregulates its non-canonical chaperone function to prevent/reverse TDP-43 aggregation.

METHOD: We developed high throughput models of TDP-43 aggregation by expressing the highly aggregation prone C-terminal fragment TDP-25 in cells through transient expression, mouse primary cortical neurons through lentiviral expression, and organotypic slices and mouse model through AAV9 expression.

RESULT: Acute and chronic treatment of JRMS reduced TDP-25 aggregation in a dose-dependent manner by ∼75% in cells. This reduction of TDP-25 aggregates was validated to be dependent on {IP-protein},
and that JRMS elevates activity of the target {IP-protein}.
Similarly, in mouse primary cortical neurons transduced with TDP-25 lentivirus, JRMS reduced TDP-25 aggregates by ∼50% reduction. We screened JRMS on organotypic slices from 10 day-old mice inoculated with AAV9-TDP-25. Over 7-days, DMSO treated slices showed ∼60% increase, while JRMS treatment showed a ∼20% reduction in number of TDP-25 aggregates observed prior to treatment. Finally, two weeks treatments of AAV9-TDP-25 expressing mice at 6 weeks of age with JRMS exhibited ∼30% reduction in number of aggregates compared to DMSO control.

CONCLUSION: We have validated JRMS as a preclinical therapeutic candidate for the treatment of TDP-43 proteinopathy, with additional preliminary evidence for Tauopathies as well. We are currently working on building a Target Product Profile (TPP) with the goal of providing a drug(s) for clinical testing.},
}

Animals
Mice
*Drug Development
*DNA-Binding Proteins/metabolism/drug effects
Humans
Neurons/drug effects/metabolism
Disease Models, Animal
Amyotrophic Lateral Sclerosis
Frontotemporal Dementia

@article {pmid41447084,
year = {2025},
author = {Fernandez, PEL and de Araujo, CF and Nascimento, RB and Dos Santos Bandeira Filho, M and Gomez, GD and Andrade, AC and de Medeiros, S and Marin, C and Bertolucci, PHF},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e101641},
doi = {10.1002/alz70857_101641},
pmid = {41447084},
issn = {1552-5279},
mesh = {Humans ; *Aphasia, Primary Progressive/genetics/pathology/diagnostic imaging ; Diffusion Tensor Imaging ; *Alzheimer Disease/genetics/pathology ; Female ; Aged ; White Matter/pathology/diagnostic imaging ; *Brain/pathology/diagnostic imaging ; Neuropsychological Tests ; Mutation/genetics ; Magnetic Resonance Imaging ; },
abstract = {BACKGROUND: Logopenic primary progressive aphasia (lvPPA) is an atypical language variant of Alzheimer's disease (AD). Non-fluent / agrammatic (nfvPPA) is related to frontotemporal lobar degeneration (FTLD) but is rarely found in AD pathology. The annexin A11 (ANXA11) gene mutation is usually associated with amyotrophic lateral sclerosis / FTLD, but recently, it has been reported in the semantic variant (svPPA). Diffusion tensor tractography (DTI) can be used in PPA to localize white matter (WM) tract changes in the inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), and uncinate fasciculus (UF). The nfaPPA WM pattern is seen in the left SLF; sv-PPA reveals focal severe left/bilateral changes in UF and anterior ILF; the lvPPA pattern is more widespread in the left FLS, FLI, and UF, marked in the middle/posterior ILF.

METHOD: We report the clinical, genetic, and imaging features of a rare case of atypical AD with mixed PPA (lvPPA / nfvPPA) phenotype and ANXA11 gene mutation.

RESULT: A right-handed 65-year-old woman with 8 years of a language progressive impairment with difficulty in finding words for expression, repeating sentences, and naming objects, which affected her daily activities, scoring 14/30 on MMSE, 3 on semantic verbal fluency, and 10/20 on the Boston Naming Test. She also had memory problems, such as forgetting recent events/appointments and losing objects, and over the years, manifested effortful speech and agrammatism. She was illiterate, her medical family history was negative, and the neurological exam was unremarkable. The CSF indicated increased t-tau/p-tau levels and a decreased Aβ 42/40 ratio, suggesting an AD pathology. The genetic testing confirmed the ANXA11 gene mutation. MRI revealed a left-predominant atrophy in the frontoinsular and perisylvian/temporoparietal areas. The DTI showed widespread WM atrophy in the left SLF, ILF, and UF tracts, predominant in ILF and SLF, consistent with this mixed PPA phenotype.

CONCLUSION: This report can provide valuable insight into considering AD when confronted with atypical clinical presentations with mixed-PPA, as in this case. It also reinforces the clinical variability of ANXA11 gene mutations and highlights the importance of using DTI for detecting WM matter-specific pattern changes in different PPA phenotypes.},
}

Humans
*Aphasia, Primary Progressive/genetics/pathology/diagnostic imaging
Diffusion Tensor Imaging
*Alzheimer Disease/genetics/pathology
Female
Aged
White Matter/pathology/diagnostic imaging
*Brain/pathology/diagnostic imaging
Neuropsychological Tests
Mutation/genetics
Magnetic Resonance Imaging

@article {pmid41447027,
year = {2025},
author = {Cashman, NR and Plotkin, SS and Napper, S and Gibbs, E and Zhao, B and Scruten, E and Coutts, J and Kaplan, J},
title = {Drug Development.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 5},
number = {},
pages = {e098670},
doi = {10.1002/alz70859_098670},
pmid = {41447027},
issn = {1552-5279},
mesh = {Humans ; *Drug Development/methods ; Animals ; *Neurodegenerative Diseases/drug therapy/immunology ; Amyloid beta-Peptides/immunology ; Epitopes/immunology ; Alzheimer Disease/drug therapy ; },
abstract = {BACKGROUND: Toxic misfolded proteins underlie the pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's disease (AD&PD), and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Generation of therapeutic antibodies selectively targeting only disease-misfolded isoforms, while sparing normal or irrelevant isoforms, has not yet been successfully achieved by conventional immunization strategies.

METHOD: ProMIS Neurosciences has developed a computational platform to identify conformational epitopes that are uniquely exposed on toxic misfolded proteins, which can then be used to generate misfolding-specific antibodies or vaccine formulations.

RESULT: Application of the ProMIS platform produced PMN310, a clinical-stage, humanized monoclonal antibody highly selective for Abeta oligomers without significant reactivity with Abeta monomers or fibrils, thereby avoiding target distraction by these more abundant species, and reducing the risk of brain edema and microhemorrhages associated with the targeting of vascular/parenchymal amyloid. Similarly, specific epitopes for alpha-synuclein toxic oligomers/soluble fibrils that drive synucleinopathies, and for pathogenic TDP-43 in ALS/FTD have been identified and lead candidate antibodies generated. The small size and precise conformation of these epitopes have been translated into vaccines, enabling the specific targeting of pathogenic molecular species in preclinical models.

CONCLUSION: ProMIS has circumvented the specificity limitations of conventional immunizations to enable selective passive and active immunotherapies for neurodegenerative diseases.},
}

Humans
*Drug Development/methods
Animals
*Neurodegenerative Diseases/drug therapy/immunology
Amyloid beta-Peptides/immunology
Epitopes/immunology
Alzheimer Disease/drug therapy

@article {pmid41446138,
year = {2025},
author = {Ozguney, B and Puterbaugh, RZ and Viswanathan, R and Shenoy, J and Mohanty, P and Mittal, J and Fawzi, NL},
title = {Site-specific methionine oxidation alters structure and phase separation of TDP-43 C-terminal domain.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.15.694486},
pmid = {41446138},
issn = {2692-8205},
abstract = {TAR DNA binding protein 43 (TDP-43), a key protein linked to ALS pathology, undergoes phase separation and forms functional assemblies via condensation within cells. The conserved region (CR) within its C-terminal domain (CTD) mediates self-assembly through helix-helix interactions, while the flanking intrinsically disordered regions (IDRs) contribute to phase separation through transient interactions involving aromatic and hydrophobic residues. The CTD contains ten methionine residues distributed equally between these regions, making it particularly susceptible to oxidative modifications. While methionine oxidation is known to impair phase separation, neither the precise mechanism nor the specific contribution of methionines in the CR compared to the IDRs has been determined. Here, we combine NMR spectroscopy and all-atom molecular dynamics (MD) simulations to reveal if and how methionine oxidation in each region differentially affects CTD structure and phase separation. We demonstrate that all methionine residues are vulnerable to oxidation, leading to distinct regional effects: oxidation of CR methionines disrupts helical structure and directly impairs intermolecular helical association, while oxidation of IDR methionines disrupts long-range contacts. Hence, oxidation of methionines in both regions contributes to impaired phase separation, albeit through different mechanisms. These findings establish methionines as critical redox-sensitive modulators of TDP-43 phase behavior and provide molecular insights into how oxidative stress may contribute to TDP-43 dysregulation in neurodegenerative diseases.},
}

@article {pmid41445403,
year = {2025},
author = {Tokita, MJ and Kwan, JY and Oler, AJ and Danielian, LE and Crook, J and Porter, K and Walkiewicz, MA and Snyder, A},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e107327},
doi = {10.1002/alz70855_107327},
pmid = {41445403},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Middle Aged ; *Amyotrophic Lateral Sclerosis/genetics/epidemiology ; *tau Proteins/genetics ; *Membrane Proteins/genetics ; *Apolipoproteins E/genetics ; *Nerve Tissue Proteins/genetics ; Polymorphism, Single Nucleotide/genetics ; Aged ; *Genetic Predisposition to Disease/genetics ; Haplotypes ; Genotype ; Cohort Studies ; Risk Factors ; *Neurodegenerative Diseases/genetics ; },
abstract = {BACKGROUND: APOE and TMEM106B genotypes and MAPT haplotypes are established risk factors for neurodegenerative disease. There is conflicting evidence in the literature regarding the association of these risk factors with amyotrophic lateral sclerosis (ALS). We aimed to perform a systematic analysis of all three risk factors in an ALS cohort to understand their prevalence and to identify associations with disease outcomes in comparison to a broader neurodegenerative cohort.

METHOD: Participants evaluated at the NIH Neurodegenerative Disorders Clinic were included in the analysis. Whole genome sequencing was performed to a mean coverage of 30x. Genome data were queried for high penetrance disease-associated variants, and the following SNPs were genotyped for MAPT haplotyping (rs8070723) and to determine APOE (rs429358 and rs7412) and TMEM106B risk allele status (rs1990622).

RESULT: This preliminary analysis included 34 study participants of whom 53% were male; mean age was 64.1 years +/- 12.3. 21% of participants (n = 7) carried a diagnosis of ALS and the remaining 79% (n = 27) had non-ALS neurodegenerative disease (FTD, AD, DLB). The average CDR NACC FTLD-M sum of boxes was 5.8 +/- 6.5. One autosomal dominant pathogenic variant was identified in each group. Heterozygosity for APOE e4 was detected in 28.6% of ALS and 48.1% of non-ALS participants; 0 ALS and 11.1% of non-ALS participants were heterozygous for APOE e2. 71.4% of ALS and 81.5% of non-ALS participants harbored at least one TMEM106B risk allele. Similarly, 71.4% of ALS and 81.5% of non-ALS subjects were homozygous for the MAPT H1 haplotype.

CONCLUSION: While the differences between cohorts did not meet statistical significance (likely due to small sample sizes) the observed patterns are consistent with known associations of the risk loci. APOE e4 genetic risk was not enriched in the ALS cohort. TMEM106B-mediated risk and, unexpectedly given its association with tauopathies, MAPT H1 haplotype status were similar in both ALS and non-ALS cohorts. Future analyses will focus on increasing our sample size and defining the relationship of risk alleles to disease characteristics.},
}

Humans
Male
Female
Middle Aged
*Amyotrophic Lateral Sclerosis/genetics/epidemiology
*tau Proteins/genetics
*Membrane Proteins/genetics
*Apolipoproteins E/genetics
*Nerve Tissue Proteins/genetics
Polymorphism, Single Nucleotide/genetics
Aged
*Genetic Predisposition to Disease/genetics
Haplotypes
Genotype
Cohort Studies
Risk Factors
*Neurodegenerative Diseases/genetics

@article {pmid41445252,
year = {2025},
author = {Spyropoulos, D and Jenkins, DP and Carroll, SL},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106736},
doi = {10.1002/alz70855_106736},
pmid = {41445252},
issn = {1552-5279},
mesh = {Animals ; *Receptor, ErbB-4/genetics/metabolism ; Male ; *Amyotrophic Lateral Sclerosis/genetics/pathology ; Female ; Mice ; Mutation/genetics ; Disease Models, Animal ; Humans ; Mice, Transgenic ; *Frontotemporal Dementia/genetics ; Maze Learning/physiology ; },
abstract = {BACKGROUND: Frontotemporal dementia (FTD) involves progressive deterioration of behavior, executive function, personality/traits and is evident structurally as frontotemporal lobar degeneration (FTLD). FTLD with pathological TDP43 neural/glial inclusions (FTLD-TDP), often coexists with TDP43-positive amyotrophic lateral sclerosis (ALS). Several families have been identified that inherit autosomal dominant FTLD/ALS or ALS alone and mutations in the gene encoding the ERBB4 receptor tyrosine kinase (RTK). Although the neuropathology associated with ERBB4 mutations remains obscure, ERBB4 with p.R927Q or p.I712M mutations show reduced phosphorylation when stimulated with the ERBB4 ligand neuregulin-1β, suggesting that reduced ERBB4 activity causes FTLD/ALS or ALS.

METHOD: We generated mice carrying p.I712M (familial FTLD/ALS) or p.R927Q (familial ALS only) Erbb4 mutations. We performed initial studies of behavior (Barnes Maze), gait-mobility (Catwalk-XT) and body composition (DXA scans) on Erbb4 heterozygous and homozygous mutants and wild-type littermates.

RESULT: Barnes Maze Acquisition was performed on males (N = 4-5/genotype) after habituation and several days training. Heatmaps of grouped averages for acquisition day 5 show that ErbB4-R927Q mutants (homozygotes > heterozygotes) take longer finding the goal box, suggesting a gene dosage-dependent defect in spatial learning. CatWalk-XT was performed on Erbb4-R927Q mutant females (N = 4-6/genotype), with six complaint post-training walks/animal. Significantly lower mean intensities of the most intense paw prints occurred in the hindlimbs of mutants (Tukey's 2-way ANOVA). Multiple gene-dosage-dependent trends in altered gait metrics occurred, including footfall patterns, 2D/3D mean/max intensities, footfall sequence, print positions, standing and diagonal mean phase dispersions. DXA scans on Erbb4-R927Q mutant and wild-type males (N = 5-9 per genotype) showed decreased body weights and fat percentages in homozygotes. Whole body and limb regions of interest showed decreases in bone mineral density and content that was greater in homozygotes than in heterozygotes.

CONCLUSION: Initial findings suggest gene dosage-dependent abnormalities in Erbb4-R927Q mutants that have features of FTLD and ALS. A wider battery of tests on more animals, at different ages and including the Erbb4-I712M mutants are underway. Neuropathology is being assessed following consensus recommendations for FTLD and ALS. Stereology/morphometry and other methods will assess loss of ErbB4-expressing inhibitory interneurons and synaptic loss and how this evolves temporally.},
}

Animals
*Receptor, ErbB-4/genetics/metabolism
Male
*Amyotrophic Lateral Sclerosis/genetics/pathology
Female
Mice
Mutation/genetics
Disease Models, Animal
Humans
Mice, Transgenic
*Frontotemporal Dementia/genetics
Maze Learning/physiology

@article {pmid41445236,
year = {2025},
author = {Campbell, MC and Acheson, L and Mason, EL and Shetty, TH and Emptage, L and Redekop, R and Kitor, M and MacKenzie, IR and Futhey, NC and Hirsch-Reinshagen, V and Hsiung, GR},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e099161},
doi = {10.1002/alz70856_099161},
pmid = {41445236},
issn = {1552-5279},
mesh = {Humans ; Biomarkers/metabolism ; Male ; Aged ; *Alzheimer Disease/pathology/metabolism/diagnosis ; Female ; *DNA-Binding Proteins/metabolism ; *Retina/pathology/metabolism ; *Brain/pathology/metabolism ; Amyloid beta-Peptides/metabolism ; Middle Aged ; Amyotrophic Lateral Sclerosis/pathology/metabolism ; Aged, 80 and over ; tau Proteins/metabolism ; *Neurodegenerative Diseases/pathology/metabolism ; },
abstract = {BACKGROUND: Our non-invasive retinal imaging, using polarized light, identifies protein deposits which predict brain pathology. Previously, our measured polarized light interactions differed between retinal deposits in Alzheimer's disease (AD) and neurodegenerative diseases (NDDs) involving alpha-synuclein. Here we report deposit polarized light interactions in NDD's, involving TDP-43, compared with amyloid deposits in AD. This inexpensive, dye-free, differential diagnostic would be accessible to underserved populations. It would also enable appropriate, early treatments and interventions.

METHOD: Eyes and brains were donated by 2 individuals with ALS, including 1 with concurrent FTLD, and 4 individuals with only FTLD, including 1 with Type C. TDP-43 was present in the brains and some had additional agerelated tau. 10 individuals had amyloid beta brain pathology and a moderate to high likelihood of AD. Retinas were fixed and flat-mounted. 270 presumed amyloid beta deposits in retinas of those with AD, and 138 presumed TDP-43 deposits in those with FTLD and/or ALS were imaged in polarized light. For each deposit imaged, differing interactions with polarized light were calculated. In 1 case of ALS with concurrent low values of brain amyloid and 1 of FTLD-Type C, only thioflavin negative deposits were classed as potential TDP-43 deposits.

RESULT: Presumed amyloid beta, consistent with AD, and TDP-43 deposits, consistent with FTLD and/or ALS, were visible in polarized light in retinas with the corresponding brain pathologies (Figure 1). The thioflavin positive deposits from the retina with FTLD type C had polarized light interactions, not significantly different from AD deposits, consistent with protein fibrils combining TDP-43 and the amyloid protein, ANXA11. The deposit means and/or standard deviations of nine different polarized light interactions were significantly different between the AD and TDP-43 retinal deposits (Table 1). However, the distributions of the strengths of polarized light interactions and deposit areas overlapped between deposit types (Figure 2).

CONCLUSION: Significant differences in many polarized light interactions are consistent with the known physical properties of the different brain (and retinal) amyloid and non-amyloid deposits. Combinations of these interactions are expected to give early, non-invasive, less expensive, differential diagnoses of neurodegenerative brain diseases, including those associated with amyloid beta, alpha-synuclein and TDP-43.},
}

Humans
Biomarkers/metabolism
Male
Aged
*Alzheimer Disease/pathology/metabolism/diagnosis
Female
*DNA-Binding Proteins/metabolism
*Retina/pathology/metabolism
*Brain/pathology/metabolism
Amyloid beta-Peptides/metabolism
Middle Aged
Amyotrophic Lateral Sclerosis/pathology/metabolism
Aged, 80 and over
tau Proteins/metabolism
*Neurodegenerative Diseases/pathology/metabolism

@article {pmid41445176,
year = {2025},
author = {Gupta, A and Adhya, A and Anjali, A and Dubey, A and Tripathi, M and Rajan, R and Garg, A and Singh, MB and Vishnu, VY and Bhatia, R and Srivastava, AK and Tripathi, M},
title = {Clinical Manifestations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 3},
number = {},
pages = {e102003},
doi = {10.1002/alz70857_102003},
pmid = {41445176},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Middle Aged ; Prospective Studies ; Atrophy/pathology ; Neuropsychological Tests ; India ; Magnetic Resonance Imaging ; Positron-Emission Tomography ; *Cognitive Dysfunction/diagnostic imaging/etiology ; Alzheimer Disease/diagnostic imaging ; Brain/diagnostic imaging/pathology ; Lewy Body Disease/diagnostic imaging ; },
abstract = {BACKGROUND: Posterior Cortical Atrophy (PCA), first described by Benson et al., is a progressive neurodegenerative disorder affecting visual and posterior cognitive functions, while sparing memory and language in early stages. Although Alzheimer's Disease (AD) pathology underlies most cases, alternative etiologies like Dementia with Lewy Bodies (DLB), Corticobasal Degeneration (CBD), and Prion disease have also been reported. This study examines the clinical, etiological, and imaging profiles of PCA patients evaluated at a tertiary care center in India, using Crutch et al. 2017 consensus criteria.

METHOD: Eight PCA patients diagnosed at a tertiary hospital in India between 2021 and 2024 were included in this prospective case series. Demographic data, neuropsychological profiles, imaging findings, and biomarker studies were analyzed. Patients were assessed for visual and posterior cognitive impairments.

RESULT: PCA predominantly presented as early-onset cognitive decline in the 5th to 6th decade, with equal gender distribution. All patients exhibited initial visuospatial, visuoperceptual, or praxis impairments. Based on Crutch et al.'s classification, 6 patients (75%) were categorized as Pure PCA, and 2 (25%) as PCA Plus, including PCA-CBS and PCA-AD/DLB mixed. Phenotypically, 3 patients were dorsal variant, 3 ventral, and 2 biparietal. CSF AD biomarkers were positive in 2 Pure PCA patients and 1 PCA-AD/DLB patient. MRI revealed posterior cortical atrophy in all cases. FDG-PET showed parieto-temporo-occipital hypometabolism, with frontal involvement in dorsal/ventral subtypes, while biparietal subtypes showed occipital sparing. Tau-PET in selected cases demonstrated increased uptake in affected regions, matching FDG-PET findings.

CONCLUSION: PCA remains underrecognized due to its atypical presentation and early onset. This series highlights the clinical and imaging heterogeneity of PCA in Indian subjects. Advanced imaging, like FDG/Tau-PET, can aid in distinguishing phenotypes. Greater research is needed to explore phenotypic variations, identify biomarkers, and develop targeted therapies.},
}

Humans
Male
Female
Aged
Middle Aged
Prospective Studies
Atrophy/pathology
Neuropsychological Tests
India
Magnetic Resonance Imaging
Positron-Emission Tomography
*Cognitive Dysfunction/diagnostic imaging/etiology
Alzheimer Disease/diagnostic imaging
Brain/diagnostic imaging/pathology
Lewy Body Disease/diagnostic imaging

@article {pmid41444845,
year = {2025},
author = {Paudel, A and Boltz, M and Galik, E and Howd, LEP},
title = {Dementia Care Research and Psychosocial Factors.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 4},
number = {},
pages = {e097944},
doi = {10.1002/alz70858_097944},
pmid = {41444845},
issn = {1552-5279},
mesh = {Humans ; *Dementia/psychology/therapy/nursing ; Delphi Technique ; Quality of Life/psychology ; Surveys and Questionnaires ; *Assisted Living Facilities ; Female ; Male ; Reproducibility of Results ; },
abstract = {BACKGROUND: Positive care interactions between staff and older adults in residential care settings such as Assisted Living (AL) can lead to positive outcomes such as fewer behavioral symptoms of distress and better quality of life among the residents living with dementia. There is a lack of comprehensive measure that can be used to both guide the desired practice of positive care interactions and evaluate the impact of practice, particularly in AL settings. QUALity of Interactions Inventory (QUALII)- a five domain 21-item tool was developed as a comprehensive measure to support positive care interactions in dementia care in ALs. This study will describe the content validity of QUALII based on the Delphi survey with expert panel.

METHOD: A Delphi survey approach was used with a panel of 10 clinical and academic experts in dementia care and communication; surveys were administered electronically. The quantitative ratings were used to compute Content Validity Index (CVI) for each item (I-CVI) and overall scale (S-CVI). The qualitative feedback and responses were reviewed using content analysis to inform item revisions.

RESULT: The expert panel had diverse background (nursing, recreation/activity, dementia research, and clinical or program administration) and experience (four to 45 years) in gerontology and geriatrics. Following three rounds of the Delphi survey, the CVI values were: I-CVI = 0.90 to 1.00 for item relevance, I-CVI = 0.80 to 1.00 for item clarity, and S-CVI = 0.93 for overall scale. Items related to supporting resident engagement and expression, individualizing communication approach, and managing pace of care during interactions were revised based on qualitative feedback from the experts.

CONCLUSION: QUALII demonstrated excellent content validity following revisions. Upon successful field-testing in AL settings, QUALII is expected to emerge as a comprehensive and psychometrically sound instrument that can be used to promote positive care interactions in dementia care in clinical settings such as AL.},
}

Humans
*Dementia/psychology/therapy/nursing
Delphi Technique
Quality of Life/psychology
Surveys and Questionnaires
*Assisted Living Facilities
Female
Male
Reproducibility of Results

@article {pmid41444821,
year = {2025},
author = {Safkhani, M and Ghorbani Fard, M},
title = {Two secure authentication protocols for mitigating vulnerabilities in IoD.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-33020-8},
pmid = {41444821},
issn = {2045-2322},
support = {1404/385773//Shahid Rajaee Teacher Training University/ ; },
abstract = {The Internet of Drones (IoD) is a network layer control system that manages the communication of Unmanned Aerial Vehicles (UAVs). Drones have emerged as a novel approach to addressing everyday human challenges and are now used in a variety of domains, such as personal activities (e.g., photography and videography), urban applications (e.g., traffic monitoring and structural inspection), commercial operations (e.g., power line and tower inspection), agriculture, and military operations. Given the rapid growth of UAVs and their expanding applications, interconnecting drones to form an IoD is a desirable trend for enhancing flight safety and quality. However, challenges related to security, privacy, and inter-drone communication remain significant obstacles. Numerous authentication protocols have been developed to address these concerns. Recently, Zhang et al. proposed a PUF-based authentication scheme that uses unique identifiers and hash functions to secure authentication in the IoD environment. However, in this paper, we demonstrate that Zhang et al.'s scheme is vulnerable to several attacks, including secret value disclosure, integrity violation, key extraction, traceability, and anonymity violation. The presented attacks are shown to have a success probability of one. We also introduce two enhanced protocols that, through both informal and formal security proofs using the Scyther tool, demonstrate that they do not suffer from the vulnerabilities found in the earlier protocol. The communication costs of the proposed protocols (a) and (b) have increased by [Formula: see text] and [Formula: see text], respectively, compared to the previous protocol. The computational costs for the proposed protocols (a) and (b) have also increased by [Formula: see text] and [Formula: see text], respectively, while the storage costs in both proposed protocols remain unchanged compared to the previous protocol. It is true that the costs in the proposed protocols have risen; however, the previous design was vulnerable to various attacks, whereas the proposed protocols have demonstrated better security and have successfully achieved all their security objectives.},
}

@article {pmid41432752,
year = {2025},
author = {Więcławski, W and Paszulewicz, J},
title = {ERP evidence of attentional selection outside of effective oculomotor range.},
journal = {Experimental brain research},
volume = {244},
number = {1},
pages = {16},
pmid = {41432752},
issn = {1432-1106},
support = {2016/21/N/HS6/02771//Narodowe Centrum Nauki/ ; },
abstract = {UNLABELLED: The close link between visual attention and the oculomotor system is well documented. Within the selection-for-action framework, two perspectives exist. According to Visual Attention Model (VAM) attention is seen as a prerequisite for successful movement execution, though it is considered a distinct cognitive and neural process. By contrast, the premotor theory of attention (PMTA) argues that the beneficial effects of attention are fully accounted for by the system’s preparation for saccadic eye movements. From this standpoint, a central prediction emerges: attentional advantages should be confined to regions within the oculomotor range, since saccadic planning is not feasible outside those limits. A common way to examine this prediction is to present cues and targets in a hemifield beyond the oculomotor range, typically achieved by occluding one eye while abducting the other. Using this method, Smith et al. showed that in a visual search task, exogenous orienting is reduced in the temporal hemifield when the eye is abducted. They concluded that exogenous attentional orienting is constrained by the range of potential saccadic movements. In our study, we sought to replicate Smith et al.’s findings while extending the paradigm with EEG recordings—an approach not yet applied in this context. PMTA predicts that, under eye abduction, stimuli appearing in the temporal hemifield would yield diminished N2pc amplitudes. An ANOVA revealed no reduction of N2pc amplitude in the temporal hemifield. Taken together, our results support the growing body of evidence suggesting that visual attention is not strictly bound to the oculomotor range.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00221-025-07219-0.},
}

@article {pmid41444140,
year = {2025},
author = {Katragadda, HV and Ghaseminejad-Bandpey, A and Keating, M and Alhneif, M and Mojtabai, M and Habes, M and Seshadri, S and Flanagan, ME and Bieniek, KF},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e106144},
doi = {10.1002/alz70855_106144},
pmid = {41444140},
issn = {1552-5279},
mesh = {Humans ; Female ; Aged ; *Frontotemporal Dementia/pathology/genetics ; *Amyotrophic Lateral Sclerosis/pathology/genetics/complications ; Neuropsychological Tests ; Magnetic Resonance Imaging ; Cognitive Dysfunction/pathology ; Brain/pathology/diagnostic imaging ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by an admixture of motor and cognitive/behavioral impairments (either concurrent or sequential). The predominant pathological hallmark is TDP-43 proteinopathy, but it encompasses multiple frontotemporal lobar degeneration (FTLD) TDP-43 subtypes, complicating both diagnosis and classification. The case report herein details a 69-year-old female with a history of cognitive decline, dysarthria, and behavioral changes, ultimately diagnosed with ALS-FTD.

METHOD: A 69-year-old right-handed Caucasian female presented with decreased short-term memory. Initial neuropsychological testing in 2019 revealed superior performance on the Dementia Rating Scale (DRS; 143/144) and Mini-Mental State Exam (MMSE; 30/30), with mild impairment in visuospatial construction, visual-motor organization, and visual memory, consistent with mild cognitive impairment (MCI). MRI revealed mild ischemic changes, more pronounced in the pons and left basal ganglia. No significant frontal or temporal lobar atrophy was observed, consistent with findings from 2017 MRI. Follow-up testing in 2020 revealed mild to moderate impairments across multiple visuospatial cognitive domains, which were consistent with MCI. By late 2021, the patient developed progressive dysarthria, executive dysfunction, and behavioral changes (inappropriate), and pseudobulbar affect resulting in an antemortem diagnosis of ALS with FTD. While delusions are typically present in most cases, they were notably absent in this case.

RESULTS: At the age of 72, Postmortem neuropathology revealed changes consistent with mild cerebrovascular disease and Intermediate-level Alzheimer's disease neuropathological changes (ADNC). Immunohistochemical analysis for phosphorylated TDP-43 demonstrated skein-like inclusions in the spinal cord as well as neocortical glial cytoplasmic inclusions, neuronal cytoplasmic inclusions, and dystrophic neurites, consistent with mixed FTLD-TDP and ALS as the primary pathological findings. TDP-43 pathology was not specific to a single FTLD-TDP subtype, rather features of both Type A and Type B were present. Additionally, p62-immunohistochemistry indicates possible C9ORF72 repeat expansion (with genetic testing pending).

CONCLUSION: Mixed Type A+B cases are typically associated with C9ORF72 repeat expansions and prominent delusions. In contrast, the case presented here lacked delusions, with early disease features predominantly characterized by visuospatial deficits. The clinical presentation, along with overlapping pathological features of FTLD-TDP subtypes A and B, underscores the atypical nature of this case relative to previously reported series.},
}

Humans
Female
Aged
*Frontotemporal Dementia/pathology/genetics
*Amyotrophic Lateral Sclerosis/pathology/genetics/complications
Neuropsychological Tests
Magnetic Resonance Imaging
Cognitive Dysfunction/pathology
Brain/pathology/diagnostic imaging

@article {pmid41443996,
year = {2025},
author = {Hung, C},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e105883},
doi = {10.1002/alz70855_105883},
pmid = {41443996},
issn = {1552-5279},
mesh = {Humans ; *Valosin Containing Protein/genetics ; *tau Proteins/metabolism/genetics ; *Neurons/metabolism/pathology ; Induced Pluripotent Stem Cells/metabolism ; *Frontotemporal Dementia/genetics/pathology/metabolism ; Mutation/genetics ; Autophagy ; Lysosomes/metabolism/pathology ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; },
abstract = {BACKGROUND: Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) share genetic and pathological features, with mutations in the valosin-containing protein (VCP) gene implicated in both disorders. However, the mechanisms linking VCP mutations to neurodegeneration remain unclear. This study investigates how 4R tau dysregulation contributes to endolysosomal and autophagy dysfunction in human neurons.

METHOD: Human induced pluripotent stem cell (hiPSC)-derived cortical neurons carrying VCP mutations were analyzed for endolysosomal integrity, RNA-binding protein (RBP) localization, and MAPT splicing. Antisense oligonucleotides (ASOs) were used to selectively increase 4R tau levels in control neurons to assess its impact on cellular homeostasis. Immunocytochemistry, western blotting, and proximity ligation assays were employed to evaluate tau phosphorylation, endolysosomal dysfunction, autophagic flux, and apoptosis.

RESULT: VCP mutations caused nuclear dissociation of fused in sarcoma (FUS) and splicing factor proline- and glutamine-rich (SFPQ), leading to aberrant MAPT pre-mRNA splicing and an increased 4R tau:3R tau ratio. These neurons exhibited enlarged endolysosomes, lysosomal membrane rupture, impaired autophagic degradation, endoplasmic reticulum stress, and apoptosis. Notably, ASO-induced 4R tau expression in control neurons replicated these pathological phenotypes, confirming 4R tau as a driver of cellular dysfunction.

CONCLUSION: Our findings demonstrate that 4R tau dysregulation contributes to neurodegeneration by disrupting endolysosomal and autophagic function in FTD. Targeting tau isoform balance may offer a promising therapeutic approach for VCP-related FTD.},
}

Humans
*Valosin Containing Protein/genetics
*tau Proteins/metabolism/genetics
*Neurons/metabolism/pathology
Induced Pluripotent Stem Cells/metabolism
*Frontotemporal Dementia/genetics/pathology/metabolism
Mutation/genetics
Autophagy
Lysosomes/metabolism/pathology
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism

@article {pmid41443670,
year = {2025},
author = {Demos, C and Padmanabhan, N and Uttarala, S and Dzantiev, L and Berry, JD and Mathew, A and Stengelin, M and Sigal, G and Wohlstadter, JN},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e098094},
doi = {10.1002/alz70856_098094},
pmid = {41443670},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *DNA-Binding Proteins/cerebrospinal fluid/blood/metabolism ; *Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood ; Male ; Female ; Aged ; Middle Aged ; Immunoassay ; Sensitivity and Specificity ; Alzheimer Disease ; },
abstract = {BACKGROUND: TAR DNA-binding protein-43 (TDP-43) has an important role in the pathogenesis of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and limbic predominant age-related TDP-43 encephalopathy (LATE). Improved immunoassays for detecting TDP-43 and its disease-associated modifications are needed, based on the hypothesis that proteins involved in disease pathology can serve as effective biomarkers.

METHODS: Antibodies were screened against purified TDP-43 proteins and fragments, brain lysate, cerebrospinal fluid (CSF) and plasma from individuals with ALS (provided by MGH) and healthy controls (commercially obtained) to develop and preliminarily evaluate research use only (RUO) standard and ultrasensitive S-PLEX assays for TDP-43 and pTDP-43.

RESULTS: The full length TDP-43 assay in standard format had a quantitative range of 10-275,000 pg/mL and sufficient sensitivity to quantitate 100% of the tested plasma samples. The assay displayed excellent dilution linearity. Whole blood, plasma and platelet-rich plasma show higher concentrations than red blood cells, serum and platelet-poor plasma, suggesting a need for good control over efficiency and timing of the separation of plasma from platelets and blood cells to avoid pre-analytical effects. To measure the lower TDP-43 levels in CSF samples, the more sensitive S-PLEX TDP-43 assay was used. It had a quantitative range of 5-34,000 pg/mL and was able to quantitate 48% of the tested CSF samples. The S-PLEX pTDP-43 assay was used to measure TDP-43 phosphorylated at S409/410 in plasma samples. It had a quantitative range of 1-50,000 pg/mL, and was able to quantitate 100% of the tested plasma samples. Specificity was confirmed by testing phosphorylated and non-phosphorylated purified protein. To preliminarily evaluate the assays, a small set of plasma and CSF samples from individuals with ALS was tested. Relative to the control samples, the ALS samples had higher median plasma TDP-43 levels (ratio = 4.8, p =  0.0018), lower median CSF TDP-43 levels (ratio = 0.49, p =  0.01), and non-significantly higher plasma pTDP-43 levels (ratio = 1.9, p =  0.11).

CONCLUSIONS: Newly developed immunoassays for TDP-43 and pTDP-43 provide powerful tools for research on neurodegeneration biomarkers.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*DNA-Binding Proteins/cerebrospinal fluid/blood/metabolism
*Amyotrophic Lateral Sclerosis/cerebrospinal fluid/blood
Male
Female
Aged
Middle Aged
Immunoassay
Sensitivity and Specificity
Alzheimer Disease

@article {pmid41443658,
year = {2025},
author = {Imam, F},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e098477},
doi = {10.1002/alz70856_098477},
pmid = {41443658},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/metabolism ; *Proteomics ; *Neurodegenerative Diseases/diagnosis/metabolism ; Alzheimer Disease ; },
abstract = {BACKGROUND: Limited understanding of biological mechanisms behind the onset and progression of major Neurodegenerative Disorders diseases [Alzheimer's Disease (AD), Parkinsons's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Dementia (FTD)] has been a burden for the discovery of novel biomarkers and treatments. Large, harmonized, patient-derived datasets will be key in unraveling the complex biology leading to neurodegeneration. The Global Neurodegeneration Proteomics Consortium (GNPC), a public-private partnership, undertook the legal and technical work to address these challenges and created one of the largest proteomic data sets in the world with ∼300 million unique protein measures from, at inception, 23 partners and nearly 40,000 biosample analyses with an associated 50 clinical data features.

METHOD: The GNPC first worked to harmonize 23 individual datasets with heterogeneous clinical and proteomic data. Developing the GNPC's large data set required addressing several barriers to open data and data sharing including legal, technological, and incentive and norms-based barriers. The complete harmonized dataset was securely provided to consortium members via the Alzheimer's Disease Data Initiative's online platform, the AD Workbench for data refinement and analysis. After one year of embargoed intra-consortium analysis, the HDS will be made accessible by the broader research community as a shared, global resource (July 2025).

RESULT: The first version of the Harmonized Dataset (HDS) includes approximately 40,000 unique proteomic analyses on the SomaScan 5k and/or 7k proteomics array platform, in addition to a smaller subset studied with Olink and mass spectrometry methods. All samples are accompanied by 50 phenotypic indicators including demographic, cognitive data, clinical scores, and disease-specific genotype. Central hosting of de-identified and harmonized data occurs within the secure AD Workbench environment, including scalable compute resources for >100 active researchers.

CONCLUSION: With over 300,000,000 unique protein measures, the GNPC represents the one of the largest protein biomarker discovery efforts for neurodegenerative diseases-or any specific disease area-to date. Results of preliminary analyses from the consortium's distinct workstreams (cross-sectional profiling, longitudinal profiling, proteogenomic mapping, multivariate prediction & modeling) will be summarized, including diagnostic and predictive proteomic biomarker signatures for pan-neurodegeneration and disease-specific states.},
}

Humans
*Biomarkers/metabolism
*Proteomics
*Neurodegenerative Diseases/diagnosis/metabolism
Alzheimer Disease

@article {pmid41443588,
year = {2025},
author = {Delaby, C and Ladang, A and Yriarte, J and Zecca, C and Logroscino, G and Koertvelyessy, P and Tumani, H and Parchi, P and Quadrio, I and Hart, M and Olsen, DA and Alcolea, D and Blennow, K and Fortea, J and Lleó, A and Algeciras-Schimnich, A and Ayrignac, X and Bedel, A and Santos, GAA and Borelli, WV and Amar, EB and Baldeiras, I and Bigot-Corbel, E and Bjerke, M and Perez, MC and Casoli, T and Chabrashvili, T and Chapman, MD and Cusato, J and Dursun, E and Fourier, A and Galimberti, D and Gezen-Ak, D and Gordon, BA and Gouju, J and de Las Heras Florez, S and Sánchez, JJH and Herwerth, M and Imperiale, D and Kaczorowski, F and Kasuga, K and Keshavan, A and Khalil, M and Kuhle, J and Leithner, C and Lewczuk, P and Letournel, F and Tsolaki, M and Giuffrè, GM and Blanc, MC and Mroszko, B and Rodríguez-Álvarez, J and Musso, G and Kulczynska-Przybik, A and Nogueira, L and Paquet, C and Baiardi, S and Gaetani, L and Parnetti, L and Garay, RP and Poesen, K and Quillard-Muraine, M and Borja, ER and Schraen-Maschke, S and Terracciano, D and Bachhuber, F and Halbgebauer, S and Tzartos, S and Tzartos, J and Unterwalder, N and Vermunt, L and Wellington, CL and Zetterberg, H and Teunissen, CE and Lehmann, S},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e104274},
doi = {10.1002/alz70856_104274},
pmid = {41443588},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/cerebrospinal fluid/blood ; *Neurofilament Proteins/cerebrospinal fluid/blood ; *Nervous System Diseases/diagnosis/blood/cerebrospinal fluid ; Alzheimer Disease/diagnosis ; Surveys and Questionnaires ; },
abstract = {BACKGROUND: The quantification of Neurofilament Light chain (NfL) in blood and cerebrospinal fluid (CSF) has proven valuable for diagnosing and prognosing various neurological disorders, including Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, parkinsonism, multiple sclerosis, and ischemic damage. However, there is considerable variability in clinical and laboratory practices between centers, primarily due to different contexts of use (COU), analytical methods, and the application of cutoffs or scales. Additionally, for the same biochemical profile, the interpretation and reporting of results may vary from one center to another, raising concerns about the commutability of the tests. To date, no consensus has been reached among laboratories to define the most appropriate use of cutoffs or conclusions/comments based on NfL profiles.

METHOD: This international project involves 38 laboratories across 18 countries, all specialized in the biochemical diagnosis of neurological disorders. Using a questionnaire, we obtained descriptions from each center regarding their COU, pre-analytical and analytical protocols (including the biological fluid and methods used to quantify NfL). Through a consensus approach, we developed a harmonized strategy for the use and reporting of NfL results across different centres according to their respective COU.

RESULTS: Among the centers, 63% quantified NfL in the CSF, 87% in blood and 53% in both fluids. COU were as follow: frontotemporal dementia (71%), Alzheimer disease (71%), multiple sclerosis (61%), amyotrophic lateral sclerosis (61%), psychiatric syndrome (45%), Creutzfeldt-Jakob disease (32%), Parkinson disease (39%), peripheral neuropathy (29%), traumatic brain injury (21%), Huntington's disease (13%), amyloid transthyretin related (11%) and cardiac arrest (8%). Most of the centers define pathological cutoffs based on publications (50%) and take age into account for this purpose (42%). Reporting is mostly transmitted through numeric results (95%).

CONCLUSION: Harmonizing cutoffs, reporting, and interpretation across various clinical contexts will facilitate the incorporation of this biomarker into routine clinical practice.},
}

Humans
*Biomarkers/cerebrospinal fluid/blood
*Neurofilament Proteins/cerebrospinal fluid/blood
*Nervous System Diseases/diagnosis/blood/cerebrospinal fluid
Alzheimer Disease/diagnosis
Surveys and Questionnaires

@article {pmid41442833,
year = {2025},
author = {Zhong, Q and Wang, X and Xu, Y and Wang, R and Zhou, M and Liu, X},
title = {Response to "Constructive appraisal of Zhong et al.'s study on Mycobacterium tuberculosis dormant antigens and PB2-DIMQ vaccine: Opportunities for translational strengthening".},
journal = {Tuberculosis (Edinburgh, Scotland)},
volume = {156},
number = {},
pages = {102723},
doi = {10.1016/j.tube.2025.102723},
pmid = {41442833},
issn = {1873-281X},
}

@article {pmid41442691,
year = {2025},
author = {Mukherjee, S and Koppisetti, R and Barthélemy, NR and Horie, K and Ly, CV and Melendez, J and Miller, TM and Sato, C and Ghoshal, N and Karch, CM and Bateman, RJ},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e105528},
doi = {10.1002/alz70855_105528},
pmid = {41442691},
issn = {1552-5279},
mesh = {Humans ; *tau Proteins/metabolism/genetics ; *Alzheimer Disease/pathology/metabolism ; *Brain/metabolism/pathology ; Male ; *Amyotrophic Lateral Sclerosis/metabolism/pathology ; Female ; Aged ; Protein Isoforms/metabolism/genetics ; Immunoprecipitation ; Aged, 80 and over ; Tandem Mass Spectrometry ; Spinal Cord/metabolism/pathology ; Middle Aged ; },
abstract = {BACKGROUND: Microtubule associated protein tau (MAPT) plays a crucial role in multiple neurodegenerative diseases such as Alzheimer disease (AD) and frontotemporal dementia (FTLD). While six isoforms are known in the central nervous system (CNS), the peripheral nervous system (PNS) expresses longer 'big tau' isoforms. Despite the knowledge of the tau mRNA transcript, 'big tau' protein distribution across the human nervous system and pathophysiological role remains largely unknown.

METHODS: We developed an immunoprecipitation coupled with mass spectrometry (IP/MS)-based assay using antibodies binding to distinct regions of human tau (anti-tau monoclonal antibodies HJ8.5, HJ8.7 and Tau1). We analysed postmortem brains (frontal, temporal, parietal, occipital and cerebellum) from AD (n = 17), disease control (n = 10) and Amyotrophic lateral sclerosis (ALS) (n =  8); postmortem spinal cord tissue (lumbar and cervical) from disease controls (n = 4) and ALS (n = 4) and sciatic nerves from ALS (n = 5) and disease control (n = 1).

RESULTS: Using tandem mass spectrometry, we discovered a novel human big tau isoform resulting from the inclusion of exon 4a-long (exon 4a-L), encoding 355 amino acids into the tau protein sequence. We demonstrated this exon 4a-L to be the sole exon 4a variant expressed in humans, unlike the previously reported exon 4a. We found big tau also has distinct isoforms due to alternative splicing of the tau gene. This expands the number of human tau isoforms from six to twelve, significantly increasing the complexity of tau protein biology and greater diversity of its functional roles across human nervous system. Finally, we observed a central-to-peripheral gradient of big tau expression, lowest in the cortical brain regions (<0.5 %), followed by the cerebellum (1 %), then spinal cord (10 %), with the highest level in the human sciatic nerve (35 %).

CONCLUSIONS: Our study provides the first protein-level evidence for expanded repertoire of tau isoforms in the human nervous system. Interestingly, brain regions overlapping with relatively lower big tau are more susceptible to neurofibrillary tangle formation, suggesting divergent roles for different tau isoforms in disease. Our findings provide new insights into the basic biology of big tau in humans, crucial for understanding its pathophysiological functions.},
}

Humans
*tau Proteins/metabolism/genetics
*Alzheimer Disease/pathology/metabolism
*Brain/metabolism/pathology
Male
*Amyotrophic Lateral Sclerosis/metabolism/pathology
Female
Aged
Protein Isoforms/metabolism/genetics
Immunoprecipitation
Aged, 80 and over
Tandem Mass Spectrometry
Spinal Cord/metabolism/pathology
Middle Aged

@article {pmid41442327,
year = {2025},
author = {Fisher, DW and Schaffer, C and Battaglia, C and Tran, N and Hendricks, N and Smith, AS and Darvas, M},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e105723},
doi = {10.1002/alz70855_105723},
pmid = {41442327},
issn = {1552-5279},
mesh = {Animals ; Female ; Male ; Disease Models, Animal ; Humans ; *Amyotrophic Lateral Sclerosis/pathology/genetics/physiopathology ; *DNA-Binding Proteins/genetics/metabolism ; Mice ; *Aging/pathology ; Mice, Transgenic ; Dependovirus ; Spinal Cord/pathology/metabolism ; },
abstract = {BACKGROUND: Aging is the greatest risk factor for neurodegenerative diseases like ALS, but studying how specific aging processes alter pathogenicity has been challenging. Though neurodegeneration is often linked with pathological protein aggregation, it is unclear whether aging simply allows the time necessary for proteins to aggregate into pathological forms or if concomitant aging-related processes further facilitate aggregation or resultant neurodegeneration.

METHODS: We developed a TDP43-opathy/ALS mouse model by retro-orbital injection of a viral vector for neuron-restrictive human TDP43 overexpression, AAV-Syn-hTDP43-Php.Eb (hTDP43). Young (5-6mo) and old (21-23mo), male and female mice were administered AAV-hTDP or AAV-Sham with daily measurements of weight, neuromuscular score (NMS; 0-4), and tremor severity (0-4). Weekly open field, y-maze, and rotarod tests were administered. Mice were euthanized at NMS = 4 or at 30 days post-injection (dpi) and the CNS or neuromuscular junction was fixed in 10% formalin, fixed with, 4% PFA, or frozen on dry ice. Immunohistochemistry was performed with commercial antibodies. qPCR with primers specific to the viral vector were performed on spinal cord DNA.

RESULTS: Young mice injected with AAV-hTDP43 developed a tremor at about 7 dpi that progressed in severity, with worsening neuromuscular impairment, weight loss, and death. The speed and severity of motor deficits, weight loss, and time to mortality were titratable by dose. Sparse but clear pTDP43 inclusions were noted in the spinal cord and layer 5 cortical cells. Surprisingly, when old and young mice were injected with a viral titer projected to cause 50% mortality, older mice demonstrated significantly less weight loss, lower NMS, and less mortality than young mice. Similar viral titers were detected in the spinal cords of old and young mice, excluding the likelihood of age-related changes in viral infectivity.

CONCLUSIONS: We developed a novel ALS-like mouse model that allows for tight temporal and dosage control of resultant pathology. This tool can enhance efficiency in experiments studying complex genetics or aging in TDP43-opathies. Surprisingly, when young and old mice were challenged with acute hTDP43 overexpression, aging played a protective role in the subsequent ALS-like phenotype. Subsequent work will explore the mechanisms behind this age-related resilience.},
}

Animals
Female
Male
Disease Models, Animal
Humans
*Amyotrophic Lateral Sclerosis/pathology/genetics/physiopathology
*DNA-Binding Proteins/genetics/metabolism
Mice
*Aging/pathology
Mice, Transgenic
Dependovirus
Spinal Cord/pathology/metabolism

@article {pmid41441862,
year = {2025},
author = {An, L and Xiao, Y and Hristovska, I and Tasaki, S and Smets, B and Xu, Y and Krish, V and Imam, F and Stomrud, E and Janelidze, S and Palmqvist, S and Binette, AP and Ossenkoppele, R and Mattsson-Carlgren, N and Hansson, O and Vogel, JW},
title = {Biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 2},
number = {},
pages = {e099373},
doi = {10.1002/alz70856_099373},
pmid = {41441862},
issn = {1552-5279},
mesh = {Humans ; *Biomarkers/blood ; Male ; *Proteomics/methods ; Female ; Aged ; *Dementia/diagnosis/blood ; Disease Progression ; Middle Aged ; Apolipoproteins E/genetics ; Alzheimer Disease/blood/diagnosis ; },
abstract = {BACKGROUND: Plasma proteomic biomarkers have shown significant potential for accurate and cost-effective dementia diagnosis. However, plasma proteomic has not been validated for multi-disease diagnosis in large neurodegenerative cohorts yet. This study develops AI models on data from the Global Neurodegeneration Proteomics Consortium (GNPC) to predict major forms of dementia, accounting for multiple underlying pathologies, and outputting probabilistic information.

METHOD: This study included 17,170 GNPC participants with SomaLogic 7K plasma proteomics, comprising controls and patients with AD, PD, FTD, ALS, or Stroke (Figure 1A). We describe 'ProtAIDe', a deep network for six clinical diagnostic categories classification using proteomics (Figure 1B). 10-fold cross-validation with built-in feature selection was used to evaluate overall performance. Leave-one-site-out scheme, with and without k-shot fine-tuning, was adopted to evaluate out-of-site generalization performance. Additionally, baseline proteomics embeddings from ProtAIDe's last layer were leveraged to predict longitudinal CDR progression (advancing from CDR 0 to >0). Predicted probabilities were validated against cognition and APOE genotype, and the cross-disease classification probability space was visualized using 2-dimensional t-SNE. Predictive importance of individual proteins was estimated by feature permutation.

RESULT: ProtAIDe achieved simultaneous balanced classification accuracy (BCA) >0.7 and AUC >0.8 across all six targets (Figure 1C) with ∼200 proteins. Performance dipped when generalizing to unseen sites, though it was partially recovered by finetuning (Figure 2A). Despite being trained only on baseline data, ProtAIDe's baseline embeddings predicted longitudinal CDR progression with an AUC of 0.76±0.09 (N = 2052; Figure 2B). AD classification probability showed a strong anti-correlation (R = -0.63) with MMSE score (Figure 2C) and reflected the protective and risk qualities of the APOE ɛ2 and ɛ4 alleles, respectively (Figure 2D). t-SNE visualization of probability spaces (Figure 2E) revealed unique (multiple PD and FTD clusters) and shared (middle regions shared by AD, Control, FTD, and Stroke) clustering patterns among neurodegenerative diseases, suggesting potential comorbidities. Key proteins emerged as major contributors to single- or multi-disease classifications (Figure 3).

CONCLUSION: Our results demonstrate that ∼200 key proteins in blood can differentiate major forms of dementia at the patient-level. ProtAIDe's probabilistic information highlights its potential for identifying co-pathologies and determining proteins driving symptoms at the individual-level.},
}

Humans
*Biomarkers/blood
Male
*Proteomics/methods
Female
Aged
*Dementia/diagnosis/blood
Disease Progression
Middle Aged
Apolipoproteins E/genetics
Alzheimer Disease/blood/diagnosis

@article {pmid41441760,
year = {2025},
author = {Zhao, H and Xu, H and Xie, J and Wu, S and Yuan, C},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e107363},
doi = {10.1002/alz70855_107363},
pmid = {41441760},
issn = {1552-5279},
mesh = {Humans ; Biosensing Techniques ; *DNA-Binding Proteins/metabolism/genetics ; *Neurons/metabolism/pathology ; *Alzheimer Disease/pathology/metabolism ; Fluorescence Resonance Energy Transfer ; Induced Pluripotent Stem Cells ; },
abstract = {BACKGROUND: Alzheimer's disease and related dementias (ADRD) affect 6.2 million people in the U.S., a number that is rapidly increasing due to an aging population, yet no effective cure or treatment exists. TDP-43 pathology, initially identified as a biomarker for ALS and FTD, is now observed in the majority of ADRD patients and is often associated with accelerated cognitive decline. However, the molecular mechanisms by which TDP-43 contributes to ADRD progression remain unclear, largely due to the lack of tools to monitor its aggregation dynamics in living cells.

METHODS: To address this gap, we engineered a FRET-based biosensor to detect TDP-43 aggregation. The biosensor was designed using various TDP-43 isoforms (full-length, C-terminal domain, and ΔNLS) fused to different linker constructs. We evaluated biosensor performance under proteostasis stress conditions known to induce TDP-43 aggregation and validated its sensitivity using preformed TDP-43 fibrils. To further explore the progression of TDP-43 pathology, we transduced the biosensor into human iPSC-derived cortical neurons. These neurons were then treated with cellular stressors that mimic aging-related proteostasis dysfunction, cellular stressors that mimic aging-related proteostasis dysfunction, i.e. preformed fibrils and pharmacological drugs. FRET signal growth was monitored over time, and neurons exhibiting high FRET signals were isolated using FACS for downstream RNA-seq analysis.

RESULTS: The engineered FRET biosensor successfully detected TDP-43 aggregation in response to proteostasis stressors. Neurons treated with aging-mimicking compounds exhibited an increase in FRET signal over time, indicating progressive TDP-43 aggregation.

CONCLUSION: This study presents a novel FRET-based biosensor for tracking TDP-43 aggregation in living neurons. Our approach enables real-time monitoring of TDP-43 pathology and facilitates the identification of molecular pathways disrupted by its accumulation.},
}

Humans
Biosensing Techniques
*DNA-Binding Proteins/metabolism/genetics
*Neurons/metabolism/pathology
*Alzheimer Disease/pathology/metabolism
Fluorescence Resonance Energy Transfer
Induced Pluripotent Stem Cells

@article {pmid41441345,
year = {2025},
author = {Endo, K and Kubota, K and Karino, K and Sato, R and Miura, S and Ueda, Y and Iwashita, Y},
title = {Setting the Next Vital Sign Observation Interval as a Learning Objective in Simulation-Based Nursing Education: A Prospective Exploratory Observational Study.},
journal = {Nursing reports (Pavia, Italy)},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/nursrep15120416},
pmid = {41441345},
issn = {2039-4403},
abstract = {Background/Objectives: Abnormal vital signs often precede in-hospital clinical deterioration, but little is known about how nurses decide when to recheck vital signs. We examined how nurse characteristics relate to the next vital sign observation interval after detecting abnormal values and how this decision could be used as a learning objective in simulation-based education. Methods: In this prospective exploratory observational study at a university hospital in Japan, twenty-seven nurses used a full-body patient simulator across three scenarios: normal, low-urgency, and moderate-risk (moderately abnormal vital signs according to National Early Warning Score 2 [NEWS2] risk bands). After each assessment, participants specified in hours the interval they considered appropriate for the next vital sign observation. Nurse characteristics included years of clinical experience, advanced life support (ALS) training, and prior experiences recognizing or responding to deterioration. Mann-Whitney U tests and multiple regression were used to explore univariate and adjusted associations. Results: In the low-urgency scenario, ALS training was associated with shorter intervals (median 1 h vs. 3 h; p = 0.04). In the moderate-risk scenario, univariate analyses showed shorter intervals among nurses with greater experience and among those with ALS training (both p < 0.01). In adjusted models for the moderate-risk scenario, years of experience and prior experiences of recognizing and responding to deterioration were independently associated with shorter intervals (all p < 0.05), whereas ALS training was not. Conclusions: The decision to shorten observation intervals appears to reflect experiential aspects of clinical judgment. Integrating "setting the next observation interval" as an explicit learning objective in simulation may help strengthen nurses' clinical judgment for early recognition of deterioration. As an exploratory, single-center study with a small sample and fixed scenario order, these findings should be interpreted cautiously and used to guide larger confirmatory studies and curricular design. This study was not registered.},
}

@article {pmid41440090,
year = {2025},
author = {Martucci, G and Bonilauri, SC and Canalini, A and Baraldi, M and Costantini, L and Mora, F and Vacondio, P},
title = {Integrating Neurology, Palliative Care and Emergency Services in ALS: A Community-Integrated Neuropalliative Pathway in Modena, Italy.},
journal = {Brain sciences},
volume = {15},
number = {12},
pages = {},
doi = {10.3390/brainsci15121294},
pmid = {41440090},
issn = {2076-3425},
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that causes severe motor, respiratory and communication impairment and imposes a high psychosocial burden on patients and families. Recent evidence shows that integrated neuropalliative care-early collaboration between neurology and palliative services with community support-improves quality of life and reduces avoidable hospitalisations. Yet there are few descriptions of how such integration is operationalised.

OBJECTIVE: This study examines a Community-Integrated Neuropalliative Pathway (CINP) implemented in the province of Modena (Emilia-Romagna, Italy), analysing how neurology, palliative care and emergency services collaborate to provide continuous, person-centred care for people with ALS.

METHODS: A single, holistic case study was conducted following Yin's analytical approach. Data sources included ten semi-structured interviews with neurologists, palliative physicians, nurses, home-care professionals and emergency clinicians; ethnographic observations in the ALS outpatient clinic; relevant organisational documents (the regional Clinical Pathway on ALS); and aggregated quantitative data from the palliative care registry (January 2023-December 2024). Thematic analysis with investigator triangulation was used to explore care integration, advance care planning and emergency coordination. Quantitative data were summarised descriptively.

RESULTS: Three interrelated themes were identified: (1) Progressive and flexible integration between neurology and palliative care. Neurologists remained longitudinal reference points while palliative teams were activated in response to evolving needs and became more relevant with the progression of the disease. Regular multidisciplinary meetings and shared discharge planning facilitated coordination. (2) The shared culture of advance care planning. Professionals framed advance care planning (ACP) as a relational, iterative process anchored in therapeutic relationships. Shared care plans, once completed, triggered an electronic Emergency Warning ("warning 118") procedure that notified the emergency service of patient preferences. (3) The integration of palliative and emergency services. The warning system enabled emergency clinicians to respect care plans and avoid aggressive interventions during crises. Quantitative data on 47 ALS patients followed by territorial palliative services showed that 16 had an active Emergency Warning flag; among these, most died at home or in a hospice rather than in hospital.

CONCLUSIONS: The Modena CINP exemplifies how a public health system can operationalise early neuropalliative integration and connect hospital, community and emergency services. The qualitative findings illustrate the cultural and organisational shifts required for continuous care, while the quantitative data show that the system is correctly used and that patients with the Emergency Warning activation died mostly at home or in a hospice. Lessons from this analytical case study can inform the development of similar pathways in other regions, although further research is needed to assess outcomes in larger populations and such models need to be adapted to local contexts.},
}

@article {pmid41440030,
year = {2025},
author = {Su, J and Alaiz Noya, J and Lingappa, AF and Solas, D and Tong, J and Daughrity, L and Castanedes-Casey, M and Kurti, A and Dickson, DW and Lingappa, VR and Petrucelli, L and Zhang, Y},
title = {Preclinical Evaluation of the Assembly Modulator PAV-615 in a Mouse Model of C9orf72-Associated ALS/FTD.},
journal = {Cells},
volume = {14},
number = {24},
pages = {},
doi = {10.3390/cells14242012},
pmid = {41440030},
issn = {2073-4409},
support = {ADSF-24-1284327-C//Alzheimer's Disease Strategic Fund grant/ ; 5P30AG0062677, ALLFTD U19AG063911, R01AG089380 and R01AG085307//National Institutes of Health/National Institute on Aging/ ; U54NS123743, R35 NS137447, P01NS084974, R01NS132330 and R01NS117461//National Institutes of Health/National Institute of Neurological Disorders and Stroke/ ; NA//Target ALS Foundation/ ; NA//Robert Packard Center for ALS Research at Johns Hopkins/ ; NA//Cure Alzheimer's Fund/ ; NA//Florida Department of Health Ed and Ethel Moore Alzheimer's Disease Research Program/ ; NA//Association for Frontotemporal Degeneration Biomarkers Initiative/ ; NA//BrightFocus Foundation/ ; NA//Kissick Family Foundation/ ; },
mesh = {Animals ; *C9orf72 Protein/genetics/metabolism ; *Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism ; Disease Models, Animal ; *Frontotemporal Dementia/drug therapy/genetics/pathology/metabolism ; Mice ; Humans ; Male ; Mice, Transgenic ; Drug Evaluation, Preclinical ; },
abstract = {Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G4C2 repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G4C2 repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD.},
}

Animals
*C9orf72 Protein/genetics/metabolism
*Amyotrophic Lateral Sclerosis/drug therapy/genetics/pathology/metabolism
Disease Models, Animal
*Frontotemporal Dementia/drug therapy/genetics/pathology/metabolism
Mice
Humans
Male
Mice, Transgenic
Drug Evaluation, Preclinical

@article {pmid41439884,
year = {2025},
author = {Di Gregorio, R},
title = {A Novel Single-Loop Mechanism for Neck Rehabilitation.},
journal = {Biomimetics (Basel, Switzerland)},
volume = {10},
number = {12},
pages = {},
doi = {10.3390/biomimetics10120814},
pmid = {41439884},
issn = {2313-7673},
support = {FAR 2023//University of Ferrara/ ; },
abstract = {Trauma, amyotrophic lateral sclerosis (ALS), and head and neck cancer (HNC), which cause neck pain, are only some of the possible issues requiring suitable therapy for alleviating or even healing the neck dysfunctions they cause. Static and dynamic neck braces are commonly employed in therapies for neck recovery and in the necessary measurements to quantify neck impairment or to set up a suitable therapy. Serial and parallel mechanisms, among others, have been proposed for neck braces. Here, a novel single-loop spherical mechanism is proposed for a possible neck brace. Its kinematics and mobility analyses are presented with reference to their specific applications in a neck brace. Then, dimensional synthesis with a set of neck brace's kinematic requirements is addressed to compute the geometric constants that guarantee an orientation workspace similar to that of the human neck. The presented analyses and syntheses show that the new proposal is effective and can alleviate some concerns about already-proposed mechanisms for neck braces.},
}

@article {pmid41439655,
year = {2025},
author = {Dolcet, SS and Sánchez-Aced, É and Belbin, O and Dols-Icardo, O and Carmona-Iragui, M and Alcolea, D and Roda, S and Lioudyno, M and Sevrioukov, E and Lacosta, AM and Canudas, J and Sánchez-Valle, R and Molina, L and Aldecoa, I and Rabano, A and Capilla-Lopez, MD and Saura, CA and Busciglio, JA and Fortea, J and Guallar, V and Gelpi, E and Lleó, A},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e104310},
doi = {10.1002/alz70855_104310},
pmid = {41439655},
issn = {1552-5279},
mesh = {Humans ; *Amyloid beta-Protein Precursor/metabolism/immunology ; Animals ; Female ; *Brain/pathology/metabolism ; Male ; Mice ; *Alzheimer Disease/pathology/metabolism ; Aged ; Cross-Sectional Studies ; Middle Aged ; Aged, 80 and over ; },
abstract = {BACKGROUND: Some studies have described that Amyloid Precursor Protein (APP) C-terminal fragments (CTFs) accumulate in the brain of patients with Alzheimer's disease (AD). These data rely mostly on biochemical techniques, but the neuroanatomical distribution in human AD brain remains unknown. In this work, we generated a novel APP antibody to investigate the morphological distribution of APP-CTF accumulation in postmortem human brain.

METHOD: Cross-sectional neuropathological study. Formalin-fixed paraffin-embedded (FFPE) post-mortem human brain samples from the hippocampus, frontal and temporal cortex were obtained from the Neurological Tissue Bank (IDIBAPS-Hospital Clinic Barcelona). The study group consisted of 48 individuals: 10 cases with neuropathological criteria of early-onset SAD, 12 with ADAD (8 PSEN1, 2 APP mutation carriers, 2 APP duplications), 5 with DS, 10 with DS-AD, 7 controls without neurodegenerative pathology and 4 individuals with other neurodegenerative diseases (1 sFTLD-TDP, 1 C9orf72-FTLD-TDP, 1 DLB and 1 ALS-TDP). Antibody generation: APP1B was obtained from 8-10-week female BALB/c mice immunized with a C-terminal APP peptide. Selected hybridomas were cloned and stable clones producing antibodies were expanded. The antibodies were purified using protein G affinity chromatography. Cell culture: Human fetal tissue was obtained to generate primary human cortical culture derived from DS fetuses. A commercially available stable cell line expressing APP-C99-GFP was used for immunocytochemistry experiments.

RESULT: We generated and characterized a novel murine antibody (APP1B) against the C-terminus of APP. APP1B showed specificity for APP-CTF in primary human cortical cell culture obtained from DS fetuses and a cell line expressing human APP-C99. Immunohistochemistry experiments with APP1B antibody in human brain revealed extensive intracellular "tangle-like" neuronal APP (iAPP) immunoreactivities in AD-vulnerable areas in sporadic, autosomal dominant AD and in Down syndrome with AD (Figure 1). The immunoreactivity pattern was absent in controls without pathology, DS without AD or other neurodegenerative conditions. iAPP pathology did not colocalize with tau or ubiquitin but followed the neuroanatomical distribution of neuronal degeneration in AD (Figure 2).

CONCLUSIONS: We propose iAPP pathology as an unrecognized core neuropathological hallmark of AD. Due to the topographical distribution and selective neuronal involvement, iAPP pathology may represent a link between APP dyshomeostasis and progressive tau aggregation.},
}

Humans
*Amyloid beta-Protein Precursor/metabolism/immunology
Animals
Female
*Brain/pathology/metabolism
Male
Mice
*Alzheimer Disease/pathology/metabolism
Aged
Cross-Sectional Studies
Middle Aged
Aged, 80 and over

@article {pmid41439297,
year = {2025},
author = {Surace, EI and Romorini, L and Marazita, M and Clas, GS and Massazza, V and Alvarez, MF and Avendaño, D and Itzcovich, T and Martinetto, H},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e103028},
doi = {10.1002/alz70855_103028},
pmid = {41439297},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/genetics ; *Frontotemporal Dementia/genetics ; *Amyotrophic Lateral Sclerosis/genetics ; Argentina ; *Neurodegenerative Diseases/genetics ; Biomarkers/cerebrospinal fluid ; },
abstract = {Understanding the biological and genetic landscape of neurodegenerative diseases in diverse populations deepens our insight into complex pathophysiological mechanisms. Our laboratory, established 14 years ago in Buenos Aires, Argentina, serves as a regional hub for Latin America, focusing on familial and sporadic cases of Alzheimer's disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). We were among the first in the region to incorporate cerebrospinal fluid AD biomarker analysis into clinical diagnostics. Our research includes genetic counseling, the study of novel genetic variants, and the development of patient-derived cell models using induced pluripotent stem cell technology. In this talk, we will discuss the challenges of staying at the forefront of technological advancements and underscore the importance of international collaboration in advancing both local and global knowledge.},
}

Humans
*Alzheimer Disease/genetics
*Frontotemporal Dementia/genetics
*Amyotrophic Lateral Sclerosis/genetics
Argentina
*Neurodegenerative Diseases/genetics
Biomarkers/cerebrospinal fluid

@article {pmid41438688,
year = {2026},
author = {Su, T and Li, Z and Yang, Y and Dai, Y and Li, Y and Zhao, H},
title = {In vitro 3D models of neuron-astrocyte interactions.},
journal = {Biochemistry and biophysics reports},
volume = {45},
number = {},
pages = {102400},
pmid = {41438688},
issn = {2405-5808},
abstract = {The pathological processes of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis) also include relationships between neuron and glia cells. Conventional two-dimensional (2D) cell cultures have limitations to mimic the microenvironment of cells inside living organisms because of flaws in intercellular relationships investigated using 2D cell cultures. Recent advances have introduced three-dimensional (3D) cell cultures that have the capability to create 3D cellular architecture to mimic advanced platforms for scientific inquiries into neurodegenerative diseases, simulating microenvironments inside living organisms.This review provides a brief overview of the development of in vitro 3D cell culture models of astrocytes and attempts to highlight the role of astrocytes in crucial pathophysiologic events occurring in 3D cultures. Studies have shown the use of in vitro 3D cultures to better represent the dual functions of astrocytes in neurodegenerative disorders. Looking ahead to the future, novel advances in microfluidics and multi-omics analysis promise to further improve 3D cultures and push forward new insights into neurological dysfunction to spark innovative advances for treatment strategies.},
}

@article {pmid41438236,
year = {2025},
author = {Li, T and Gao, Y and Zhou, J and Chen, Y and Zhang, S and Gong, X and Liu, Y},
title = {Advancements in the application of brain-computer interfaces based on different paradigms in amyotrophic lateral sclerosis.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1658315},
pmid = {41438236},
issn = {1662-4548},
abstract = {Amyotrophic lateral sclerosis (ALS) is a progressive neurological condition that leads to the gradual loss of movement and communicative abilities, significantly diminishing the quality of life for affected individuals. Recent advancements in neuroscience and engineering have propelled the swift evolution of brain-computer interfaces (BCIs), which are now extensively utilised in medical rehabilitation, military applications, assistive technologies, and various other domains. As a communication medium facilitating direct interaction between the brain and the external world independent of the peripheral nervous system, BCI provides ALS patients with an innovative method for communication and control, offering unparalleled prospects for improving their quality of life. Recent collaborative endeavours among several specialists have markedly enhanced the precision and velocity of diverse BCI paradigms, signifying a breakthrough in BCI applications for ALS. Nonetheless, obstacles and constraints remain. This study methodically extracted pertinent literature from the Web of Science and PubMed databases in accordance with PRISMA guidelines. Following stringent inclusion and exclusion criteria, 23 studies were identified. This data allows us to summarise the application results and current limitations of several BCI paradigms in motor control and communication, while delineating prospects in multimodal fusion and adaptive calibration. This review presents evidence-based references for the effective translation and application of BCI technology in ALS rehabilitation.},
}

@article {pmid41437944,
year = {2026},
author = {Tannemann, N and Tsarenko, O and Herbstreit, F and Gestmann, M and Brenner, T and Szalai, C},
title = {Enhancing theoretical BLS knowledge with virtual reality: a randomized controlled trial in medical students.},
journal = {Resuscitation plus},
volume = {27},
number = {},
pages = {101169},
pmid = {41437944},
issn = {2666-5204},
abstract = {BACKGROUND: High-quality cardiopulmonary resuscitation (CPR) training, including both technical and non-technical skills, is essential for medical students. Virtual reality (VR) offers immersive learning environments that may enhance traditional teaching methods. This study investigates the impact of a single VR session prior to an Advanced Life Support (ALS) course on knowledge and performance of basic life support skills among medical students.

METHODS: In this single blind randomized controlled trial, 126 fourth-year medical students with prior Basic Life Support (BLS) training were assigned to either an intervention group (n = 66) with an additional 3-part immersive VR session covering BLS theory and practice or a control group (n = 60) receiving standard preparation. All participants underwent a seminar based on advanced life support principles as dictated by the European Resuscitation Council (ERC) and International Liaison Committee on Resuscitation (ILCOR) guidelines. Theoretical knowledge was assessed via multiple-choice questionnaires at three time points (baseline, post-course, 12 weeks later). Practical skills were evaluated through an Objective Structured Clinical Examination (OSCE). Data were analyzed using Wilcoxon tests, repeated-measures ANOVA, and linear mixed models. Student evaluations were used to gauge subjective satisfaction with the scenario during teaching.

RESULTS: No significant differences were observed between groups at baseline. The intervention group demonstrated significantly greater gains in knowledge at both post-course (p < 0.01) and follow-up (p = 0.04). However, no significant differences were found in OSCE performance. The VR group's improvement over time was significantly higher, suggesting a positive effect of VR on knowledge retention. Students were satisfied with the addition of a VR scenario in the teaching format.

CONCLUSION: A single VR session prior to ALS training enhanced theoretical knowledge but did not significantly affect practical performance. Students were open to integration of the technology into training, so that VR may serve as a valuable adjunct in CPR education. Further research is needed to evaluate its long-term impact and the optimal integration method into curricula.},
}

@article {pmid41437896,
year = {2025},
author = {Lona-Durazo, F and Byrne, RP and Pilon, MO and Greicius, MD and Dubé, MP and Belloy, ME and McLaughlin, RL and Gagliano Taliun, SA},
title = {Sex-aware causal inference assessment of the immune system in complex neurodegenerative diseases.},
journal = {Brain : a journal of neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/brain/awaf474},
pmid = {41437896},
issn = {1460-2156},
abstract = {Sex differences, in terms of prevalence, symptoms and disease progression, are established in the etiology of complex neurodegenerative diseases, including amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease, but the underlying biology driving these differences remains poorly understood. There is emerging evidence, through genetic and functional analyses, affirming the role of the immune system in such diseases, but a thorough assessment of sex differences linking the immune system and neurodegenerative diseases is understudied. Here, we applied a robust causal inference approach, two-sample Mendelian randomization, to evaluate the causal effect of immune-related protein levels on three neurodegenerative diseases with large-scale sex-stratified genome-wide association data available: amyotrophic lateral sclerosis (females = 10,895 cases, 57,062 controls; males = 15,547 cases, 50,145 controls), Parkinson's disease (females = 7,947 cases, 90,662 controls; males = 13,020 cases, 89,660 controls) and Alzheimer's disease (females = 18,822 cases, 281,415 controls; males = 17,293 cases, 213,339 controls). As exposures, we focused on 932 immune system-related proteins with significant protein cis-quantitative trait loci (FDR cutoff < 0.01) from a large sex-combined plasma protein dataset (N = 33,477), for which corresponding genes were included in the Immunology Database and Analysis Portal gene list. We tested for a causal relationship between genetically predicted levels of each of these proteins and each neurodegenerative disease in sex-stratified and sex-combined data, followed by colocalization and estimation of sex-differential effects. We additionally performed exploratory analyses using sex-combined CSF protein cis-quantitative trait loci (N = 971) as exposures. We observed evidence for a sex-differential causal relationship between FCGR2A and Parkinson's disease, and between CD2AP, MAMDC2, PCDH17 or CSF3 and Alzheimer's disease. We validated significant results using two independent protein cis-quantitative trait loci datasets for those plasma proteins available. After performing sensitivity analyses, we validated the potential causal relationships of OMG on Parkinson's disease and of GRN, SERPINF2 and TREM2 on Alzheimer's disease. Mendelian randomization with CSF protein cis-quantitative trait loci showed a potential causal effect of ADGRE2, GPNMB and COLEC11 on Parkinson's disease and of CD33 on Alzheimer's disease, without evidence of sex-differential effects. Finally, we substantiated our findings of protein-disease pairs using triangulation, specifically reporting independent supporting evidence from the literature and drug-related databases. Overall, our results point to potential causal effects of genetically predicted levels of immune system-related plasma and CSF proteins in Alzheimer's disease and Parkinson's disease, some of which may be considered as potential candidates for drug development.},
}

@article {pmid41437419,
year = {2025},
author = {McKeever, PM},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e103455},
doi = {10.1002/alz70855_103455},
pmid = {41437419},
issn = {1552-5279},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; *Frontotemporal Lobar Degeneration/genetics/pathology/metabolism ; Microglia/metabolism/pathology ; *Neurons/metabolism/pathology ; Male ; Female ; DNA-Binding Proteins/metabolism ; Aged ; 3' Untranslated Regions ; Middle Aged ; },
abstract = {BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia, often co-occurring with amyotrophic lateral sclerosis (ALS). Despite shared genetic and pathological features, the cell type-specific molecular mechanisms underlying FTLD in ALS remain poorly understood.

METHOD: Excitatory neurons exhibited synaptic dysfunction in ALS with and without FTLD, while inhibitory neurons were more affected in ALS without FTLD. Microglia displayed a disease-associated state in both groups, with ALS with FTLD showing elevated JAK-STAT signaling, indicative of a proinflammatory phenotype. We identified widespread shifts toward distal 3'UTR usage in ALS with and without FTLD, implicating APA dysregulation. APA-Net revealed coordinated RBP interactions, including TDP-43, HNRNPA1, and MBNL1, as key regulators of APA in ALS with and without FTLD. These findings highlight distinct and overlapping molecular signatures between the two disease subtypes.

RESULT: We identified cell type-specific transcriptional dysregulation, with excitatory neurons showing synaptic dysfunction in both C9-ALS and sALS, while inhibitory neurons were more affected in sALS. Microglia exhibited a disease-associated state, with C9-ALS microglia showing elevated JAK-STAT signaling, indicative of a proinflammatory phenotype. We detected widespread shifts toward distal 3'UTR usage in ALS/FTLD, implicating APA dysregulation. APA-Net revealed coordinated RBP interactions, including TDP-43, HNRNPA1, and MBNL1, as key regulators of APA in ALS/FTLD. These findings highlight distinct and overlapping molecular signatures in C9-ALS and sALS, with implications for FTLD pathogenesis.

CONCLUSION: This study provides a comprehensive single-nucleus transcriptomic atlas of the frontal cortex in ALS with and without FTLD, uncovering cell type-specific dysregulation of APA and RBP interactions. Our findings offer new insights into the molecular mechanisms driving FTLD and provide a resource for future therapeutic development.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
*Frontotemporal Lobar Degeneration/genetics/pathology/metabolism
Microglia/metabolism/pathology
*Neurons/metabolism/pathology
Male
Female
DNA-Binding Proteins/metabolism
Aged
3' Untranslated Regions
Middle Aged

@article {pmid41437192,
year = {2025},
author = {Gebregergis, B and Ralph, LT and Zhang, L and Collingridge, GL and Robertson, J},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e102329},
doi = {10.1002/alz70855_102329},
pmid = {41437192},
issn = {1552-5279},
mesh = {Animals ; *Hippocampus/pathology/metabolism ; Mice, Knockout ; *C9orf72 Protein/genetics ; Receptors, AMPA/metabolism ; Mice ; Disease Models, Animal ; Kainic Acid ; Dendritic Spines/pathology ; Neurons/pathology/metabolism ; Male ; *Frontotemporal Dementia/genetics ; Neuronal Plasticity ; Synapses/pathology ; Mice, Inbred C57BL ; },
abstract = {BACKGROUND: Hexanucleotide repeat expansions in C9orf72, the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), are associated with haploinsufficiency, synaptic dysfunction, and neurodegeneration. Synaptic hyperexcitability and excitotoxicity are emerging hallmarks in C9orf72-associated neurodegeneration; however, the underlying mechanisms in dementia-related pathology remain poorly understood.

METHOD: Using C9orf72-knockout (C9-KO) mice as a model, we investigated the role of C9orf72 in synaptic function and excitotoxic vulnerability. We assessed hippocampal synaptic markers, including GluA1 surface expression, dendritic spine morphology, and calcium-permeable AMPA receptor (CP-AMPAR)-mediated plasticity. Kainic acid (KA)-induced excitotoxic stress was used to evaluate seizure susceptibility, network stability via EEG analysis, and hippocampal GluA1 dysregulation. CP-AMPAR antagonists were applied to examine their therapeutic potential.

RESULT: C9-KO mice exhibited enhanced synaptic hyperexcitability, characterized by elevated surface GluA1 expression, reduced dendritic spine density, and enlarged spine heads in hippocampal neurons. These changes correlated with enhanced CP-AMPAR-mediated synaptic plasticity and heightened excitotoxic vulnerability following KA treatment. C9-KO mice displayed more severe seizures, abnormal EEG spectral power, and persistent hippocampal GluA1 elevation. Selective CP-AMPAR antagonism effectively reduced excitotoxic damage and normalized synaptic function.

CONCLUSION: Our findings demonstrate that C9orf72 deficiency drives synaptic hyperexcitability and excitotoxic vulnerability through CP-AMPAR dysregulation, implicating this pathway in the pathophysiology of FTD. At the network level, C9orf72 loss amplifies excitatory signaling, linking synaptic dysfunction to network instability and neuronal degeneration. By identifying CP-AMPARs as central mediators of excitotoxicity, this study highlights a novel therapeutic target for C9orf72-associated dementia and other neurodegenerative diseases characterized by excitatory network dysfunction.},
}

Animals
*Hippocampus/pathology/metabolism
Mice, Knockout
*C9orf72 Protein/genetics
Receptors, AMPA/metabolism
Mice
Disease Models, Animal
Kainic Acid
Dendritic Spines/pathology
Neurons/pathology/metabolism
Male
*Frontotemporal Dementia/genetics
Neuronal Plasticity
Synapses/pathology
Mice, Inbred C57BL

@article {pmid41437053,
year = {2025},
author = {Su, WM and Duan, QQ and He, SY and Liu, RY and Wen, XJ and Zhang, N and Chen, T and Cao, B and Chen, YP},
title = {Loss of Y chromosome and its implications in male amyotrophic lateral sclerosis: insights from the UK Biobank.},
journal = {BMC medicine},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12916-025-04594-x},
pmid = {41437053},
issn = {1741-7015},
support = {no. 82371422 and no. 81971188//the National Natural Science Fund of China/ ; no. 2022YFC2703101//the National Key Research and Development Program of China/ ; no. 2023HXFH032//the 1·3·5 project for disciplines of excellence Clinical Research Fund, West China Hospital, Sichuan University/ ; },
abstract = {BACKGROUND: Amyotrophic lateral sclerosis (ALS) shows a male predominance, yet the underlying mechanism remains unclear. Although the loss of Y chromosome (LOY) in peripheral blood - a male-specific genetic alteration - has been implicated in certain neurodegenerative disorders (NDDs), its association with ALS in men remains unexplored and has not been explored.

METHODS: We focused on men in the UK Biobank to investigate whether LOY influences the risk and prognosis of ALS. Initially, the LOY level for each male participant was determined using sequencing data. Subsequently, Cox proportional hazards (Cox PH) model analysis was used to assess LOY-associated risk of ALS; thirdly, piecewise linear regression, Kaplan-Meier, and Cox PH analysis assessed LOY's associations with ALS age at onset (AAO) and survival. Fourthly, multiple analytical methods were implemented to explore the relationship between LOY and ALS indicators, including plasma GFAP (glial fibrillary acidic protein) and NfL (neurofilament light chain). Finally, sensitivity analysis was carried out.

RESULTS: Our final cohort consisted of 158,953 male participants, with a mean follow-up of 11.7 years. Among them, 297 individuals developed ALS. After adjusted multiple confounding factors, including C9orf72 hexanucleotide repeat expansion (HRE), male participants with LOY exhibited an elevated risk of developing ALS (HR [95% CI]: 1.619 [1.059-2.475], p = 0.026). LOY carrier may be more likely to be associated with a later AAO and shorter survival; however, this association did not reach statistical significance in multivariate models. Additionally, our findings revealed that LOY was significantly associated with elevated plasma NfL levels (p = 0.004). Moreover, the median Log2 R ratios of Y chromosome (mLRRY value) exhibited a modest inverse correlation with plasma GFAP levels (Pearson's r = - 0.059). Nevertheless, LOY did not exert an influence on the longitudinal trends of NfL and GFAP and was not clearly associated with C9orf72 HRE status.

CONCLUSIONS: Our results indicate that LOY makes a potential contribution to the risk of ALS and the elevation of plasma NfL levels. While LOY's impact on ALS AAO and survival requires further validation, these findings identify it as a promising sex‑specific therapeutic target and support its potential for stratifying male ALS patients toward personalized treatments.},
}

@article {pmid41436842,
year = {2025},
author = {Mao, H and Matsubara, T and Tanaka, N and Peled, N and Farzaneh, H and Melania Lon, D and Suzuki, N and Richardson, RM and Cole, AJ and Fang, X and Stufflebeam, SM},
title = {Transcriptomic decoding of regional cortical vulnerability to drug-resistant epilepsy using 7T MRI.},
journal = {Communications biology},
volume = {},
number = {},
pages = {},
doi = {10.1038/s42003-025-09397-7},
pmid = {41436842},
issn = {2399-3642},
abstract = {The mechanism by which genetic risk leads to cortical vulnerability in drug-resistant epilepsy (DRE) remains unclear. This study used 7T structural and resting-state functional MRI to investigate cortical neural activity alterations in 105 DRE patients and 105 healthy controls (HCs), and to explore related genetic mechanisms. Vertex-wise analyses of mean amplitude of low-frequency fluctuation (mALFF) and regional homogeneity (ReHo) revealed that DRE patients primarily exhibited decreased mALFF and increased ReHo in the Cingulo-Opercular Network. Using the Allen Human Brain Atlas, we conducted spatial transcriptomic analysis via partial least squares (PLS) and gene enrichment analysis to identify gene categories associated with these functional changes. The results showed that cortical alterations were related to epilepsy-general genes (e.g., TMEM74, KCNN2, RBFOX1) and brain-relevant genes. Genes positively correlated with mALFF alterations enriched in mitochondrial inner membrane, matrix, and carboxylic acid metabolism; negatively in chromatin remodeling, binding, and postsynapse. Genes positively correlated with ReHo alterations enriched in nucleic acid-related catalytic activity, ribonucleoprotein granule, and centrosome; negatively in amyotrophic lateral sclerosis, mitochondrial membrane, and pyrophosphatase activity. These findings link spatial brain activity abnormalities in DRE to specific genetic signatures and biological pathways, suggesting new mechanistic insights and potential therapeutic targets for this difficult-to-treat condition.},
}

@article {pmid41436064,
year = {2025},
author = {Kartono, B and Attisano, L and Robertson, J},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e099957},
doi = {10.1002/alz70855_099957},
pmid = {41436064},
issn = {1552-5279},
mesh = {Animals ; Mice ; *C9orf72 Protein/genetics ; *Neurons/drug effects/metabolism/pathology ; Haploinsufficiency ; *Frontotemporal Dementia/genetics ; Amyotrophic Lateral Sclerosis/genetics ; *Lactams, Macrocyclic/pharmacology ; },
abstract = {BACKGROUND: Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat expansions cause C9orf72 haploinsufficiency and reduced C9orf72 protein expression. C9orf72 haploinsufficiency disrupts normal synaptic function, causing alterations in neuronal morphology, glutamatergic imbalances, and dysregulation of pre- and post-synaptic proteins, linked to aberrant actin dynamics. These disruptions are central to the pathogenesis of C9orf72-related FTD. Lorlatinib, an ALK inhibitor used in cancer therapy, has known effects on regulating actin dynamics, acting through the PI3K-LIMK-cofilin pathway. Here, we explored lorlatinib as a potential therapeutic by testing its effects on rescuing neuronal phenotypes caused by C9orf72 haploinsufficiency.

METHODS: To assess lorlatinib's potential in mitigating synaptic dysfunction associated with C9orf72 haploinsufficiency, we used primary cortical neurons from C9orf72+/- mouse embryos (E13-16). We focused on dendritic arborization and vulnerability to glutamate excitotoxicity. Analyses were performed at DIV12-15 using immunocytochemistry and immunoblots to evaluate dendritic complexity and protein expression.

RESULTS: Primary cortical neurons with C9orf72 haploinsufficiency exhibit alterations in dendritic branching, indicating disrupted neuronal connectivity. Additionally, C9orf72 haploinsufficiency increases neuronal vulnerability to excitotoxicity and cell death under stress, evidenced by reduced viability following high glutamate exposure. Glutamate excitotoxicity is a common pathomechanism in neurodegenerative diseases, including FTD/ALS. This can be explained by elevated calcium-permeable AMPAR subunit GluA1 levels at post-synaptic sites, increasing vulnerability. These synaptic dysfunction phenotypes arise from aberrant activity of interrelated PI3K/Akt and LIMK1/cofilin pathways. Importantly, inhibition of ALK by lorlatinib rescues dendritic complexity and enhances neuronal resilience to glutamate-induced damage by normalizing PI3K/Akt and LIMK1/cofilin activity. Lorlatinib may mitigate synaptic dysfunction and preserve neuronal connectivity, addressing key pathomechanisms underlying C9orf72-FTD.

CONCLUSION: Our findings highlight the therapeutic potential of lorlatinib, an ALK inhibitor, in mitigating synaptic deficits caused by C9orf72 haploinsufficiency. We emphasize the role of synaptic pathology in C9orf72-FTD pathogenesis and suggest that targeting ALK with drugs like lorlatinib could offer promising therapeutic strategies for treating synaptic dysfunction caused by C9orf72 haploinsufficiency.},
}

Animals
Mice
*C9orf72 Protein/genetics
*Neurons/drug effects/metabolism/pathology
Haploinsufficiency
*Frontotemporal Dementia/genetics
Amyotrophic Lateral Sclerosis/genetics
*Lactams, Macrocyclic/pharmacology

@article {pmid41435843,
year = {2025},
author = {Lim, S and Kim, YK and Pae, AN},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e100815},
doi = {10.1002/alz70855_100815},
pmid = {41435843},
issn = {1552-5279},
mesh = {Humans ; *DNA-Binding Proteins/metabolism/genetics ; Histone Deacetylase Inhibitors/pharmacology ; Acetylation ; *Protein Aggregation, Pathological/metabolism ; Histone Deacetylases/metabolism ; *TDP-43 Proteinopathies/metabolism/pathology ; },
abstract = {BACKGROUND: TDP43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), are characterized by the pathological aggregation and mislocalization of TDP43 protein. These aberrant aggregates disrupt cellular functions and contribute to neurodegeneration. However, the molecular mechanisms driving TDP43 aggregation remain unclear. Histone deacetylases (HDACs) regulate protein acetylation, a process implicated in protein aggregation and neurodegenerative diseases. This study aims to elucidate the role of HDAC inhibition and acetylation in TDP43 aggregation, particularly focusing on its mislocalization and oligomerization dynamics.

METHOD: We established a TDP43-BiFC (Bimolecular Fluorescence Complementation) cell model to visualize TDP43 oligomerization in living cells. Using this system, we examined the effects of cellular stress activators and HDAC inhibitors on TDP43 aggregation. The localization and aggregation patterns of TDP43 were analyzed via fluorescence microscopy, and biochemical characterization of aggregates was performed using SDS-PAGE, Western blotting, and immunocytochemistry.

RESULT: Cellular stress activators induced distinct nuclear and cytoplasmic TDP43 aggregation patterns, indicating the involvement of multiple stress-dependent pathways in TDP43 pathology. Broad HDAC inhibition triggered a time-dependent mislocalization of TDP43 from the nucleus to the cytoplasm, suggesting that HDAC-regulated acetylation is crucial for nuclear TDP43 retention. Furthermore, HDAC inhibition led to increased cellular acetylation, which promoted the formation of stable, SDS-resistant TDP43 oligomers via disulfide-linked aggregation. While phosphorylation was detected within these aggregates, our findings suggest that disulfide bonding plays a primary role in driving aggregation, rather than phosphorylation.

CONCLUSION: Our findings highlight the critical role of acetylation-mediated disulfide-linked aggregation in TDP43 pathology and suggest that HDAC inhibition contributes to TDP43 mislocalization and stable oligomer formation. Targeting this pathway may provide a novel therapeutic strategy for TDP43 proteinopathies, including ALS and FTLD.},
}

Humans
*DNA-Binding Proteins/metabolism/genetics
Histone Deacetylase Inhibitors/pharmacology
Acetylation
*Protein Aggregation, Pathological/metabolism
Histone Deacetylases/metabolism
*TDP-43 Proteinopathies/metabolism/pathology

@article {pmid41435524,
year = {2025},
author = {Zanellati, MC},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e100362},
doi = {10.1002/alz70855_100362},
pmid = {41435524},
issn = {1552-5279},
mesh = {*Induced Pluripotent Stem Cells ; *Neurons/pathology/metabolism ; Humans ; Cell Differentiation/physiology ; *Organelles/pathology/metabolism ; Mitochondria ; Alzheimer Disease/pathology ; Cells, Cultured ; },
abstract = {BACKGROUND: Dysfunctional organelle communication networks are a common hallmark of various neurodegenerative diseases, including Alzheimer's disease (AD). Imaging organelles and their interactions in iPSC-derived neurons that harbor disease-associated mutations holds promise for understanding the mechanistic basis of neurodegeneration.

METHOD: We developed a method for multispectral imaging of eight organelles simultaneously in live cells and used this method to visualize organelle morphology and dynamics (morphodynamics) along neuronal differentiation. We transfected induced pluripotent stem cells (iPSCs) and iPSC-derived cortical neurons (iNeurons) with genetically encoded organelle markers and collected multispectral z-stack and timelapse images at five-time points throughout neuronal differentiation and maturation: iPSCs, and iNeurons at day 7, day 14, day 21, and day 28. Raw images were then subjected to linear unmixing and run through a Napari-InferSubC image analysis pipeline for segmentation and analysis of approximately 1400 morpho-metrics including organelle volume, size, shape, and number, as well as number and volume of the contacts between organelles (2- to 6-way).

RESULT: We observed dramatic remodeling of organelles during differentiation of iPSCs into iNeurons. For example, endoplasmic reticulum (ER) and mitochondria volumes increased as iPSCs differentiated into cortical neurons. We observed an increase in the overall number of the contacts throughout iNeuron maturation, accompanied by an increase in higher order contacts (3- and 4-way contacts). Examples of organelle contacts that increased during iNeuron differentiation and maturation include ER-mitochondria, known to be dysregulated in AD and Parkinson disease; mitochondria-lysosome, previously reported defective in Charcot-Marie-Tooth; and ER-peroxisome. We found that expression of VAPB, which mediates ER-peroxisome contacts and is mutated in ALS, increases as iPSCs differentiate into iNeurons. This contact is implicated in the production of plasmalogens, which are essential for the growth and maintenance of synapses in the nervous system. Knockdown of VAPB reduced plasmalogen levels and prevented the formation of synapses during iNeuron differentiation.

CONCLUSION: We uncovered a novel role for VAPB-mediated ER-peroxisome contacts in neuronal differentiation, suggesting that multi-spectral imaging can be used to interrogate organelle morphology and contacts during neuronal differentiation and neurodegeneration. As a future direction, we will use this method to reveal defects in organelle communication networks in iNeurons with AD-associated mutations.},
}

*Induced Pluripotent Stem Cells
*Neurons/pathology/metabolism
Humans
Cell Differentiation/physiology
*Organelles/pathology/metabolism
Mitochondria
Alzheimer Disease/pathology
Cells, Cultured

@article {pmid41435398,
year = {2025},
author = {Guo, J and You, L and Chen, Y and Zhang, M},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e100010},
doi = {10.1002/alz70855_100010},
pmid = {41435398},
issn = {1552-5279},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism ; Animals ; *Alzheimer Disease/genetics/pathology/metabolism ; Mice ; *Motor Cortex/metabolism/pathology ; Transcriptome ; *Prefrontal Cortex/metabolism/pathology ; Gene Expression Profiling ; Brain/metabolism/pathology ; },
abstract = {BACKGROUND: Spatial architecture of cell types and gene expression is the foundation of cell-cell interactions, biological function and disease pathology, but is not well investigated in human cortex, which are highly related to neurodegenerative diseases, such as Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Recent studies indicated single nucleus transcriptomic features of excitatory neuron vulnerability in AD entorhinal cortex, and motor neuron vulnerability in ALS motor cortex. However, it remains unclear what is the brain regional vulnerability of AD or ALS associated genes.

METHOD: We developed an entropy-weighted differential gene expression matrix-based tool (SpatialE) to identify the spatial enrichment of gene sets in spatial transcriptomics (ST). We benchmarked SpatialE against another enrichment tool (Multimodal Intersection Analysis, MIA) using ST data from human and mouse brain tissues. To investigate regional vulnerability, we analyzed three human motor cortex and two dorsolateral prefrontal cortex (DLPFC) tissues for spatial enrichment analyses of AD and ALS associated genes. We also used Cell2location to estimate the abundance of cell types in AD and ALS related cortex layers.

RESULT: SpatialE showed more accurate and specific spatial enrichment of regional cell type markers than MIA in both mouse brain and human DLPFC. Spatial transcriptomic analyses of human motor cortex and dorsolateral prefrontal cortex showed heterogenous cell types and spatial gene expression profiles. We found that the expression of AD associated genes (n = 139, n = 162) that were indicated from two AD genome-wide association studies are significantly enriched in layer 1 (L1) motor cortex (P_bonferroni<0.01 for 3 ST data), but not in DLPFC. Cell type deconvolution analysis identified abundant expression of astrocytes in human L1 motor cortex. Additionally, the expression of 260 manually curated ALS-associated genes are significantly enriched in layer 5 (L5) motor cortex and DLPFC (P_bonferroni<0.03 for 5 ST data). Cell type deconvolution analysis revealed an abundant expression of upper motor neurons and L5 excitatory neurons in human L5 motor cortex.

CONCLUSION: We developed a novel computational tool (SpatialE) to characterize spatial enrichment expression of a gene set in spatial transcriptomics data. Spatial enrichment analyses identified regional brain vulnerability of AD and ALS associated genes in human brain.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/pathology/metabolism
Animals
*Alzheimer Disease/genetics/pathology/metabolism
Mice
*Motor Cortex/metabolism/pathology
Transcriptome
*Prefrontal Cortex/metabolism/pathology
Gene Expression Profiling
Brain/metabolism/pathology

@article {pmid41435189,
year = {2025},
author = {Stein, TD and Aytan, N and Empawi, JA and Nicks, R and Cherry, JD and Alvarez, VE and Alosco, ML and Mez, J and Labadorf, AT and McKee, AC and Zhang, X and Mordes, DA},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e096742},
doi = {10.1002/alz70855_096742},
pmid = {41435189},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Middle Aged ; *DNA-Binding Proteins/metabolism/genetics ; *Chronic Traumatic Encephalopathy/pathology/metabolism/genetics ; Aged ; *Brain/pathology/metabolism ; Adult ; Cognitive Dysfunction/pathology/etiology ; Inclusion Bodies/pathology/metabolism ; },
abstract = {BACKGROUND: Repetitive head impacts that occur in contact/collision sports, military service, and physical violence are associated with TDP-43 pathology, and TDP-43 inclusions are frequently present in the hippocampus and frontal cortex in chronic traumatic encephalopathy (CTE). Individuals with CTE and TDP-43 inclusions are more likely to show severe cognitive impairment; however, the underlying mechanism is unknown. In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 inclusions are associated with widespread gene mis-splicing and cryptic exon expression. We hypothesized that TDP-43 pathology in CTE similarly contributes to gene mis-splicing, leading to selective protein loss and neurodegeneration.

METHODS: A total of 212 brain donors with a history of repetitive head impacts were examined for CTE and the presence and distribution of TDP-43 inclusions. Clinical outcomes, including measures of cognitive impairment, were obtained from informants and medical records. Bulk RNA sequencing and SomaScan 7K aptamer-based proteomics were performed on the dorsolateral prefrontal cortex. After excluding those with AD, FTLD-TDP, or ALS, variable splicing events were determined using LeafCutter in those with CTE and TDP-43 inclusions in the hippocampus or frontal cortex (CTE-TDP) compared to CTE without TDP-43 in those regions (CTE).

RESULTS: Out of 142 with CTE, 72 (51%) had TDP-43 inclusions within the hippocampus, frontal cortex, or both (CTE-TDP). Differential analysis revealed altered splicing within 836 genes in CTE-TDP compared to CTE with a false discovery rate <0.01. Of these, 23 overlapped with previously identified mis-spliced genes in ALS and FTLD-TDP. Seven of these genes had protein levels measured with SomaScan proteomics, including CAMK2B, DLGAP4, EPB41L1, NCAM1, PTPRD, RAP1GAP, and SH3KBP1. Notably, protein levels of erythrocyte membrane protein band 4.1 like 1 (EPB41L1) and RAP1 GTPase-activating protein (RAP1GAP) were significantly reduced in CTE-TDP frontal cortex compared to CTE (p's <0.01) and negatively correlated with both amygdala and hippocampal TDP-43 inclusions. Furthermore, decreased levels of EPB41L1 and RAP1GAP were associated with dementia adjusting for age (p's <0.05).

CONCLUSIONS: Both EPB41L1 and RAP1GAP are involved in synaptic plasticity and signaling. Mis-splicing and decreased protein expression of these synapse-related genes may partially underlie the neurodegeneration and cognitive impairments in CTE with TDP-43 inclusions.},
}

Humans
Male
Female
Middle Aged
*DNA-Binding Proteins/metabolism/genetics
*Chronic Traumatic Encephalopathy/pathology/metabolism/genetics
Aged
*Brain/pathology/metabolism
Adult
Cognitive Dysfunction/pathology/etiology
Inclusion Bodies/pathology/metabolism

@article {pmid41435135,
year = {2025},
author = {Pak, V and Hong, JH and Bezgin, G and Dadar, M and Zeighami, Y and Medina, YI},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e099186},
doi = {10.1002/alz70855_099186},
pmid = {41435135},
issn = {1552-5279},
mesh = {Humans ; *Brain/pathology/metabolism/diagnostic imaging ; *Neurodegenerative Diseases/pathology/diagnostic imaging/metabolism ; Atrophy/pathology ; Neurons/metabolism/pathology ; Male ; Neuroimaging ; *Cell Communication/physiology ; Female ; },
abstract = {BACKGROUND: Disrupted interactions among neurons, glial and vascular cell types can lead to inflammation, vascular dysfunction, and neuronal death, highlighting the need to understand how functional interactions between these cells predispose the development of different neurodegenerative conditions. Here we identified cell-cell interactions across the whole human brain that explain atrophy patterns characteristic to 13 neurodegenerative conditions.

METHOD: We generated 1,050 whole-brain neuroimaging maps of ligand-receptor interactions specific to neurons, astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells, and endothelial cells. These maps were created by inferring literature-curated ligand-receptor interaction pairs from microarray gene expression derived from post-mortem tissues of six healthy human donors, sourced from the Allen Human Brain Atlas (Figure 1a-b). Next, using Partial Least Squares Regression (PLS) analysis, we identified key LR pairs whose patterns of communication explain the spatial distribution of atrophy maps specific to 13 neurodegenerative conditions (Figure 1c). Atrophy maps were previously generated for early- and late-onset Alzheimer's disease (EOAD and LOAD), clinical and pathological subtypes of frontotemporal lobar degeneration (FTLD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and amyotrophic lateral sclerosis (ALS). Finally, we performed gene enrichment analyses to uncover underlying signaling pathways that explain future atrophy in neurodegeneration.

RESULT: The first latent variable (LV1) accounted for 84.21% of the covariance (p < 0.05), with the COL1A1-CD36 interaction and other CD36-associated pairs playing a dominant role in explaining atrophy patterns (Figure 2a). Atrophy patterns common to five FTLD-related disorders contributed the most to LV1, followed by EOAD and LOAD (Figure 2b). Among the top 10% of ligand-receptor pairs, 28 of 107 showed strong bi-directional signaling between astrocytes and neurons, along with prominent contributions from neuron-microglia and neuron-neuron signalling (Figure 2d). These top ligands and receptors were significantly enriched for pathways including Slit/Robo-mediated axon guidance, opioid prodynorphin, enkephalin release, and Alzheimer's disease presenilin pathway (Figure 2e; p < 0.001, FDR-corrected).

CONCLUSION: We identified whole-brain ligand-receptor interactions involved in neuron-astrocyte, neuron-microglia, and neuron-neuron signaling pathways that explain the observed atrophy patterns in multiple neurodegenerative conditions. These key ligands and receptors may serve as potential therapeutic targets and advance our understanding of neurodegeneration.},
}

Humans
*Brain/pathology/metabolism/diagnostic imaging
*Neurodegenerative Diseases/pathology/diagnostic imaging/metabolism
Atrophy/pathology
Neurons/metabolism/pathology
Male
Neuroimaging
*Cell Communication/physiology
Female

@article {pmid41434986,
year = {2025},
author = {Bronskill, SE and Maclagan, LC and Matai, L and Emdin, AL and Roberts, AC and Binns, M and McLaughlin, PM and Black, SE and Swartz, RH},
title = {Public Health.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 6},
number = {},
pages = {e101213},
doi = {10.1002/alz70860_101213},
pmid = {41434986},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; Aged ; Ontario/epidemiology ; Prospective Studies ; *Neurodegenerative Diseases/epidemiology/mortality/therapy ; *Public Health ; Middle Aged ; Amyotrophic Lateral Sclerosis ; Nursing Homes/statistics & numerical data ; Cognitive Dysfunction/epidemiology ; Aged, 80 and over ; Parkinson Disease ; Cohort Studies ; Alzheimer Disease ; },
abstract = {BACKGROUND: The Ontario Neurodegenerative Disease Research Initiative (ONDRI) was a prospective cohort study that enrolled persons with varied neurodegenerative pathologies including Alzheimer's disease and/or mild cognitive impairment (ADMCI), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and cerebrovascular disease± cognitive impairment (CVD) who underwent clinical and functional assessments in Ontario, Canada. We sought to examine long-term differences in health system use, transition to nursing home, and mortality across neurodegenerative pathologies via linkage with provincial health administrative data.

METHODS: Of 520 participants enrolled in the ONDRI study, 478 provided consent and were linked to health administrative databases. This included 122 persons with ADMCI, 38 with ALS, 47 with FTD, 116 with PD, and 155 with CVD. Participants were followed from the year prior to their enrollment date (2014-2017) to March 31[st] 2024, death, or loss of health insurance eligibility, whichever occurred first. Rates of health service use, transition to nursing home, and mortality were calculated by neurodegenerative pathology and expressed per 100 person-years.

RESULTS: Persons with PD were most likely to be male, while those with ADMCI showed the lowest proportion males (75.9% vs. 54.1%). Those with ADMCI were older compared to persons with ALS (mean 70.2 vs. 61.7 years). Follow-up time ranged from an average of 2.8 years in persons with ALS to 8.0 years in those with CVD. Persons with ALS had the highest mortality rate, while those CVD had the lowest (35.3 vs. 2.4 per 100 person-years). Persons with all neurodegenerative diseases showed a high use of health services, varying by service type. Persons with ALS showed the highest rate of home care visits, including visits for nursing, personal support, and therapies, followed by persons with FTD. Persons with PD had the highest rate of fall-related emergency department visits and hospitalizations. Persons with FTD had the highest rate of transition to nursing home.

CONCLUSIONS: Our findings demonstrate that persons with neurodegenerative pathologies require different health services, with varying intensity, to meet their needs. Linkage of health administrative data to clinical cohorts supports examination of health service milestones and allows for long-term follow-up at relatively low cost.},
}

Humans
Male
Female
Aged
Ontario/epidemiology
Prospective Studies
*Neurodegenerative Diseases/epidemiology/mortality/therapy
*Public Health
Middle Aged
Amyotrophic Lateral Sclerosis
Nursing Homes/statistics & numerical data
Cognitive Dysfunction/epidemiology
Aged, 80 and over
Parkinson Disease
Cohort Studies
Alzheimer Disease

@article {pmid41434870,
year = {2025},
author = {Paço, SL and Andrews, SJ and Naslavsky, MS},
title = {Public Health.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 6},
number = {},
pages = {e107188},
doi = {10.1002/alz70860_107188},
pmid = {41434870},
issn = {1552-5279},
mesh = {Humans ; Male ; Female ; *Alzheimer Disease/genetics ; Aged ; *Public Health ; Polymorphism, Single Nucleotide/genetics ; *Genetic Predisposition to Disease/genetics ; *Cognitive Dysfunction/genetics ; Brazil ; Apolipoprotein E4/genetics ; Aged, 80 and over ; White People/genetics ; Multifactorial Inheritance/genetics ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is linked to cognitive decline, with genetic factors like the APOE4 allele increasing risk. Polygenic risk scores (PRS) combine genetic variants to predict AD susceptibility. This project applies PRS models to two datasets: SABE (Brazilian admixed elderly population) and ADNI (European population), aiming to understand how genetic factors and ancestry influence cognitive impairment.

METHOD: PRS are generated using PRSice-2, including Sofer et al.'s PRS_SUM for cognitive impairment prediction. Models analyzed: Bel (1,937 SNPs), Kunkle (12,002 SNPs), Kunkle-AFR (157 SNPs), and PRS_SUM (14,107 SNPs). The Dataset areSABE - ABraOM: 1,103 Brazilian elderly individuals, 64% European ancestry. ADNI: 785 individuals, mostly European ancestry, with clinical data on AD.

STATISTICS: Linear regression with bootstrapping (n = 1000), considering variables like age, sex, education, APOE4, and local ancestry.

RESULTS: In SABE, age negatively impacts cognition, while education improves it. APOE4's effect is small but suggests higher risk in individuals with European ancestry. PRS models vary, with R[2] between 0.266 and 0.268. Local ancestry analysis shows greater homozygosity in European and East Asian ancestries. In ADNI, APOE4 significantly affects MMSE, with age also negatively impacting cognition. PRS_Kunkle explained more variability (R[2]=0.155), while PRS_Kunkle_AFR explained less (R[2]=0.131).

CONCLUSION: The project highlights the complex relationships between PRS, cognitive performance, and genetic ancestry in AD. PRS models vary across populations, and local ancestry analysis in SABE emphasizes the importance of considering ancestry in admixed populations.},
}

Humans
Male
Female
*Alzheimer Disease/genetics
Aged
*Public Health
Polymorphism, Single Nucleotide/genetics
*Genetic Predisposition to Disease/genetics
*Cognitive Dysfunction/genetics
Brazil
Apolipoprotein E4/genetics
Aged, 80 and over
White People/genetics
Multifactorial Inheritance/genetics

@article {pmid41434745,
year = {2025},
author = {Westergard, T},
title = {Basic Science and Pathogenesis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 1},
number = {},
pages = {e096500},
doi = {10.1002/alz70855_096500},
pmid = {41434745},
issn = {1552-5279},
mesh = {Humans ; *Progranulins/metabolism ; Astrocytes/metabolism/drug effects ; DNA-Binding Proteins/genetics/metabolism ; Induced Pluripotent Stem Cells/metabolism ; *Motor Neurons/metabolism/drug effects/pathology ; *Intercellular Signaling Peptides and Proteins/metabolism ; Adaptor Proteins, Vesicular Transport/metabolism ; Cells, Cultured ; },
abstract = {BACKGROUND: Reduced levels of progranulin (PGRN) protein are associated with frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Sortilin (SORT1) is a scavenger receptor responsible for the uptake of PGRN into the cell targeting its degradation. GSK5862611 (S60-11) is an anti-Sortilin (SORT1) human IgG1 antibody developed to inhibit binding of PGRN to sortilin receptors and deplete sortilin receptors from the cell surface, resulting in an increase in extracellular PGRN levels. Similar anti-sortilin antibodies are currently in phase 2 and phase 3 clinical trials for AD and FTD-GRN, respectively. Given that PGRN plays an important role in maintaining lysosomal functions and neuronal survivability we evaluated whether enhancing PGRN levels could be effective in reversing phenotypes associated with TDP43 G298S risk variant in complex hiPSC-derived cellular models.

METHOD: hiPSC-derived bi- and tricultures comprising spinal motor neurons and astrocytes carrying TDP43 risk variant G298S mutation and wild-type or GRN edited microglia were established and treated with GSK5862611, isotype control hIgG1, or recombinant PGRN. Impacts on neurite length and TDP43 mislocalization in motor neurons as well as levels of PGRN, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in the culture media were assessed.

RESULTS: Recombinant PGRN rescued the loss of neuritic length and TDP-43 mislocalization in hiPSC-derived bicultures from TDP43 G298S risk variant. Like PGRN, GSK5861611 also rescued loss of neuritic length and TDP43 mislocalization compared to untreated bicultures, however the effect was not significant when compared to isotype control hIgG1. In hiPSC-derived tricultures including GRN edited microglia, GSK5862611 increased extracellular PGRN levels and reduced TDP43 mislocalization in a dose-dependent manner. Additionally, GSK5862611 reduced NfL and GFAP levels in TDP43 tricultures with PGRN Het microglia (HumIgG1 had similar reduction in NfL).

CONCLUSION: Taken together, these results indicate that blocking Sortilin receptors increases extracellular PGRN levels while reducing TDP43 mislocalization in motor neurons, and reducing NfL and GFAP levels in complex hiPSC cellular models carrying a TDP43 G298S risk variant. These data support the hypothesis that increasing PGRN levels with an anti-sortilin antibody may be a promising therapeutic strategy in ALS.

ACKNOWLEDGEMENTS: S60-11 anti-sortilin mAb was provided by Alector.},
}

Humans
*Progranulins/metabolism
Astrocytes/metabolism/drug effects
DNA-Binding Proteins/genetics/metabolism
Induced Pluripotent Stem Cells/metabolism
*Motor Neurons/metabolism/drug effects/pathology
*Intercellular Signaling Peptides and Proteins/metabolism
Adaptor Proteins, Vesicular Transport/metabolism
Cells, Cultured

@article {pmid41434728,
year = {2025},
author = {Campbell, MC and Acheson, L and Mason, EL and Shetty, TH and Emptage, L and Redekop, R and Kitor, M and MacKenzie, IR and Futhey, NC and Hirsch-Reinshagen, V and Hsiung, GR},
title = {Developing Topics.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 7},
number = {},
pages = {e108465},
doi = {10.1002/alz70861_108465},
pmid = {41434728},
issn = {1552-5279},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/pathology/diagnosis/metabolism ; Male ; Female ; Aged ; *Alzheimer Disease/pathology/diagnosis ; *Retina/pathology/metabolism/diagnostic imaging ; Machine Learning ; Amyloid beta-Peptides/metabolism ; Brain/pathology/metabolism ; DNA-Binding Proteins/metabolism ; Middle Aged ; tau Proteins/metabolism ; *Frontotemporal Dementia/pathology ; Diagnosis, Differential ; Aged, 80 and over ; },
abstract = {BACKGROUND: We have shown that interactions with polarized light differed significantly between retinal amyloid beta deposits, associated with Alzheimer's disease, and deposits of TDP-43 found in the neurodegenerative diseases Frontotemporal Lobular Dementia (FTLD) and Amyotrophic Lateral Sclerosis (ALS). Our non-invasive retinal imaging could be the first differential diagnostic of these neurodegenerative diseases. Here, the deposits' polarized light interactions are used in machine learning to classify the deposits.

METHOD: Post-mortem eyes and brains were obtained from 2 individuals with ALS, 1 of whom also had FTLD, and 4 individuals with FTLD, including 1 with Type C. Brain TDP-43 was present in the FTLD cases and some had age-related tau. Flat-mounted retinas were imaged using a polarimeter and then in thioflavin fluorescence. 270 presumed amyloid beta deposits in 10 individuals who had brain amyloid beta and tau and a moderate to high likelihood of AD, and 138 presumed TDP-43 deposits in those with FTLD and/or ALS were imaged. In 1 individual with concurrent low values of brain amyloid and 1 with FTLD-Type C, only thioflavin negative deposits were classed as potential TDP-43 deposits. Interactions of polarized light with deposits were analyzed. Random forest (RF), an ensemble learning method and convolutional neural networks (CNN), were then used to differentiate amyloid beta from TDP-43 deposits.

RESULT: The deposit means and/or standard deviations of nine different polarized light interactions were significantly different between the presumed TDP-43 retinal deposits, found in ALS and FTLD, and amyloid deposits found in AD. With borderline SMOTE augmentation of the data, we achieved a classification accuracy of 86.5± 0.6% using random forest, utilizing 6 of these interactions. CNN achieved a classification accuracy of >96% accuracy using images of the distributions of 3 polarimetric properties.

CONCLUSION: Machine learning, using the averages and standard deviations of polarized light properties in RF or images showing the distribution of these properties across the deposits (CNN) can differentiate retinal deposits associated with Alzheimer's disease from those associated with ALS and FTLD, with a relatively high accuracy. This first differential diagnostic of Alzheimer's disease from TDP-43 related diseases, is early, non-invasive and inexpensive and would reach underserved populations.},
}

Humans
*Amyotrophic Lateral Sclerosis/pathology/diagnosis/metabolism
Male
Female
Aged
*Alzheimer Disease/pathology/diagnosis
*Retina/pathology/metabolism/diagnostic imaging
Machine Learning
Amyloid beta-Peptides/metabolism
Brain/pathology/metabolism
DNA-Binding Proteins/metabolism
Middle Aged
tau Proteins/metabolism
*Frontotemporal Dementia/pathology
Diagnosis, Differential
Aged, 80 and over

@article {pmid41433810,
year = {2025},
author = {Zhang, Y and Wu, Y and Shao, W and Gendron, TF and Noya, JA and Jones, CJ and Jansen-West, K and Daughrity, L and Castanedes-Casey, M and Oskarsson, B and Dickson, DW and Petrucelli, L},
title = {Developing Topics.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 7},
number = {},
pages = {e108268},
doi = {10.1002/alz70861_108268},
pmid = {41433810},
issn = {1552-5279},
mesh = {Animals ; Humans ; C9orf72 Protein/genetics ; *Brain/metabolism/pathology ; Mice ; Frontotemporal Dementia/genetics/metabolism ; *Stress Granules/metabolism ; Amyotrophic Lateral Sclerosis/genetics/metabolism ; DNA Repeat Expansion/genetics ; Dipeptides/metabolism/genetics ; HEK293 Cells ; },
abstract = {BACKGROUND: G4C2 repeat expansions in C9orf72 gene are the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mounting evidence indicates that dipeptide repeat (DPR) proteins translated from the expanded repeats, in particular poly(GR) and poly(PR), play a significant role. We and others have shown that these positively-charged arginine-rich DPR proteins induce the assembly of stress granules (SGs) and impair their disassembly. While distinct from SGs, processing bodies (PBs) are also cytoplasmic messenger ribonucleoprotein condensates that assemble upon stress. However, the impacts of arginine-rich DPR proteins on PB assembly and dynamics have yet to be investigated.

METHOD: We conducted immunofluorescence staining for arginine-rich DPR proteins, SG- and PB-associated markers in cultured cells and mouse brain. Additionally, we performed in vitro liquid-liquid phase separation (LLPS) using recombinant proteins and assessed molecular dynamics of SG and PB through fluorescence recovery (FRAP) after photobleaching in living cells.

RESULT: Here, we observed that both GFP-(GR)100 and GFP-(PR)100 formed cytosolic inclusions immunopositive PB proteins. Unlike GFP-(GR)100 and GFP-(PR)100 inclusions, cellular cytoplasmic GFP-(GA)100 inclusions did not contain PB proteins. We subsequently examined whether the phenomena observed in cultured cells occur in vivo. We observed that PB proteins were recruited to poly(GR) inclusions in cells with aggregated poly(GR). Next, we examined the dynamics of poly(GR)-induced PBs in cultured cells using the FRAP technique. We observed that the recovery of stress-induced PBs was more rapid than that of PBs in HEK293T cells expressing GFP-(GR)100. Lastly, mechanistic studies revealed that poly(GR) interacts with PB proteins to form condensates in vitro via LLPS.

CONCLUSION: Our results provide both in vitro and in vivo evidence that arginine-rich DPRs induce the spontaneous formation of PBs via LLPS. Our results also indicate that poly(GR)-induced PBs are more stable than the transient and dynamic conventional PBs. Given that PBs uniquely enriched with mRNA degradation and decay factors, the consequences of impairing these processes are expected to contribute to abnormal RNA metabolism in c9FTD/ALS.},
}

Animals
Humans
C9orf72 Protein/genetics
*Brain/metabolism/pathology
Mice
Frontotemporal Dementia/genetics/metabolism
*Stress Granules/metabolism
Amyotrophic Lateral Sclerosis/genetics/metabolism
DNA Repeat Expansion/genetics
Dipeptides/metabolism/genetics
HEK293 Cells

@article {pmid41433645,
year = {2025},
author = {Joshi-Awasthi, S},
title = {Developing Topics.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 7},
number = {},
pages = {e108065},
doi = {10.1002/alz70861_108065},
pmid = {41433645},
issn = {1552-5279},
mesh = {Humans ; *Alzheimer Disease/diagnosis/cerebrospinal fluid/diagnostic imaging ; Magnetic Resonance Imaging ; Biomarkers/cerebrospinal fluid ; Male ; Female ; Disease Progression ; Aged ; Cross-Sectional Studies ; Early Diagnosis ; Middle Aged ; },
abstract = {BACKGROUND: Current methods of early detection of Alzheimer's Disease (AD) are not universally available across all geographies. An AI/DL based approach could accelerate the early detection of AD.

METHOD: We investigated the feasibility of developing an AI/DL based model for early detection of AD using cross-sectional (T-1 MRI scans) and longitudinal (CSF) biomarkers. T1 MRI data, was used to develop a ML model to classify subjects with and without AD. We were able to disambiguate "healthy" vs late-stage AD and our model can disambiguate "healthy" and "early onset AD". Using CSF data, we developed a model to predict the progression rate of AD given age and a variety of other covariates. ML techniques were applied to i) T1 MRI imaging to classify subjects as "normal aging", "early-onset", or "moderate AD" measured in terms of ADNC and ii) CSF biomarker data to predict ALSFRS-r (Amyotrophic Lateral Sclerosis Functional Rating Scale) scores and monthly progression factor.

RESULTS: Accuracy and F1 metrics on the test/train dataset were 94.3% and 94.3% for Random Forests, 92.4% and 93.2% for Stochastic Gradient Descent, and 97% and 97% for CNNs. The CNN was able to differentiate early onset patients from normal aging with an accuracy of 94%. Using CSF data, the NN achieved a final MAE: 39.39/40.51; RMSE: 39.95/40.6 in training/testing respectively. Additionally, for evaluating ML methods as a predictive model for AD, we performed meta-analysis using the predicted ALSFRS-r scores, which calculated the time (in years) when patients might reach different points of AD progression (Normal Aging, Low/Moderate ADNC) thereby predicting the window of early detection and intervention for AD.

CONCLUSION: Utilizing the outputs of the MRI-imaging model and CSF sample model, we estimated approximately when a patient may enter stages of Low and Moderate ADNC, potentially helping reveal the otherwise 'missed period of intervention'. This could result in faster treatments for patients still in a treatable phase of their disease, and provide a model for understanding disease progression overtime. Finally, computing a salience map we can potentially determine plaque, NFT, and other biomarkers' locations, enabling higher treatment accuracy, thus more 'personalized' treatment for patients.},
}

Humans
*Alzheimer Disease/diagnosis/cerebrospinal fluid/diagnostic imaging
Magnetic Resonance Imaging
Biomarkers/cerebrospinal fluid
Male
Female
Disease Progression
Aged
Cross-Sectional Studies
Early Diagnosis
Middle Aged

@article {pmid41433413,
year = {2025},
author = {Pak, V and Hong, JH and Bezgin, G and Dadar, M and Zeighami, Y and Medina, YI},
title = {Alzheimer's Imaging Consortium.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21 Suppl 8},
number = {},
pages = {e109795},
doi = {10.1002/alz70862_109795},
pmid = {41433413},
issn = {1552-5279},
mesh = {Humans ; *Brain/pathology/diagnostic imaging/metabolism ; *Neuroimaging ; *Alzheimer Disease/pathology/diagnostic imaging ; Atrophy/pathology ; Male ; Female ; *Neurodegenerative Diseases/pathology/diagnostic imaging ; Neurons/pathology/metabolism ; Aged ; },
abstract = {BACKGROUND: Disrupted interactions among neurons, glial and vascular cell types can lead to inflammation, vascular dysfunction, and neuronal death, highlighting the need to understand how functional interactions between these cells predispose the development of different neurodegenerative conditions. Here we identified cell-cell interactions across the whole human brain that explain atrophy patterns characteristic to 13 neurodegenerative conditions.

METHOD: We generated 1,050 whole-brain neuroimaging maps of ligand-receptor interactions specific to neurons, astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells, and endothelial cells. These maps were created by inferring literature-curated ligand-receptor interaction pairs from microarray gene expression derived from post-mortem tissues of six healthy human donors, sourced from the Allen Human Brain Atlas (Figure 1a-b). Next, using Partial Least Squares Regression (PLS) analysis, we identified key LR pairs whose patterns of communication explain the spatial distribution of atrophy maps specific to 13 neurodegenerative conditions (Figure 1c). Atrophy maps were previously generated for early- and late-onset Alzheimer's disease (EOAD and LOAD), clinical and pathological subtypes of frontotemporal lobar degeneration (FTLD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), and amyotrophic lateral sclerosis (ALS). Finally, we performed gene enrichment analyses to uncover underlying signaling pathways that explain future atrophy in neurodegeneration.

RESULT: The first latent variable (LV1) accounted for 84.21% of the covariance (p < 0.05), with the COL1A1-CD36 interaction and other CD36-associated pairs playing a dominant role in explaining atrophy patterns (Figure 2a). Atrophy patterns common to five FTLD-related disorders contributed the most to LV1, followed by EOAD and LOAD (Figure 2b). Among the top 10% of ligand-receptor pairs, 28 of 107 showed strong bi-directional signaling between astrocytes and neurons, along with prominent contributions from neuron-microglia and neuron-neuron signalling (Figure 2d). These top ligands and receptors were significantly enriched for pathways including Slit/Robo-mediated axon guidance, opioid prodynorphin, enkephalin release, and Alzheimer's disease presenilin pathway (Figure 2e; p < 0.001, FDR-corrected).

CONCLUSION: We identified whole-brain ligand-receptor interactions involved in neuron-astrocyte, neuron-microglia, and neuron-neuron signaling pathways that explain the observed atrophy patterns in multiple neurodegenerative conditions. These key ligands and receptors may serve as potential therapeutic targets and advance our understanding of neurodegeneration.},
}

Humans
*Brain/pathology/diagnostic imaging/metabolism
*Neuroimaging
*Alzheimer Disease/pathology/diagnostic imaging
Atrophy/pathology
Male
Female
*Neurodegenerative Diseases/pathology/diagnostic imaging
Neurons/pathology/metabolism
Aged

@article {pmid41432316,
year = {2025},
author = {Genge, A and Rothstein, J and De Silva, S and Zinman, L and Chum, M and Chiò, A and Sobue, G and Aoki, M and Yoshino, H and Doyu, M and Selness, D and Todorovic, V and Hirai, M and Sasson, N and Takahashi, F and Cecić, M and Wamil, A and Apple, S},
title = {Phase 3b Extension Study MT-1186-A04 to Evaluate the Continued Efficacy and Safety of Edaravone Oral Suspension for Up to an Additional 48 Weeks in Patients With Amyotrophic Lateral Sclerosis.},
journal = {Muscle & nerve},
volume = {},
number = {},
pages = {},
doi = {10.1002/mus.70120},
pmid = {41432316},
issn = {1097-4598},
support = {//Tanabe Pharma America, Inc./ ; },
abstract = {INTRODUCTION/AIMS: An On/Off dosing regimen of intravenous (IV) edaravone and edaravone oral suspension is currently approved in the US for treatment of amyotrophic lateral sclerosis (ALS). Placebo-controlled clinical trials showed that IV edaravone slows physical functional decline. Study MT-1186-A04 continued to examine the efficacy and safety of investigational once daily and approved on/off dosing of edaravone oral suspension in patients with ALS.

METHODS: Study MT-1186-A04 (NCT05151471) was a phase 3b, multicenter, randomized, double-blind, parallel group extension study for up to an additional 48 weeks following 48-week Study MT-1186-A02 that randomized patients to investigational once daily or approved 105-mg on/off dosing of edaravone oral suspension. Patients who met Study MT-1186-A04 eligibility criteria, including Study MT-1186-A02 completion, continued in the same treatment regimen as Study MT-1186-A02. The primary efficacy endpoint for MT-1186-A04 was time from randomization in Study MT-1186-A02 to a ≥ 12-point decrease in ALS Functional Rating Scale-Revised (ALSFRS-R) or death, whichever happened first.

RESULTS: Over 96 weeks, including Study MT-1186-A02, daily dosing did not show a statistically significant difference vs. approved on/off dosing for the primary endpoint (p = 0.78). Edaravone oral suspension was well tolerated, and no new safety concerns were identified in either group.

DISCUSSION: Similar to Study MT-1186-A02, once daily edaravone oral suspension in extension Study MT-1186-A04 did not show superiority in terms of the primary efficacy endpoint, but had equivalent efficacy, safety, and tolerability, compared with the approved On/Off regimen. The results reinforce the appropriateness of the approved dosing regimen.},
}

@article {pmid41431415,
year = {2026},
author = {Cho, W and Lee, SY and Yoo, SH and Cho, B and Kim, KH and Hwang, IY},
title = {Home Healthcare Needs and Characteristics of Patients with Serious Illnesses Who Use Hospital-Affiliated Home-Based Medical Care in Korea.},
journal = {Yonsei medical journal},
volume = {67},
number = {1},
pages = {62-70},
doi = {10.3349/ymj.2025.0087},
pmid = {41431415},
issn = {1976-2437},
support = {RS-2021-KH120239//Patient-Centered Clinical Research Coordinating Center/Korea ; },
mesh = {Humans ; Male ; Female ; Republic of Korea ; Aged ; Retrospective Studies ; Middle Aged ; Aged, 80 and over ; Emergency Service, Hospital/statistics & numerical data ; *Home Care Services/statistics & numerical data ; *Health Services Needs and Demand ; *Home Care Services, Hospital-Based/statistics & numerical data ; Neoplasms/therapy ; },
abstract = {PURPOSE: The number of homebound adults with serious illnesses is increasing. This study aimed to examine the healthcare needs and characteristics of patients who use a hospital-affiliated physician-led home-based medical care (HBMC) program and identify factors associated with emergency department (ED) visits in Korea.

MATERIALS AND METHODS: This retrospective observational study included patients who used a HBMC program at a tertiary hospital between 2020 and 2023. Patient characteristics and home healthcare needs were analyzed by disease category: cancer, advanced neurologic disease, and others. Multivariable logistic regression analysis was used to identify factors associated with ED visits within 30 days of a physician's home visit.

RESULTS: A total of 600 patients were registered and received home visits; 58.5% had cancer and 29.7% had advanced neurologic diseases, e.g., amyotrophic lateral sclerosis. The median age was 72 years [interquartile range (IQR), 62.8-81.0], and 87.0% were dependent in daily activities. The median number of medications per patient was 6 (IQR, 3-10); 66.3% took ≥5 medications and 25.7% took ≥10 (excessive polypharmacy). Physicians provided not only physical examinations (100%) and symptom assessment (90.8%), but also home environment evaluation (86.7%), medical device management (62.0%), advanced care planning (40.7%), and acute health issue management (32.5%). Within 30 days, 19.2% of patients visited the ED. Excessive polypharmacy and cancer diagnosis were associated with increased ED visits.

CONCLUSION: Most patients who used the hospital-affiliated HBMC program had cancer, advanced neurologic disease, and polypharmacy. Targeted HBMC programs are needed for patients with serious illnesses living at home.},
}

Humans
Male
Female
Republic of Korea
Aged
Retrospective Studies
Middle Aged
Aged, 80 and over
Emergency Service, Hospital/statistics & numerical data
*Home Care Services/statistics & numerical data
*Health Services Needs and Demand
*Home Care Services, Hospital-Based/statistics & numerical data
Neoplasms/therapy

@article {pmid41431371,
year = {2025},
author = {Dobbertin, T and Schirmer, L},
title = {Spatially Resolved Profiling of Compartmentalized Muscle and Brain Inflammation.},
journal = {European journal of immunology},
volume = {55},
number = {12},
pages = {e70119},
doi = {10.1002/eji.70119},
pmid = {41431371},
issn = {1521-4141},
support = {P1180016//Gemeinnützige Hertie-Stiftung/ ; GRK2727(InCheck)//Deutsche Forschungsgemeinschaft/ ; FOR2690(SCHI1330/7-2)//Deutsche Forschungsgemeinschaft/ ; SPP2395(SCHI1330/10-1)//Deutsche Forschungsgemeinschaft/ ; FOR5705(SCHI1330/13-1)//Deutsche Forschungsgemeinschaft/ ; SCHI1330/2-1//Deutsche Forschungsgemeinschaft/ ; SCHI1330/4-1//Deutsche Forschungsgemeinschaft/ ; SCHI1330/11-1//Deutsche Forschungsgemeinschaft/ ; 950584//H2020 European Research Council/ ; },
mesh = {Humans ; Animals ; *Muscle, Skeletal/immunology/pathology/metabolism ; Proteomics/methods ; *Brain/immunology/pathology ; Inflammation/immunology ; *Neuroinflammatory Diseases/immunology ; *Encephalitis/immunology ; Transcriptome ; },
abstract = {Spatial omics technologies enable high-resolution mapping of transcriptomic, proteomic, and metabolic profiles within intact tissues, revealing how immune, stromal, and parenchymal cells interact in situ during inflammation. Chronic inflammation in skeletal muscle and the central nervous system is spatially organized within defined niches that shape disease progression and therapeutic response. In skeletal muscle, spatial analyses have uncovered fiber-type-specific vulnerability, regenerative trajectories, and immune-stromal crosstalk in disorders such as Duchenne muscular dystrophy and inclusion body myositis. In the central nervous system, these approaches have revealed compartmentalized neuroinflammation in multiple sclerosis, innate immune activation in amyotrophic lateral sclerosis, and immune evasion in glioma. Integration with single-cell gene expression enables inference of cell-cell communication networks and identification of spatial gradients of immune activation and tissue remodeling. Despite major advances, clinical translation remains limited by small cohorts, methodological variability, and insufficient functional validation. As spatial profiling becomes more accessible, standardized, and scalable, it promises to stratify inflammatory disease states, identify tissue-resident immune programs, and guide mechanism-based therapies. Hence, spatial omics provide an unprecedented opportunity to resolve the cellular architecture of inflammation, revealing not only where immune activity occurs, but how it is orchestrated within complex tissue microenvironments.},
}

Humans
Animals
*Muscle, Skeletal/immunology/pathology/metabolism
Proteomics/methods
*Brain/immunology/pathology
Inflammation/immunology
*Neuroinflammatory Diseases/immunology
*Encephalitis/immunology
Transcriptome

@article {pmid41430470,
year = {2025},
author = {Piol, D and Khalil, B and Robberechts, T and Killian, T and Georgopoulou, M and Partel, G and Wouters, D and Hecker, N and Tziortzouda, P and Verresen, Y and Corthout, N and Kint, S and Vandereyken, K and Van Damme, P and Voet, T and Davie, K and Poovathingal, S and Van Den Bosch, L and Aerts, S and Sifrim, A and Da Cruz, S},
title = {Axonal Eif5a hypusination controls local translation and mitigates defects in FUS-ALS.},
journal = {Nature neuroscience},
volume = {},
number = {},
pages = {},
pmid = {41430470},
issn = {1546-1726},
support = {962700//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; 1060285//Muscular Dystrophy Association (Muscular Dystrophy Association Inc.)/ ; },
abstract = {Local protein synthesis is vital for neuronal function, but its dysregulation in neurodegenerative diseases remains poorly defined. Here we applied spatial transcriptomics to adult mouse motor nerve axons and cell bodies to enable subcellular mapping. Among transcripts found in mature axons, the most enriched biological process is protein translation, and localization of translation machinery was confirmed using multiplexed single-molecule spatial transcriptomics combined with immunofluorescence. Amyotrophic lateral sclerosis (ALS)-associated mutations in the RNA-binding protein fused in sarcoma (FUS), which suppress local translation, disrupt the compartment-specific RNA signatures, including components of the translation machinery. In particular, eukaryotic initiation factor 5a (Eif5a), a translation factor involved in elongation and termination, is found to be locally impaired in mutant FUS axons with reduced levels of its active hypusinated form. Axon-specific treatment with polyamine spermidine restores Eif5a hypusination and ameliorates mutant FUS-dependent neuronal defects, including suppression of local protein synthesis. Finally, in vivo spermidine treatment reduces ALS-related toxicity in mutant FUS and TDP-43 Drosophila models, which may have implications for therapy development.},
}

@article {pmid41430073,
year = {2025},
author = {Fava, VM and Perico, J and Orlova, M and Dallmann-Sauer, M and Xu, YZ and Thuc, NV and Thai, VH and Belone, AF and Latini, ACP and Schurr, E},
title = {Bridging pleiotropic mechanisms in leprosy type-1 reactions and neurodegenerative diseases.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-025-30734-7},
pmid = {41430073},
issn = {2045-2322},
support = {FP 22/9//Leprosy Research Initiative/ ; },
abstract = {Leprosy is an infectious disease of the skin and peripheral nervous system. Sudden episodes of hyperinflammation, known as Type 1 Reactions (T1R), are a main contributor to permanent nerve damage in leprosy. The genetic component associated with the neuro-inflammatory phenotype of T1R displays pleiotropic effects with Parkinson's disease (PD). In this study, we explored the genetic overlap between PD and T1R and expanded the evaluation of pleiotropic effects between T1R and other neurodegenerative disorders. We replicated the association of PD-linked rare variants in PRKN with T1R in Vietnamese leprosy patients. Analysis of 24 PD associated-genes revealed compound effects between rare protein-altering variants and T1R in the interacting genes PRKN/PINK1 (P = 2.7[-05]; OR = 4.0) and a combination of rare/low frequency variants in the LRRK2/GAK pair (P = 6.7[-05]; OR = 0.54). These findings validated a genetic overlap between T1R and PD with two distinct axes, one of shared risk via PRKN/PINK1 and a second of antagonistic pleiotropic via LRRK2/GAK. When testing an additional 94 genes associated with neurodegenerative diseases we identified variants in the amyotrophic lateral sclerosis disease-linked gene TBK1 associated with T1R (P = 0.004; OR = 12.9). Our results highlight shared biological processes between leprosy and neurodegenerative diseases, which may indicate candidate drugs for repurposing to improve T1R management.},
}

@article {pmid41429969,
year = {2025},
author = {Caimi, E and Vaccari, S and Vinci, V},
title = {Comment to "Artificial Intelligence (AI)-Assisted Patient Education and Concerns Following Facelift Surgery: A Study on ChatGPT-4 and Gemini".},
journal = {Aesthetic plastic surgery},
volume = {},
number = {},
pages = {},
pmid = {41429969},
issn = {1432-5241},
abstract = {INTRODUCTION: Artificial intelligence (AI) is increasingly integrated into patient education and postoperative care. Almousa et al. recently evaluated ChatGPT-4 and Gemini for postoperative facelift counseling, reporting high accuracy and clarity. While their study represents an important step toward AI-assisted communication in aesthetic surgery, several methodological issues may limit the validity and clinical applicability of their findings.

METHODS: We critically appraised Almousa et al.'s study design, data collection, and analytic methods. Specific attention was given to question selection, evaluation metrics, reproducibility, and statistical robustness, comparing them with established standards for AI evaluation and inter-rater reliability.

RESULTS: The study used ChatGPT-4 itself to generate the five "most common" postoperative questions, introducing circularity and potential selection bias. Responses were assessed on a dichotomous (Yes/No) scale by five surgeons, without reporting inter-rater reliability or use of scaled metrics. It was unclear whether prompts were entered sequentially or independently, raising reproducibility concerns. The limited sample size (five questions per model) provided only 25 binary data points per system, precluding meaningful statistical inference. Furthermore, AI responses lacked individualized safety guidance and escalation advice, limiting clinical safety in real-world postoperative settings.

CONCLUSION: Although the study highlights the promise of LLMs in aesthetic surgery, future studies should employ patient-derived question sets, graded and reproducible evaluation scales, transparent prompt protocols, and inclusion of complication-related queries to accurately determine the safety and educational value of AI-generated postoperative information.

LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.},
}

@article {pmid41429156,
year = {2025},
author = {Gomes, MDM and Freitas, MRG},
title = {Jean-Martin Charcot at 200: revolutionizing neurology through a multidisciplinary lens.},
journal = {Arquivos de neuro-psiquiatria},
volume = {83},
number = {11},
pages = {1-5},
doi = {10.1055/s-0045-1813236},
pmid = {41429156},
issn = {1678-4227},
mesh = {History, 19th Century ; *Neurology/history ; Humans ; },
abstract = {As we near the bicentenary of his birth, Jean-Martin Charcot (1825-1893) is remembered not only as the founder of modern neurology but also as a uomo universale. His multidisciplinary approach transcended 19[th]-century medicine, establishing neurology as a distinct discipline while integrating art, psychology, and philosophy into his study of the nervous system. His work laid foundations for neurodegenerative diseases (amyotrophic lateral sclerosis [ALS], Parkinson's disease, multiple sclerosis [MS]), functional neurological disorders (FNDs), and psychoanalysis, foreshadowing neuroplasticity and the mind-body connection. His innovative teaching at Salpêtrière-merging anatomy with artistic documentation-revolutionized medical education, inspiring figures from Freud to modern neuroscientists. Two centuries later, Charcot's legacy endures not just in eponyms but in his unifying vision of brain, mind, and art - a timeless model for interdisciplinary medicine. The present paper explores his impact on neurodegenerative research, functional disorders, medical pedagogy, and the humanities.},
}

History, 19th Century
*Neurology/history
Humans

@article {pmid41429137,
year = {2025},
author = {Li, S},
title = {Rethinking Global Trends in Pediatric Lung Transplantation Research.},
journal = {The Thoracic and cardiovascular surgeon},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2776-6215},
pmid = {41429137},
issn = {1439-1902},
abstract = {This letter discusses Yuan et al.'s bibliometric analysis of pediatric lung transplantation (PLT) research, recognizing its value in mapping global publication trends and collaborative networks. We affirm the study's contribution to understanding the evolution of PLT research but highlight several critical considerations. The current geographic imbalance, dominated by North American institutions, underscores the need for broader international collaboration and capacity building in developing regions. Moreover, while the shift from surgical to outcome-oriented research is notable, bibliometric metrics alone may not fully reflect clinical progress in perioperative management, immunotherapy, or donor ethics. We advocate for integrating bibliometric insights with systematic clinical evidence to better connect research output with improvements in graft survival, rejection control, and pediatric patient quality of life.},
}

@article {pmid41428955,
year = {2025},
author = {Jih, KY and Tsai, YS and Fang, SY and Hsu, FC and Sytwu, HP and Liao, YC and Tsai, PC and Lee, YC},
title = {SOD1 mutations in Taiwanese ALS patients: Clinical characteristics, frequency, and a p.T138R founder effect.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2604236},
pmid = {41428955},
issn = {2167-9223},
abstract = {OBJECTIVE: Mutations in SOD1 are a well-established genetic cause of amyotrophic lateral sclerosis (ALS), exerting toxic gain-of-function effects that promote protein misfolding and aggregation in motor neurons and glial cells. The emergence of SOD1-targeted antisense oligonucleotide therapy underscores the clinical importance of precise genetic diagnosis. This study aimed to determine the frequency, clinical characteristics, and potential founder effect of SOD1 mutations in a large Taiwanese ALS cohort, and to evaluate their aggregation propensity in vitro.

METHODS: All coding exons of SOD1 were analyzed by Sanger sequencing in 650 unrelated Taiwanese patients with ALS. Haplotype analysis using single nucleotide polymorphism markers flanking SOD1 was conducted to assess a potential founder effect. Protein cross-linking assays were performed to assess the aggregation propensity of 11 SOD1 variants.

RESULTS: Seventeen pathogenic SOD1 variants were identified in 26 probands and 12 affected relatives. Mean age at onset was 48.9 ± 14.9 years, and 8% had bulbar-onset ALS. The most frequent variant was p.T138R (8 probands), followed by p.G11A (3 probands). The other 15 variants each occurred in a single family. A shared ancestral haplotype was observed among p.T138R carriers. Cross-linking experiments demonstrated oligomer formation in all tested mutant SOD1 proteins compared to the wild-type protein, supporting their pathogenicity.

CONCLUSIONS: SOD1 mutations account for approximately 4% of ALS cases in Taiwan, are associated with earlier onset and predominantly spinal-onset ALS, and include a p.T138R founder variant. These findings highlight the importance of genetic screening in ALS, particularly in guiding eligibility for emerging targeted therapies.},
}

@article {pmid41428942,
year = {2025},
author = {Sannes, A and Rognli, EW and Hanssen-Bauer, K and Torp, NC and Storfossen, SK and Høstaker, MN and Aalberg, M},
title = {Barriers to and Facilitators of Implementation of Internet-Delivered Therapist-Guided Therapy in Child and Adolescent Mental Health Services: Systematic Review and Bayesian Meta-Analysis.},
journal = {Journal of medical Internet research},
volume = {27},
number = {},
pages = {e83543},
doi = {10.2196/83543},
pmid = {41428942},
issn = {1438-8871},
mesh = {Humans ; Adolescent ; Child ; *Mental Health Services ; Bayes Theorem ; *Internet ; *Adolescent Health Services ; *Psychotherapy/methods ; *Child Health Services ; },
abstract = {BACKGROUND: Internet-delivered therapist-guided therapy (e-therapy) represents a promising approach for enhancing accessibility, treatment fidelity, and scalability within child and adolescent mental health services (CAMHS).

OBJECTIVE: This systematic review aimed to (1) identify and synthesize determinants of implementation, specifically barriers to and facilitators of e-therapy in CAMHS structured according to the Consolidated Framework of Implementation Research (CFIR); and (2) provide pooled benchmark estimates of key implementation outcomes for fidelity, cost-effectiveness, and acceptability.

METHODS: A PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)-compliant systematic review was performed across PsycINFO, MEDLINE, Web of Science, CINAHL, Embase, Cochrane, and ProQuest Dissertations & Thesis on June 6, 2025-to identify peer-reviewed studies assessing implementation outcomes or determinants of e-therapy in the context of outpatient CAMHS (ages 8-18 years). Barriers and facilitators were synthesized qualitatively with thematic analysis applying CFIR. A parallel quantitative synthesis of Proctor et al's taxonomy of implementation outcomes was performed using Bayesian multilevel random-effects meta-analyses to estimate pooled effect sizes and 95% credible intervals (CIs). By combining quantitative benchmarks of implementation success with qualitative insights into contextual determinants, the review provides an integrated understanding of what drives effective e-therapy implementation in CAMHS. Study quality was assessed using the CASP (Critical Appraisal Skills Programme) checklist, Cochrane Risk of Bias tool, and Risk Of Bias In Non-randomized Studies-of Interventions tool. Small study effects were evaluated using funnel plots, sensitivity analyses, and the Egger test.

RESULTS: From 50,026 screened reports, 50 studies published between 2007 and 2025 were included: 18 randomized controlled trials, 17 cohort, and 15 qualitative or mixed methods studies. Most studies originated from Western Europe (n=34), Northern America (n=11), and Oceania (n=5), targeting anxiety (n=24) and depression (n=9), through cognitive behavioral therapy-based programs (n=47), with parallel parent content (n=31). Therapist guidance was primarily asynchronous (n=43). Among the 39 studies reporting determinants, common barriers and facilitators were identified across intervention, organization, therapist, and patient domains, structured via CFIR. Pooled implementation outcomes showed modest dropout rates (~20%, CI 14%-27%), high module completion (~68%, CI 60%-75%), low therapist time (24 min per wk per patient, 95% CI 19-28), and high patient satisfaction (24/32 on Client Satisfaction Questionnaire-8, 95% CI 22-27; and 76% satisfaction rate, 95% CI 62%-87%), suggesting e-therapy is resource efficient and acceptable if implemented successfully.

CONCLUSIONS: This review provided the first integrated synthesis of pooled benchmarks for implementation outcomes of e-therapy in CAMHS and modifiable determinants to inform future service planning and scale-up. These findings highlighted service-level enablers, such as leadership anchoring, targeted use, technical stability, structured patient flow, and therapist training, that organizations could prioritize to strengthen sustainable e-therapy implementation in CAMHS.},
}

Humans
Adolescent
Child
*Mental Health Services
Bayes Theorem
*Internet
*Adolescent Health Services
*Psychotherapy/methods
*Child Health Services

@article {pmid41428861,
year = {2025},
author = {Soliman, R and Swelam, MS and Fahmy, N and Rashed, HR},
title = {Translation and validation of the Arabic version of the amyotrophic lateral sclerosis assessment questionnaire (ALSAQ40-AR).},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-10},
doi = {10.1080/21678421.2025.2603311},
pmid = {41428861},
issn = {2167-9223},
abstract = {AIM: To validate Arabic version of the ALSAQ-40, (ALSAQ40-AR) and assess the QOL in a cohort of Egyptian patients with ALS.

METHODS: This is a prospective study. One hundred consecutive ALS patients were included from the Neuromuscular Unit, Ain Shams University Hospital, in the period from February 2022 to June 2024. Functional and cognitive assessments were done using the Arabic version of ALSFRS-R and ECAS-EG questionnaires, respectively. Disease stage was identified via Kings Clinical Staging. QOL was evaluated using the Arabic WHOQOL-BREF and an Arabic version of ALSAQ-40.

RESULTS: ALSAQ40-AR showed high internal consistency using Cronbach's alpha of >0.9, Inter-rater reliability was tested, values for all variables were compared, and no statistically significant differences were found (ICC = .997). Both WHOQOL-BREF and ALSAQ40-AR domains demonstrated significant correlation with each other and with ALSFRS-R (p-value < 0.0001), denoting construct validity. Moreover, ALSAQ40-AR domains correlated significantly with time since disease onset, and showed significant increase across disease stages (p-value < 0.0001). Ceiling and floor effects were analyzed in both QOL scales, but only WHOQOL-BREF showed ceiling and floor effects.

CONCLUSION: ALSAQ40-AR and the WHOQOL-BREF were reliable and valid tools to evaluate QOL in patients with ALS; we suggest that the validated ALSAQ40-AR is more suited for ALS patients because it is a disease specific questionnaire that showed higher internal consistency with no floor or ceiling effects. QOL in ALS was correlated with time since disease onset, disease stage, functional, and cognitive disabilities.},
}

@article {pmid41428860,
year = {2025},
author = {Curtis, SE and Tatlock, S and O'Hara, L and Seçinti, E and Mehdiyoun, NF and Ayala-Nunes, L and Flynn, J and Fernelius, K and Hodson, N and Delbecque, L},
title = {Patient experience and clinical outcome assessment validity in amyotrophic lateral sclerosis: a targeted literature review.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-16},
doi = {10.1080/21678421.2025.2604233},
pmid = {41428860},
issn = {2167-9223},
abstract = {OBJECTIVE: To identify relevant concepts of measurement for people with amyotrophic lateral sclerosis (ALS) and to evaluate the face and content validity of clinical outcome assessments (COAs) that can be used to measure treatment benefits in ALS clinical trials.

METHODS: A targeted literature review was conducted to explore patient experience (stage 1) and COAs used in ALS research (stage 2). Abstracts were screened against predefined eligibility criteria; full-text articles were reviewed for eligible abstracts and relevant data were extracted. Face and content validity of the identified COAs were assessed.

RESULTS: Stage 1 searches identified 3,527 abstracts, of which 12 full-text articles, two summary reports, and one conference poster were included in this review. Twenty-five symptoms and 35 health-related quality of life (HRQoL) impacts were identified. Frequently reported symptoms included breathing and speech difficulties and muscle/limb weakness, each associated with a diverse range of impacts, including those related to emotional wellbeing, physical function, social and leisure activities, and activities of daily living. Stage 2 searches identified 119 COAs, of which 28 were reviewed. Many had acceptable face (13/28) and content validity (15/28), but 13 had not involved patients during development; only 10 were clearly worded and seven were lengthy, increasing patient burden risk.

CONCLUSIONS: This review identified wide-ranging symptoms and HRQoL impacts experienced by people with ALS, but detailed qualitative evidence is sparse. Multiple COAs were identified as potential measures in ALS clinical trials.},
}

@article {pmid41428513,
year = {2025},
author = {Román-Caballero, R},
title = {Reassessing the cognitive benefits of physical activity: A meta-analytic reanalysis of Mavilidi et al. (2025).},
journal = {Psychological bulletin},
volume = {151},
number = {11},
pages = {1382-1388},
doi = {10.1037/bul0000490},
pmid = {41428513},
issn = {1939-1455},
support = {//European Union's Horizon 2020 research and innovation program/ ; },
mesh = {Humans ; *Cognition/physiology ; *Exercise/psychology/physiology ; Publication Bias ; Meta-Analysis as Topic ; },
abstract = {Recent reviews and meta-analyses suggest the cognitive benefits of physical exercise observed in primary studies may be inflated due to multiple sources of bias, including selection bias, placebo effects, regression to the mean, and publication bias. When these biases are accounted for, the evidence for the purported enhancements has been shown to be inconclusive. The recent meta-analysis by Mavilidi et al. (2025) makes a relevant contribution by pointing out the potential role of moderating variables and therefore the possibility that, under certain conditions, the effect may be more substantive. Yet, a critical evaluation of Mavilidi et al.'s methods reveals several issues in the statistical analyses and interpretation of publication bias analyses. These appear to have led Mavilidi et al. to conclude the presence of an overall cognitive benefit of physical activities. The present commentary provides a reanalysis of the data, applying appropriate methodological corrections. After an adequate analytical strategy, the final effect was reduced and yielded inconclusive evidence of an overall cognitive benefit. Particularly, publication bias methods highlight that the overall effect of chronic physical activity on cognition is likely smaller and therefore inconclusive. Yet, as in the original meta-analysis, the cognitive benefits were significantly larger for chronic interventions with an evidence-based delivery, programs with a clear cognitive component, or high cognitive demands compared to other physical exercise interventions. These results support the possibility that motor-cognitive training/sports games and holistic movement practices/martial arts may be effective activities to improve cognitive functioning. (PsycInfo Database Record (c) 2025 APA, all rights reserved).},
}

Humans
*Cognition/physiology
*Exercise/psychology/physiology
Publication Bias
Meta-Analysis as Topic

@article {pmid41428348,
year = {2025},
author = {Elman, L and Wymer, J and Lomen-Hoerth, C},
title = {Tofersen, SOD1, and the Treatability of Amyotrophic Lateral Sclerosis.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.4927},
pmid = {41428348},
issn = {2168-6157},
}

@article {pmid41428212,
year = {2025},
author = {Grønbæk-Thygesen, M and Kampmeyer, C and Eschger, P and Tatham, MH and Arts, M and Hofmann, K and Lindorff-Larsen, K and Boomsma, W and Hartmann-Petersen, R},
title = {The Importance of UBQLN2 Ubiquitylation for Its Turnover and Localization.},
journal = {Biochemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.biochem.5c00619},
pmid = {41428212},
issn = {1520-4995},
abstract = {UBQLN2 is a member of the UBL-UBA domain protein family that functions as extrinsic substrate receptors for the 26S proteasome. UBQLN2 has been shown to undergo phase separation in vitro. In cells, UBQLN2 forms condensates that may be of importance for tuning protein degradation via the ubiquitin-proteasome system and potentially of relevance for UBQLN2-linked amyotrophic lateral sclerosis (ALS). Here we show that UBQLN2 is ubiquitylated on lysine residues in the N-terminal UBL domain. The C-terminal region of UBQLN2 is lysine-depleted, and we show that introducing lysine residues in this region leads to its E6AP-dependent degradation. The UBL domain critically stabilizes UBQLN2 and protects it from proteasomal degradation. Fusion of ubiquitin to the UBQLN2 N-terminus stabilizes UBQLN2 and increases its propensity for locating in puncta, indicating that ubiquitylation of the UBQLN2 UBL domain regulates abundance and localization.},
}

@article {pmid41428120,
year = {2025},
author = {Freri, F and Spinelli, EG and Canu, E and Basaia, S and Castelnovo, V and Müller, HP and Kassubek, J and Ludolph, AC and Krishnamurthy, SS and Roselli, F and Filippi, M and Agosta, F},
title = {Uncovering hypothalamic network disruption in ALS.},
journal = {Journal of neurology},
volume = {273},
number = {1},
pages = {37},
pmid = {41428120},
issn = {1432-1459},
support = {EU Joint Programme - Neurodegenerative Disease Research (JPND) - HiCALS project//European Commission/ ; Next Generation EU/National Recovery//European Union/ ; Resilience Plan//European Union/ ; Investment PE8-Project Age-It. Project code: PE00000015; CUP master: D43C22003100007//European Union/ ; },
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology ; Female ; Male ; Middle Aged ; *Hypothalamus/diagnostic imaging/physiopathology/pathology ; Magnetic Resonance Imaging ; Aged ; Adult ; *White Matter/diagnostic imaging/pathology ; *Nerve Net/diagnostic imaging/physiopathology ; Disease Progression ; *Connectome ; },
abstract = {BACKGROUND: Structural MRI studies have shown hypothalamic atrophy and altered white matter (WM) connectivity in amyotrophic lateral sclerosis (ALS), as a possible substrate of hypermetabolism in this condition. However, hypothalamic functional connectivity and its association with clinical features in ALS remain unclear. This study explored hypothalamic resting-state functional connectivity (RS-FC) in ALS patients compared to controls and its relationship with disease severity defined by the ALS Functional Rating Scale (ALSFRS-r), body mass index (BMI), disease duration, progression rate, survival, hypothalamic volume, and WM integrity.

METHODS: Seventy-one ALS patients and 39 healthy controls underwent structural and RS functional MRI. The bilateral hypothalamus was segmented, and a seed-based RS-FC analysis was performed. Group differences in hypothalamic RS-FC and their correlations with ALSFRS-r scores, BMI, disease duration, progression rate, survival, hypothalamic volume, and WM integrity were assessed. Tract-based spatial statistics was performed to estimate the correlation between WM damage in ALS and hypothalamic RS-FC.

RESULTS: ALS patients showed increased hypothalamic RS-FC with caudate nuclei compared to controls. Additionally, greater disease severity correlated with increased hypothalamic RS-FC with the caudate nuclei and orbitofrontal cortex. Hypothalamic RS-FC mean values also associated with FA in the genu of corpus callosum and forceps minor and disease progression rate. No significant correlations were observed with other clinical features.

CONCLUSIONS: These findings support hypothalamic alterations in ALS. Early detection of hypothalamic changes could be useful in prognostic stratification and evaluating intervention effects.},
}

Humans
*Amyotrophic Lateral Sclerosis/diagnostic imaging/physiopathology/pathology
Female
Male
Middle Aged
*Hypothalamus/diagnostic imaging/physiopathology/pathology
Magnetic Resonance Imaging
Aged
Adult
*White Matter/diagnostic imaging/pathology
*Nerve Net/diagnostic imaging/physiopathology
Disease Progression
*Connectome

@article {pmid41427945,
year = {2026},
author = {Gruda, D and Hanges, P and McCleskey, JA},
title = {Decomposing Spatial Effects of State-Level Health Outcomes: A Methodological Demonstration and Re-Analysis.},
journal = {International journal of psychology : Journal international de psychologie},
volume = {61},
number = {1},
pages = {e70152},
doi = {10.1002/ijop.70152},
pmid = {41427945},
issn = {1464-066X},
mesh = {Humans ; *Narcissism ; Hypertension/mortality/epidemiology ; United States/epidemiology ; Machiavellianism ; Neoplasms/epidemiology ; Depression/epidemiology ; Antisocial Personality Disorder/epidemiology ; Male ; Female ; },
abstract = {While spatial autoregressive (SAR) models are increasingly used in population-level psychological studies, researchers often overlook the crucial step of parsing effects into direct, indirect and total impacts, a standard practice in spatial econometrics. In this paper, we demonstrate the necessity of this practice by re-analyzing Gruda et al.'s (2024) U.S. Dark-Triad and health dataset with heteroskedasticity-robust SAR models and full impact decomposition, revealing significant changes. The previously observed direct protective effect of state-level narcissism on hypertension mortality disappeared when accounting for interstate spillovers. Conversely, the association with lower cancer prevalence and depression strengthened. Several health-behaviour findings reversed direction, indicating naïve regressions conflated within- and between-state effects. Machiavellianism and psychopathy coefficients also shifted. These results demonstrate that spatial spillovers can dilute, negate or reverse local effects, cautioning against policy inferences based solely on direct estimates.},
}

Humans
*Narcissism
Hypertension/mortality/epidemiology
United States/epidemiology
Machiavellianism
Neoplasms/epidemiology
Depression/epidemiology
Antisocial Personality Disorder/epidemiology
Male
Female

@article {pmid41427267,
year = {2025},
author = {Finney, CA and An, L and Winchester, LM and Vogel, J and Wilkins, HM and Burns, JM and Swerdlow, RH and Slawson, C and Rothstein, JD and , and Lutz, MW and Saloner, R and Shvetcov, A},
title = {Mapping the circulating proteome across neurodegeneration: A harmonized, consortium-scale framework for uncovering molecular pathophysiology.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.09.693329},
pmid = {41427267},
issn = {2692-8205},
abstract = {Large-scale plasma proteomics offers unprecedented opportunities to investigate the systemic biology of neurodegeneration, yet technical heterogeneity, site-specific artifacts, and clinical confounding remain major barriers to reproducible discovery. Leveraging data from 13,733 individuals with Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), Parkinson's disease dementia (PDD), amyotrophic lateral sclerosis (ALS), and non-impaired controls in the Global Neurodegeneration Proteomics Consortium (GNPC), we present a scalable and generalizable analytical framework for harmonizing and interpreting consortium-scale proteomic datasets. Using a high-dimensional perturbation framework, we systematically benchmark five commonly used batch correction methods across a range of realistic confounding structures, including site-disease imbalance, nonlinear effects, and heteroskedasticity. Empirical Bayes modelling via limma consistently emerged as the most robust method, optimally balancing removal of site-related technical variance with retention of disease-relevant biological signal. On this harmonized foundation, we resolve neurodegenerative disease plasma signatures, including a shared immune-metabolic axis in AD and PD, neuromuscular disruption in ALS, and proteostatic imbalance in PD. Tissue and cell-type enrichment highlight widespread immune-endocrine involvement in AD and hematopoietic activation in PD. Demographically matched analyses nominate distinct, candidate biomarkers across diseases, including lipid, redox, and complement factors in AD, lysosomal and cytoskeletal proteins in PD, and muscle-derived markers in ALS. This study establishes a scalable analytical framework for integrating real-world proteomic data and provides a disease-resolved catalogue of circulating signatures to inform biomarker development and targeted intervention across neurodegenerative diseases.},
}

@article {pmid41426554,
year = {2025},
author = {Liang, L and Zhang, Y and Zhang, X and Guo, X and Yan, Y},
title = {Historical evolution, research hotspots and emerging trends of pediatric hand, foot, and mouth disease: a bibliometric worldview since the 21st century.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1722750},
pmid = {41426554},
issn = {2296-858X},
abstract = {BACKGROUND: Hand, foot, and mouth disease (HFMD) poses a significant challenge to global public health. Primarily caused by enterovirus and coxsackievirus infections, the disease has a particularly pronounced impact in the Asia-Pacific region. However, systematic analysis and discussion regarding the developmental trajectory, core research entities, current status, key research directions, and future prospects of pediatric HFMD research remain lacking.

METHODS: This study collected and analyzed papers and reviews on pediatric HFMD published between January 1, 2000, and February 1, 2025, from the Web of Science Core Collection and PubMed. Key research indicators were analyzed through bibliometric visualization, using tools including Excel, CiteSpace, VOSviewer, and BibliomeTools (an R-based tool in R-Studio).

RESULTS: Since the start of the 21 st century, academic publications in pediatric HFMD have steadily increased, with a cumulative total of 2,034 papers published by February 1, 2025. Global research distribution exhibits uneven patterns, with China emerging as core contributors. Specifically, Lin, Tzou-Yien from China, has published the largest number of papers, while Chang, Luan-Yin is the co-cited author with the highest citation rate. Solomon T et al.'s "Virology," Epidemiology, Pathogenesis, and Control of Enterovirus 71" being the most cited study in the field. Research on pediatric HFMD is closely integrated with disciplines such as virology and epidemiology, forming core research themes around "HFMD," "enterovirus 71," and "enteroviruses." Recent research has focused on the pathogenesis, epidemiology, novel therapeutic discoveries and vaccine development for pediatric HFMD. Looking ahead, it is essential to delve deeper into the molecular mechanisms underlying the interaction between the human HFMD virus and its host, and to develop multivalent vaccines targeting multiple serotypes.

CONCLUSION: This study employs bibliometric methods to visualize research in the field of pediatric hand, foot, and mouth disease, revealing trends and frontiers in this area. It will provide valuable reference for scholars seeking key research questions and potential collaborators.},
}

@article {pmid41426430,
year = {2025},
author = {van Vugt, JJFA and Zwamborn, RAJ and Dolzhenko, E and Eberle, MA and Weisburd, B and Bekema, E and Kooyman, M and Wang, BN and , and Kamsteeg, EJ and Losekoot, M and Baas, F and Novy, C and Høyer, H and van Eijk, RPA and van Es, MA and van Rheenen, W and Al-Chalabi, A and van den Berg, LH and Veldink, JH},
title = {The role of disease-associated short tandem repeats in amyotrophic lateral sclerosis.},
journal = {Brain communications},
volume = {7},
number = {6},
pages = {fcaf482},
pmid = {41426430},
issn = {2632-1297},
abstract = {Short tandem repeats (STRs) are recognized contributors to various neurodegenerative disorders, with evidence supporting genetic pleiotropy among these STRs. Multiple STRs have been associated with amyotrophic lateral sclerosis (ALS), although the strength of evidence supporting each association varies. To establish the role of disease-associated repeat expansions as pleiotropic risk factors in ALS susceptibility and progression, we genotyped a panel of 39 STRs, known to cause neurological diseases, within Project MinE in 6519 patients and 2412 controls, utilizing 100 and 150 bp short-read sequencing technology. Pathogenic allele frequencies were compared to those in a control cohort comprising 4930 Genome Aggregation Database (gnomAD) genomes. Repeat sizes and motif changes were detected using ExpansionHunter and ExpansionHunter Denovo. We developed a model to predict genotyping failures in STRs and established a best-practice protocol for assessing the accuracy of STR genotyping in short-read sequencing data. Following our genotyping assessment, 11 out of the 39 STRs exhibited insufficient genotyping accuracy, warranting caution in studying these STRs using these tools in combination with short-read sequencing. Furthermore, the observed differences in STR genotyping accuracy across studies applying different sequencing technologies and genotyping tools in control cohorts highlight the importance of a carefully designed experimental setup when interpreting potential disease-associated STR findings. Pathogenic C9orf72 and premutated ATXN2 expansions were confirmed to be significantly associated with ALS susceptibility. Additionally, pathogenic C9orf72 expansions were significantly associated with reduced mean ALS survival by 11.5 months and an earlier mean age at onset by 2.4 years. Premutation expansions in ATXN1 showed a nominally significant association with ALS susceptibility, while pathogenic expansions in NIPA1 displayed a nominally significant association with ALS survival. Previously reported ALS-associated pleiotropy in HTT and STMN2 could not be confirmed. Motif changes were identified in BEAN1, RFC1, ATXN8, C9orf72, DAB1, FXN and SAMD12; however, none of the motif changes were linked to ALS. Re-evaluation of clinical data from patients with ALS and a repeat expansion typically associated with another disease revealed that 7% of these patients' diagnoses had to be reclassified to the disease associated with the repeat expansion (e.g. Kennedy's disease or spinocerebellar ataxia). This underscores the value of broad STR screening in neurodegenerative cases. Pathogenic and premutation STRs were also found in controls in unexpected high frequencies, suggesting reduced penetrance or underdiagnosis, and highlighting the need for caution when interpreting genetic associations with disease without a proper control cohort.},
}

@article {pmid41423699,
year = {2025},
author = {Luan, W and San Gil, R and Madrid San Martin, L and Cao, MC and Vassallu, F and Venturato, J and West, PK and Brown-Wright, H and Bademosi, AT and Chye, YJ and Wu, HY and Harutyunyan, A and Robinson, KJ and Chang, MS and Blizzard, CA and Scotter, EL and Igaz, LM and Walker, AK},
title = {Synaptic changes contribute to persistent extra-motor behaviour deficits in amyotrophic lateral sclerosis.},
journal = {Acta neuropathologica communications},
volume = {},
number = {},
pages = {},
doi = {10.1186/s40478-025-02150-5},
pmid = {41423699},
issn = {2051-5960},
support = {IG2422//Motor Neurone Disease Australia/ ; Discovery grant//FightMND/ ; Bill Guest Mid-Career Research Fellowship//FightMND/ ; },
}

@article {pmid41423553,
year = {2025},
author = {Tang, C and Foucher, J and Öijerstedt, L and Ombelet, F and Ingre, C and Van Damme, P and Van Laere, K and De Vocht, J and Koole, M},
title = {Support vector machine classification of [18]F-FDG PET scans across subtypes of amyotrophic lateral sclerosis.},
journal = {European journal of nuclear medicine and molecular imaging},
volume = {},
number = {},
pages = {},
pmid = {41423553},
issn = {1619-7089},
support = {12AQF24N//FWO/ ; fundamental clinical investigatorship//KU Leuven/ ; Een Hart voor ALS//KU Leuven/ ; Laeversfonds voor ALS Onderzoek//KU Leuven/ ; E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders//E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders/ ; ALS Liga België//ALS Liga België/ ; },
abstract = {PURPOSE: While [18]F-FDG PET imaging has demonstrated diagnostic value in people with Amyotrophic Lateral Sclerosis (PwALS) and group-level differences were identified between different disease subtypes (e.g., genetic and clinical variants), refining and validating a machine-learning-based subject-level diagnostic algorithm may improve the general applicability and reliability of [18]F-FDG PET as a diagnostic tool in ALS. In this study, we employed support vector machines (SVM) to further explore the diagnostic potential of [18]F-FDG PET in ALS, alongside its ability to classify between different genetic subtypes or clinical phenotypes.

METHODS: [18]F-FDG PET data of 36 healthy volunteers (HV), 25 people with ALS-mimicking diseases (Mimics), and 167 PwALS, grouped by genetic status (e.g., sporadic (sALS) or carrying a C9orf72 hexanucleotide repeat expansion (ALS[C9orf72RE]) and onset (bulbar or spinal) type, acquired with Biograph 'TruePoint' PET/CT scanner, were included in the study (Dataset 1). A second dataset of 183 PwALS and 31 Mimics acquired with Biograph 'HiRez' scanner was included as an independent cross-validation set (Dataset 2). PET images were spatially normalised to MNI space to fit linear SVMs with cross-validation. Only age-matched groups were considered to eliminate age-related effects.

RESULTS: For Dataset 1, the linear SVM resulted in an average accuracy of 0.86 for the classification of ALS vs. HV, 0.53 for ALS vs. Mimics, 0.83 for ALS[C9orf72RE] vs. sALS, and 0.58 for bulbar vs. spinal onset. These findings were corroborated with Dataset2, with an accuracy of up to 0.76 for ALS[C9orf72RE] vs. sALS, and 0.59 for bulbar vs. spinal.

CONCLUSION: [18]F-FDG brain PET imaging, combined with SVM and age-matching, can distinguish between ALS[C9orf72RE] and sALS with good accuracy, but lacks sufficient discriminative power to differentiate between ALS and Mimics and between different sites of onset.},
}

@article {pmid41422089,
year = {2025},
author = {Jun, YW and Lee, S and Almeida, S and Freude, KK and Ichida, JK and Gao, FB},
title = {The Ku80-p53-SIRT1 axis in DNA damage response contributes to sporadic and familial ALS and FTD.},
journal = {Nature communications},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41467-025-67749-7},
pmid = {41422089},
issn = {2041-1723},
support = {R37NS057553//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; R01NS101986//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; NA/ALZ/Alzheimer's Association/United States ; NRF-2019R1A6A3A03034014//National Research Foundation of Korea (NRF)/ ; },
abstract = {Although TDP-43 pathology is found in most sporadic and familial ALS and FTD cases, other shared pathogenic mechanisms remain largely unknown. Here we show that SIRT1 levels are decreased and acetylated p53 levels are increased in iPSC-derived neurons from sALS patients and with the FTD3-causing CHMP2B mutation. Ectopic expression of SIRT1 in these patient neurons rescues neurodegeneration and reduces acetylated p53 levels. DNA damage is elevated in both sALS and FTD3 neurons, leading to increased phosphorylation of p53 at Serine 15 and elevated levels of Ku80. Knockdown of either p53 or Ku80 rescues neurodegeneration and increases SIRT1 levels in these neurons. Moreover, ectopic expression of SIRT1 or genetic knockdown of either p53 or Ku80 suppresses retinal neurodegeneration caused by FTD3-associated mutant CHMP2B protein in an in vivo Drosophila model. These findings identify a dysregulated SIRT1-p53 feedback loop as a common pathogenic mechanism and promising therapeutic target in both sporadic and familial ALS/FTD.},
}

@article {pmid41420983,
year = {2025},
author = {Garcia-Delgado, AB and Bega, S and Campos-Cuerva, R and Martín-Banderas, L and Paradas, C and Fernandez-Muñoz, B},
title = {Generation of the human iPSC line ESi148-A from a patient with sporadic amyotrophic lateral sclerosis.},
journal = {Stem cell research},
volume = {90},
number = {},
pages = {103889},
doi = {10.1016/j.scr.2025.103889},
pmid = {41420983},
issn = {1876-7753},
abstract = {Nearly 90% of patients with amyotrophic lateral sclerosis (ALS) do not carry mutations in genes previously associated with the disease and are classified as sporadic cases with no identified genetic cause. In this study, peripheral blood mononuclear cells from a patient with sporadic ALS were reprogrammed to generate the human induced pluripotent stem cell (iPSC) line ESi148-A. The line was thoroughly characterized for pluripotency and genomic stability. These cells provide a valuable resource for generating 3D biomodels, such as cortical or spinal cord organoids, to investigate disease mechanisms and develop novel therapeutic approaches for sporadic ALS.},
}

@article {pmid41420832,
year = {2025},
author = {Wang, X and Wei, M and Qiao, Y},
title = {Modulation of Liquid-to-Solid Phase Transition in Coacervates for Neurodegenerative Disease Treatments.},
journal = {Chembiochem : a European journal of chemical biology},
volume = {},
number = {},
pages = {e202500795},
doi = {10.1002/cbic.202500795},
pmid = {41420832},
issn = {1439-7633},
support = {2023YFC2507000//National Key R&D Program of China/ ; 22272183//National Natural Science Foundation of China/ ; T2425001//National Natural Science Foundation of China/ ; },
abstract = {Coacervates formed through liquid-liquid phase separation represent a fundamental model for protocell and serve as a membraneless organelle in living cells, modulating various biological processes. During aging or under stress, protein misfolding and oligomerization trigger aberrant liquid-to-solid phase transition (LSPT), a process driven by multivalent interactions. These phase transitions disrupt cellular equilibrium, leading to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The regulatory strategies is summarize to enhance molecular interactions in coacervate LSPT into three categories, including physical stimulation, molecular modulation, and sequence regulation. This review aims to establish a conceptual framework for modulating coacervate LSPT and further explores potential clinical treatments for neurodegenerative diseases.},
}

@article {pmid41420107,
year = {2025},
author = {Campos-Ribeiro, MA and Donnarumma, E and Nolte, H and Cobine, P and Vimont, E and Milenkovic, D and Hernandez-Camacho, JD and Langa-Vives, F and Kornobis, E and Pénard, E and Yde, S and Langer, T and Paquis-Flucklinger, V and Wai, T},
title = {Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.},
journal = {EMBO molecular medicine},
volume = {},
number = {},
pages = {},
pmid = {41420107},
issn = {1757-4684},
support = {ANR-21-CE14 0052-02//Agence Nationale de la Recherche (ANR)/ ; ANR-23-CE13-0043-01//Agence Nationale de la Recherche (ANR)/ ; ANR-10-INSB-04-01//Agence Nationale de la Recherche (ANR)/ ; ANR-10-LABX-62-IBEID//Agence Nationale de la Recherche (ANR)/ ; INNOV 164-2022//Institut Pasteur (Pasteur Institute)/ ; },
abstract = {Mutations in CHCHD10, a mitochondrial intermembrane space (IMS) protein implicated in proteostasis and cristae maintenance, cause mitochondrial disease. Knock-in mice modeling the human CHCHD10[S59L] variant associated with ALS-FTD develop a mitochondrial cardiomyopathy driven by CHCHD10 aggregation and activation of the mitochondrial integrated stress response (mtISR). We show that cardiac dysfunction is associated with dual defects originating at the onset of disease: (1) bioenergetic failure linked to impaired mitochondrial copper homeostasis and cytochrome c oxidation, and (2) maladaptive mtISR signaling via the OMA1-DELE1-HRI axis. Using protease-inactive Oma1[E324Q/E324Q] knock-in mice, we show that blunting mtISR in Chchd10[S55L/+] mice delays cardiomyopathy onset without rescuing CHCHD10 insolubility, cristae defects or OXPHOS impairment. Proteomic profiling of insoluble mitochondrial proteins in Chchd10[S55L/+] mice reveals widespread disruptions of mitochondrial proteostasis, including IMS proteins involved in cytochrome c biogenesis. Defective respiration in mutant mitochondria is rescued by the addition of cytochrome c, pinpointing IMS proteostasis disruption as a key pathogenic mechanism. Thus, mutant CHCHD10 insolubility compromises metabolic resilience by impairing bioenergetics and stress adaptation, offering new perspectives for the development of therapeutic targets.},
}

@article {pmid41419928,
year = {2025},
author = {An, J and Hendricks, N and Wheeler, J and Hincks, J and Benitez, JAR and Snyder, JM and Kraemer, BC and Liachko, NF and Elkon, KB},
title = {Neuronal TDP-43 pathology drives astrocytic interferon response in a mouse model of ALS.},
journal = {Journal of neuroinflammation},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12974-025-03658-2},
pmid = {41419928},
issn = {1742-2094},
support = {IK6BX006467//The United States Department of Veterans Affairs/ ; I01BX004044//The United States Department of Veterans Affairs/ ; RF1AG055474/NH/NIH HHS/United States ; R01AG066729/NH/NIH HHS/United States ; },
abstract = {Neuroinflammation is implicated in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Amongst potential innate immune mediators of disease, Type I interferon (IFN-I) could play an important role due to its ability to inhibit protein synthesis and affect neuronal synapses and metabolism. These effects could be cell intrinsic or non-cell autonomous mediated by glia or immune cells. We examined IFN-I in rNLS8 mice that have been engineered to express doxycycline suppressible human Transactive response DNA binding protein 43 kDa (hTDP-43) with a defective nuclear localization signal (hTDP-43ΔNLS) regulated by the neurofilament heavy chain (NEFH) promoter. Following induction of hTDP-43ΔNLS in rNLS8 mice, we observed upregulation of IFN-I stimulated genes (ISG) and, specifically, activation of the DNA sensor, cyclic GMP-AMP synthase (cGAS), as determined by mass spectrometry identification of the cyclic dinucleotide, cGAMP, in whole brain. To determine the cellular source of IFN-I, we performed single nucleus RNA sequencing of whole brain. We observed that ISG were most highly upregulated in astrocytes suggesting that astrocytes themselves were largely responsible for IFN-I production and / or response in rNLS8 mice. This observation was confirmed by immunohistochemical and immunofluorescence staining of IFN-I stimulated proteins in astrocytes in the cerebrum, especially in the hippocampus. These results point to a pivotal role of astrocytes in responding to cell damage at a relatively early phase of disease which prior studies have shown is partially reversible.},
}

@article {pmid41419800,
year = {2025},
author = {Sun, Y and Zhong, Q and Chu, X and Wan, D and Peng, Y},
title = {Total intravenous anesthesia without neuromuscular blockers for ureteral lithotripsy in an ALS patient with orthopnea: a case report.},
journal = {BMC anesthesiology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12871-025-03561-6},
pmid = {41419800},
issn = {1471-2253},
}

@article {pmid41419286,
year = {2025},
author = {Phillips, G and Sharma, D and O'Reilly, G and Romero, L and Cameron, P},
title = {Developing emergency care systems in low-income and middle-income countries: a scoping review to examine the role of leadership and governance.},
journal = {BMJ open},
volume = {15},
number = {12},
pages = {e102624},
doi = {10.1136/bmjopen-2025-102624},
pmid = {41419286},
issn = {2044-6055},
mesh = {Humans ; *Developing Countries ; *Leadership ; *Emergency Medical Services/organization & administration ; },
abstract = {BACKGROUND: More knowledge and resources are required to strengthen 'leadership and governance' (L+G) as a central building block to further develop emergency care (EC) systems in low-income and middle-income countries (LMICs).

OBJECTIVES: This scoping review aimed to examine and map the impact of individual, collective or institutional L+G on the development of EC systems (prehospital and facility-based) in LMICs.

ELIGIBILITY CRITERIA: English language publications from January 2005 to April 2024 that linked any L+G action with the development and capacity of everyday EC in LMICs, specifically excluding disaster responses.

SOURCES OF EVIDENCE: Medline (Ovid), Embase (Ovid), CINAHL, Web of Science (Clarivate), Central (Cochrane Central Register of Controlled Trials), Global Health (Ovid) and select grey literature.

CHARTING METHODS: Data from all eligible papers were jointly extracted using a piloted tool developed from the literature and WHO's EC Systems Framework. L+G descriptors included level (from clinical to national) and components (informed by Siddiqi et al's LMIC health system 'good governance' framework and a synthesis of EC policy documents). Impact of L+G on EC systems and key lessons were extracted from each publication.

RESULTS: From an initial 9713 items, 129 papers were included for final analysis and divided by EC component: prehospital (n=35), facility-based (n=53) and 'whole of EC system' (n=41). Qualitative and descriptive papers were most common, and 72 out of a possible 131 LMICs were represented. Findings were heterogeneous across all building blocks of EC systems and for different components of leadership and/or governance. Cross-cutting L+G themes were identified that demonstrated consistent impact across all EC systems development: government recognition, vision and human rights framing; coalition-building for effective partnerships and trained, empowered EC clinicians demonstrating emotionally intelligent, transformational leadership.

CONCLUSIONS: Applying new models such as Theories of Change and Social Network Analysis concepts may assist to illuminate how effective L+G is attained, what are the essential components and how these influence EC systems for better patient-centred outcomes. Further understanding the role of L+G for EC systems has utility for future EC clinician leadership training and policy-maker awareness, to strengthen resilience of overall health systems against likely future shocks.},
}

Humans
*Developing Countries
*Leadership
*Emergency Medical Services/organization & administration

@article {pmid41419037,
year = {2025},
author = {Henriksson, S and Bäckström, M and Westberg, H and Hagberg, J},
title = {PCDD/Fs in food products produced near a contaminated former sawmill - concentrations, congener profiles and risk assessment.},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {},
number = {},
pages = {127529},
doi = {10.1016/j.envpol.2025.127529},
pmid = {41419037},
issn = {1873-6424},
abstract = {Hillringsberg, a former sawmill site in Sweden, is severely contaminated with polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). This study collected site-specific data to assess the human health risks associated with locally produced food. To evaluate potential exposure, samples of salmon, perch, cow's milk, cattle, and sheep were collected near the site and analyzed for PCDD/Fs. The findings reveal that the most frequently detected congeners in the food samples corresponded with the most abundant congeners in the soil, underscoring the impact of contaminated sites on PCDD/F concentrations in locally produced food. Particularly concerning is the level of PCDD/Fs in sheep meat, which was found to be 11 times higher than the Tolerable Weekly Intake (TWI) for adults and 26 times higher for children. Comparing food samples from the sawmill site to those from the National Swedish Control Programme revealed that all food samples from Hillringsberg exhibited some level of contamination, even though the concentrations of PCDD/Fs remained below the European Maximum Limits (MLs) and Action Limits (ALs). The concentrations and patterns of contaminants in nearly all samples, particularly those from sheep, cattle and perch, were influenced by local contamination from the historical use of pentachlorophenol (PCP) at the old sawmill site. PCA showed that sheep and soil samples from the storage area exhibited strong covariance. Perch and sediment samples from the sawmill pond were also grouped together. These findings highlight the necessity of evaluating food production activities near contaminated sites during the initial stages of site-specific risk assessments. Ensuring food safety in these areas is crucial, and if necessary, relocating grazing lands, fish farms, and similar operations can help mitigate health risks associated with contaminated food.},
}

@article {pmid41417753,
year = {2025},
author = {Lam, P and Zygmunt, DA and Bennett, M and Ashbrook, A and Hefty, J and Martin, PT},
title = {Gne deletion in adult mice can cause thrombocytopenia, anemia, myopathy, bleeding, and death.},
journal = {Journal of neuromuscular diseases},
volume = {},
number = {},
pages = {22143602251405918},
doi = {10.1177/22143602251405918},
pmid = {41417753},
issn = {2214-3602},
abstract = {The GNE gene encodes the UDP-GlcNAc-2-epimerase/ManNAc kinase, a bifunctional enzyme required for the synthesis of sialic acid. The mouse Gne gene is essential for embryonic development, but humans with recessive partial loss of function GNE mutations can develop infantile thrombocytopenia, juvenile amyotrophic lateral sclerosis, or adult-onset myopathy (GNE myopathy). We have created inducible Gne[lox/lox] gene deletion mice to study how loss of Gne in adult mice relates to these disease states. Systemic Gne gene deletion in tamoxifen-treated Rosa-CreER[T2]/Rosa-CreER[T2]Gne[lox/lox] mice caused uniform fatality within 30 days of gene deletion with spontaneous bleeding, thrombocytopenia, and anemia. Skeletal myofiber-specific Gne deletion in tamoxifen-treated HSA-CreER[T2/+]Gne[lox/lox] mice had no bleeding and no muscle pathology at 60 or 270 days post-treatment. Intramuscular injection of AAV.MCK.GFP-Cre in Gne[lox/lox] mice also showed little to no evidence of muscle pathology, while AAV.CMV.GFP-Cre caused extensive muscle damage, reduced muscle force, and changed expression of markers for muscle regeneration, muscle cell senescence, muscle denervation, and muscle atrophy. These data demonstrate that Gne is an essential gene in adult mice that can mimic aspects of human hematologic and muscle diseases caused by GNE mutations, but suggests induction of muscle disease requires loss of gene GNE expression in cell types beyond skeletal myofibers.},
}

@article {pmid41417080,
year = {2025},
author = {Zafar, U and Abdullah, M and Butt, TN and Uddin, MMZ and Masood, MH and Chu, LC and Zaheer, A},
title = {A bibliometric analysis of the 100 most cited radiology papers on pancreatic diseases (1990-Present).},
journal = {Abdominal radiology (New York)},
volume = {},
number = {},
pages = {},
pmid = {41417080},
issn = {2366-0058},
abstract = {PURPOSE: To map the intellectual evolution of pancreatic radiology through a comprehensive bibliometric analysis of the 100 most-cited articles, identifying influential contributors and publications, geographical and institutional patterns, and delineating the thematic and technological trends shaping research from 1990 to the present.

METHODS: A systematic search of the Scopus database, conducted on May 11, 2025, identified the top 1,000 most-cited pancreatic radiology records between 1990 and 2025. Two reviewers independently screened articles for a primary focus on pancreatic imaging within core radiology journals. The final 100 articles were analyzed using the Bibliometrix R package to evaluate publication trends, contributor influence, and collaborative networks. The conceptual structure and thematic evolution of the field were mapped using VOSviewer (version 1.6.20).

RESULTS: The median citation count was 223 (IQR: 190.2-264.5). A significant temporal bias was evident: the most-cited article was Balthazar et al.'s 1990 study on CT in pancreatitis (1,424 citations), while a 2015 deep learning paper achieved the highest citation velocity (58.5 citations/year). Analysis of research topics revealed a strong oncologic focus, with pancreatic neoplasms accounting for 51% of all articles. CT was the predominant imaging modality (55%), followed by MRI (24%). The research ecosystem was concentrated, with the United States contributing 46 articles and Radiology publishing 44 of the top 100 papers. Leading institutions included Johns Hopkins University and the Mayo Clinic. Co-authorship network analysis identified Megibow AJ as the researcher with the highest network centrality, highlighting the importance of collaborative hubs.

CONCLUSION: This bibliometric analysis charts the field's evolution from foundational CT/MRI applications to the current AI frontier. Our findings serve as a guide to the characteristics of high-impact research, highlighting a consistent focus on oncology, driven by key authors and US institutions. While historical benchmarks focused on morphological assessment, citation metrics confirm computational methods as the principal driver of future innovation.},
}

@article {pmid41417044,
year = {2025},
author = {Rott, N and Reinsch, L and Dirks, B and Böttiger, BW},
title = {[The new European Resuscitation Council (ERC) guidelines 2025-Overview of the most important changes; the first 3-5 min are decisive].},
journal = {Die Anaesthesiologie},
volume = {},
number = {},
pages = {},
pmid = {41417044},
issn = {2731-6866},
abstract = {In October 2025 the new resuscitation guidelines of the European Resuscitation Council (ERC) were published. In the chapter on advanced life support (ALS) for adults the update emphasizes topics such as efficient ventilation with adequate chest compressions, early defibrillation, identification and treatment of reversible causes as rapidly as possible and the administration of epinephrine in cases of non-defibrillatable cardiac arrest. The aim of the guidelines is to sustainably improve survival rates after cardiac arrest through structured and evidence-based care systems.},
}

@article {pmid41416937,
year = {2025},
author = {Jensen, TR and Jacobs, I and Kverková, K and Lalić, L and Polonyiová, A and Stehlík, P and Reber, SA and Osvath, M},
title = {T. rex cognition was T. rex-like-A critical outlook on diverging views of the neurocognitive evolution in dinosaurs.},
journal = {Anatomical record (Hoboken, N.J. : 2007)},
volume = {},
number = {},
pages = {},
doi = {10.1002/ar.70074},
pmid = {41416937},
issn = {1932-8494},
abstract = {A recent debate has emerged between Caspar et al. (2024) and Herculano-Houzel (2023) on inferring extinct dinosaur cognition by estimating brain neuron counts. While thought-provoking, the discussion largely overlooks the function of cognition, as well as partly neglects the difficulties involved in estimating neuron numbers, which according to us leads to oversimplified conclusions. We use this exchange as a springboard to further explore how extinct cognition might be studied and the potential pitfalls involved. One of the main emphases is on introducing basic concepts and contemporary views of cognition and its evolution. In relation to this, we highlight the shift in thermobiology during the Mesozoic-from ectothermy to endothermy-and its major impact on cognition and brain evolution. We also examine the challenges of estimating neuron counts in extinct dinosaurs based on current knowledge and take issue with several aspects of the approaches used by both Caspar et al. and Herculano-Houzel. At the same time, we challenge Caspar et al.'s claim that telencephalic neuron numbers, if estimable, would be largely uninformative about extinct dinosaur cognition, while also disagreeing with Herculano-Houzel's somewhat reductive view. We further emphasize the value of comparative cognitive studies in extant animals, alongside neural correlates, to infer the cognitive evolution of non-avian dinosaurs. We briefly outline how cognition is studied in living species and the extent to which such research can inform evolutionary inference. Our focus here is on non-avian theropods, as they are central to the current debate and belong to the lineage that led to modern birds.},
}

@article {pmid41415845,
year = {2025},
author = {Harsa, HS and González Domenech, CM and Prvulović, M and Agirbasli, Z and Bagherzadehsurbagh, E and Simeunović, V and Naziri, E and Adesemoye, E and Yigit Cinar, A and Mukherjee, A and Laranjo, M and Vidović, B and Alves, E and Vukojević, A and Özmen Toğay, S and Düven, G and Saar, H and Salminen, S and Matalas, A and Paveljšek, D and Schneider, E and Liwinski, T and Chassard, C and Vergères, G and Bär, C and Praćer, S},
title = {The effects of Lactobacillus and/or Bifidobacterium in fermented foods on cognitive health: a systematic review.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1682419},
pmid = {41415845},
issn = {2296-861X},
abstract = {BACKGROUND: Psychobiotics are microorganisms that modulate brain function via the gut-brain axis and are increasingly studied for their cognitive benefits. Lactobacillus and Bifidobacterium species, widely present in fermented foods, are considered safe and may influence cognition by modulating neuroinflammation, neurotransmitters, and gut barrier integrity. This systematic review examined the effects of foods fermented with these species on cognitive performance in healthy adults and individuals with mild cognitive impairment.

METHODS: We conducted the systematic review following EFSA guidelines, Cochrane methodology, and a PROSPERO protocol, using CADIMA for study selection and data extraction. PubMed, Scopus, and Cochrane Library were searched (1 January 1970-31 August 2023) for human intervention and observational studies assessing cognitive outcomes after ingestion of foods fermented with Lactobacillus or Bifidobacterium. Eligible populations included healthy adults and individuals with mild cognitive impairment; studies involving disease were excluded. Screening, data extraction, and bias assessment followed Muka et al.'s 24-step guide using ROBINS and Cochrane/CADIMA frameworks. Evidence was synthesized narratively, while a non-systematic component examined food characteristics, potential mechanisms, and factors affecting bioavailability of bioactive constituents.

RESULTS: We included 21 studies (8 interventional, 13 observational). The majority of studies reported benefits, particularly in episodic memory, executive functions, and global cognition, but evidence was limited by inadequate controls, small sample sizes, short interventions, inconsistent domain assessment, and incomplete food characterization. Observational studies had larger populations and longer follow-ups but were limited by exposure assessment and depth of cognitive testing.

CONCLUSION: Consumption of foods fermented with Lactobacillus and/or Bifidobacterium species may offer promising cognitive benefits. However, following EFSA's guidance on the substantiation of health claims, the current evidence is "neither convincing nor sufficient" to establish a causal relationship. Well-designed studies with thorough product characterization are needed to substantiate effects and support potential health claims.

This study was registered at the Open Science Framework (10.17605/OSF.IO/Z6GRW).},
}

@article {pmid41414999,
year = {2025},
author = {Kamadi, EN and Shah, J and Hooker, J and Jenkins, TM and Sokhi, DS},
title = {Clinical phenotypes of motor neurone disease in a Kenyan hospital-based population.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1662690},
pmid = {41414999},
issn = {1664-2295},
abstract = {BACKGROUND: Motor neurone disease (MND) presentation is globally heterogenous and data on the clinical phenotype in Sub-Saharan Africa (SSA) is scarce. We sought to address this by describing the profile of MND patients in a Kenyan hospital-based population.

METHODS: The medical charts of all adult MND patients assessed in the facility between January 2010 and December 2023 were retrospectively reviewed. The biographical data and clinical features of these patients were captured from their electronic and manual health records and statistical analysis performed.

RESULTS: In total, 160 patients had their data analyzed. The male to female ratio was 1.76:1. The median age at presentation was 55.0 (IQR: 45.0-68.0) years with a median diagnosis delay of 4.0 (IQR: 2.0-8.5) months. The site of first symptom onset was the lower limbs in 34.4% and the bulbar region in 33.1% [95% CI (26.4-42.5%)]. Notably, 59% of the patients were not tested for HIV and amongst those tested, 13.9% were HIV positive on ART. Majority (56.2%) of the patients were on Riluzole.

CONCLUSION: This Kenyan case series of MND patients demonstrated a higher rate of bulbar onset disease [33.1, 95% CI (26.4-42.5%), p = 0.018] in comparison to what has been demonstrated in other African studies. A finding that supports geographic variation in MND presentation and that emphasizes the need for region specific genetic studies.},
}

@article {pmid41412960,
year = {2025},
author = {Goutman, SA and Stouffer, DG and Jang, DG and Park, J and Murdock, BJ and Auchus, RJ},
title = {Sex Hormones Associate With Amyotrophic Lateral Sclerosis Risk and Survival.},
journal = {Annals of clinical and translational neurology},
volume = {},
number = {},
pages = {},
doi = {10.1002/acn3.70281},
pmid = {41412960},
issn = {2328-9503},
support = {R01TS000339/ACL/ACL HHS/United States ; AL200064//U.S. Department of Defense/ ; //Eric and Linda Novak/ ; //James and Margaret Hiller/ ; //Robert A. Epstein and Joan M. Chernoff-Epstein Emerging Scholar Fund/ ; //Stanford Morris ALS Research Fund/ ; K23ES027221/NH/NIH HHS/United States ; R01ES030049/NH/NIH HHS/United States ; R01NS120926/NH/NIH HHS/United States ; R01NS127188/NH/NIH HHS/United States ; //University of Michigan/ ; },
abstract = {Amyotrophic lateral sclerosis (ALS) risk differs by sex and age, implicating sex hormones as potential modifiers. This study examined plasma levels of biologically active sex hormones and their association with ALS odds and survival in cases (females n = 131, males n = 189) and controls (females n = 138, males n = 150) from the University of Michigan Pranger ALS Clinic. Higher 11-ketotestosterone levels were associated with increased ALS odds. In females, higher estrone, androstenedione, and 11-hydroxyandrostenedione were associated with increased ALS odds, while elevated estrone and estradiol predicted shorter survival. These findings highlight the potential significance of sex hormones in ALS.},
}

@article {pmid41411702,
year = {2025},
author = {Lebkuecher, AL and Coslett, HB and Buxbaum, LJ},
title = {The cognitive neuropsychology of action semantics: A review.},
journal = {Cortex; a journal devoted to the study of the nervous system and behavior},
volume = {194},
number = {},
pages = {159-190},
doi = {10.1016/j.cortex.2025.11.008},
pmid = {41411702},
issn = {1973-8102},
abstract = {The conceptual knowledge that mediates our ability to use familiar objects, understand viewed actions, and engage in communication about actions is often termed "action semantics". The underlying format, cognitive organization, and neural substrates of these representations are matters of active scientific investigation. This review synthesizes the large and diverse literature on action semantics in individuals with neurological disorders characterized by prominent motor deficits (e.g., Parkinson's disease and Amyotrophic lateral sclerosis), as well as those for whom motor deficits are often less prominent (e.g., Alzheimer's disease, Frontotemporal Dementia, stroke). Research in these two groups of disorders is strikingly "siloed" and offers many contradictory findings with respect to whether action semantic representations are abstract (i.e., "disembodied") or grounded in sensory and motor features that reflect the way knowledge was acquired. Findings across these populations also disagree as to whether action semantic representations are organized somatotopically or with a semantic feature-based architecture, and mediated by anterior motor-related or relatively posterior sensory-related brain regions. Many of these disparate findings can be reconciled with consideration of a multidimensional, multimodal representational architecture mediated by a distributed left-lateralized network of brain regions. We provide suggestions for specific methodological approaches for research with neurological populations that may further our understanding of the format, organization, and neural substrates of action semantics.},
}

@article {pmid41411011,
year = {2025},
author = {Lawley, KS and Kang, TW and Rech, RR and Karmakar, M and Carroll, R and Perez Gomez, AA and Amstalden, K and Jones-Hall, Y and Threadgill, DW and Welsh, CJ and Young, CR and Brinkmeyer-Langford, C},
title = {The association between virus-induced spinal cord pathology and the genetic background of the host.},
journal = {Journal of neuropathology and experimental neurology},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnen/nlaf127},
pmid = {41411011},
issn = {1554-6578},
support = {//National Institute for Neurological Disorders and Stroke (NINDS)/ ; R01 NS103934/NS/NINDS NIH HHS/United States ; 2P30 ES029067//National Institute for Environmental Health Sciences (NIEHS)/ ; DGE 1746932//National Science Foundation Graduate Research/ ; },
abstract = {Theiler's murine encephalomyelitis virus (TMEV) infection in mice has been used to study diverse neurological diseases, including multiple sclerosis and epilepsy. In this investigation, 5 strains of collaborative cross (CC) mice were infected with TMEV and examined clinically and histologically at days 4, 14, and 90 post-infection (dpi). All CC strains tested exhibited lumbar spinal cord and/or ventral peripheral nerve lesions by 14 dpi; CC027, CC023, and CC078 strains exhibited lesions at 4 dpi. At 90 dpi, lesions were remnants of the inflammatory responses associated with earlier infection; there was skeletal muscle atrophy in the CC023 strain. Increased microglial/macrophage reactivity was observed in all strains at 4 and 14 dpi, but not at 90 dpi. TMEV mRNA expression was greatest in the CC023 and CC078 strains at the acute timepoints; TMEV was completely cleared in all mice at 90 dpi. The neuropathological and clinical profiles in CC023 mice, mainly at 14 dpi, share some clinical and histologic features with those in amyotrophic lateral sclerosis patients. This work demonstrates how viral infection might interact with the genetic background of a susceptible individual to contribute to the onset, clinical presentation and persistence of lesions despite viral clearance.},
}

@article {pmid41409685,
year = {2025},
author = {Ran, X and Wuu, J and Qin, ZS and Cooper-Knock, J and Granit, V and Grignon, AL and Li, Y and Lin, E and Fernandez, MC and Colato, D and Carberry, N and Lill, CM and Piazza, P and Malaspina, A and Benatar, M},
title = {Predicting Phenoconversion to Clinically Manifest ALS: Results of a Large-Scale Proteomic Study.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
doi = {10.64898/2025.12.06.25341403},
pmid = {41409685},
abstract = {The study of pre-symptomatic amyotrophic lateral sclerosis (ALS) and the design of disease prevention trials are greatly hampered by our inability to predict which unaffected carriers of ALS-associated pathogenic variants will phenoconvert to clinically manifest disease, and when. In this longitudinal Olink Explore high-throughput proteomic study, 516 serially collected plasma samples from 33 phenoconverters, 35 patients with ALS, 10 pre-symptomatic pathogenic variant carriers and 59 controls were included. We identified 81 proteins whose concentrations changed prior to phenoconversion; characterized the longitudinal trajectory of these proteins; and identified a core panel of 19 proteins that, collectively, predicted phenoconversion over the 0.5- to 5-year time horizons (areas under curve 0.80-0.89) and yielded estimates of time-to-phenoconversion with a mean absolute error of 1.6 years. These findings were replicated in UK Biobank data, confirming pre-symptomatic increases in several proteins (e.g. NEFL, EDA2R, CA3) and that a multi-protein panel outperformed NEFL alone in estimating time-to-phenoconversion. This work sheds light on the biology of pre-symptomatic ALS. Moreover, our identification of a panel of novel susceptibility/risk biomarkers based on empirical longitudinal data furthers the ultimate goal of ALS prevention.},
}

@article {pmid41408351,
year = {2025},
author = {Ibragimov, U and Giordano, NA and Amaresh, S and Getz, T and Matuszewski, T and Steck, AR and Li, Y and Blum, EH and Tuttle, J and Pipalia, H and Cooper, HLF and Carpenter, JE},
title = {Implementation outcomes and strategies of a peer recovery coach program: findings from a qualitative assessment in the U.S. South, 2024-2025.},
journal = {Addiction science & clinical practice},
volume = {20},
number = {1},
pages = {95},
pmid = {41408351},
issn = {1940-0640},
support = {R01CE003509/CC/CDC HHS/United States ; },
mesh = {Humans ; *Peer Group ; *Substance-Related Disorders/rehabilitation/therapy ; Qualitative Research ; *Emergency Service, Hospital ; Male ; Female ; Georgia ; Adult ; Program Evaluation ; Middle Aged ; *Mentoring ; Interviews as Topic ; },
abstract = {INTRODUCTION: Successful implementation of peer recovery coach (PRC) programs may help improve linkage to services and clinical outcomes for emergency department (ED) patients with substance use disorder (SUD). However, literature on implementation outcomes and strategies of PRC programs is limited. We conducted a qualitative assessment of implementation outcomes and strategies for an ED-based PRC program in Atlanta, Georgia.

METHODS: We conducted qualitative interviews with 27 program participants (ED patients with SUD served by PRC program) and 29 service providers and partners (peer recovery coaches, ED physicians and staff, SUD treatment and other service providers) in October 2023 - March 2025. We transcribed audio-recordings and analyzed data using rapid qualitative analysis approach mapping emerging themes to Proctor's model of implementation outcomes and Leeman et al.'s implementation strategies framework.

RESULTS: We identified two major themes related to implementation outcomes: (1) PRC program acceptability (patients' positive interactions with PRCs) and (2) appropriateness (sub-themes include: successful linkage to community services; PRC program as an important resource for patients; added value of PRC team; no negative impact on ED workflow). Themes related to implementation strategies include (1) streamlined communication between PRC and ED teams (direct communication via electronic medical records system, single contact phone number, informing ED service providers of clinical and program outcomes), (2) addressing barriers to community-based services (preparing patient's medical documentation, insurance, transportation to community services); (3) supportive supervision of PRCs (addressing daily and long-term issues through regular meetings; limiting caseload; and providing orientation, on-job training and mental health support) and (4) addressing telehealth implementation challenges (ensuring access to electronic medical records system).

CONCLUSION: This study outlines key implementation outcomes and strategies for PRC programs, offering practical guidance for successful ED-based PRC program implementation.},
}

Humans
*Peer Group
*Substance-Related Disorders/rehabilitation/therapy
Qualitative Research
*Emergency Service, Hospital
Male
Female
Georgia
Adult
Program Evaluation
Middle Aged
*Mentoring
Interviews as Topic

@article {pmid41408263,
year = {2025},
author = {Doughty, J and Booth, J and Smith, M and Saini, K and Paisi, M and Rodriguez, A and Levine, A and Bedos, C and Muirhead, V and Martins de Barros, C and Freeborn, C},
title = {Unmasking oral health stigma: a qualitative scoping review.},
journal = {BMC oral health},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12903-025-07329-9},
pmid = {41408263},
issn = {1472-6831},
abstract = {INTRODUCTION: Health-related stigma can limit access to care, impair adherence to treatment, and negatively impact mental health and quality-of-life. Oral health stigma, defined as stigma arising from oral conditions that diverge from sociocultural norms, operates through labelling, stereotyping, othering, and exclusion. Oral health stigma can lead to shame, diminished self-confidence, and avoidance of dental care, creating a self-perpetuating cycle of poor oral health and reinforcing internalised and anticipated stigma. While previous research has explored the social implications of oral appearance, little is known about the broader concept of oral health stigma or strategies to mitigate it.

METHODS: This scoping review adopted Levac et al.'s six-stage framework. The review utilised data from qualitative studies to explore lived experiences of oral health stigma and consider ways to mitigate it. Patient and public involvement (PPI) informed the development of the research question, search strategy, and interpretation of findings.

RESULTS: Seventy-two qualitative studies were included, comprising 2,455 participants. Themes included stigma associated with physical appearance and attractiveness, judgement, labelling, and stereotyping. Consequences included low self-esteem, social exclusion, impacts to care seeking behaviours, and efforts to conceal oral appearance. Participants highlighted the transformative value of dental care and described coping strategies to build resilience. Other proposed solutions included fostering social connection and implementing trauma-informed, non-judgemental dental care.

CONCLUSION: Oral health stigma has significant social and psychological consequences and impacts on care-seeking behaviours. Addressing it requires targeted interventions at multiple levels, including individual, community, professionals and wider system / policy.},
}

@article {pmid41407165,
year = {2025},
author = {Ghosh, N and Ghosh, J and Ghosh, S and Sinha, K and Sil, PC},
title = {Nutraceutical interventions for neuroprotection: a comprehensive review.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117637},
doi = {10.1016/j.bcp.2025.117637},
pmid = {41407165},
issn = {1873-2968},
abstract = {Nutraceuticals, bioactive compounds derived from food sources, are emerging as promising agents for neuroprotection, particularly through their modulation of gut health. Unlike conventional single-molecule therapeutics that often target isolated pathways, nutraceuticals offer a multi-targeted approach by influencing the gut-brain axis, a bidirectional communication network linking the gut microbiota and the central nervous system. Key nutraceuticals such as probiotics, prebiotics, polyphenols, omega-3 fatty acids, and vitamins have been shown to beneficially alter microbiota composition, reduce intestinal inflammation, and strengthen gut barrier integrity. These changes can significantly influence brain function by modulating neurotransmitter activity and systemic immune responses. This review compares the holistic action of nutraceuticals with the more focused effects of single-molecules, particularly in the context of neurodegenerative diseases like Alzheimer's, Parkinson's, Huntington's Disease and Motor Neuron Diseases like amyotrophic lateral sclerosis. It discusses how nutraceuticals may mitigate key pathological features of these conditions-including neuroinflammation, oxidative stress, and mitochondrial dysfunction, through gut-mediated pathways. Despite their potential, challenges remain regarding the standardization of formulations, bioavailability, dosage optimization, and long-term safety. Further clinical research is needed to validate the efficacy of nutraceuticals as complementary or alternative strategies to traditional neuroprotective agents.},
}

@article {pmid41406788,
year = {2025},
author = {Vijayakumar, S and Schwaighofer, A and de Juan, A and Rocha de Oliveira, R and Mach-Aigner, A and Lendl, B and Ramer, G},
title = {Fusion of incomplete QCL-IR and ECD datasets using MCR-ALS to extend the viable concentration range for studying protein denaturation.},
journal = {Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy},
volume = {349},
number = {},
pages = {127340},
doi = {10.1016/j.saa.2025.127340},
pmid = {41406788},
issn = {1873-3557},
abstract = {While several techniques exist to study the secondary structure of proteins, mid-IR and electronic circular dichroism spectroscopy are complementary techniques that stand out for liquid measurements due to their non-destructive nature, broad applicability and ease of use. CD spectroscopy however is only used to measure low protein concentrations and suffers from signal interferences from common buffers. With advances in laser-technology, the achievable pathlengths used in IR-spectroscopy have increased with the use of external cavity quantum cascade lasers (EC-QCL) as light sources. This has not only enabled protein denaturation to be studied without aggregates clogging the measurement cell, as was the case with shorter pathlengths, but also expanded the concentration range that can be measured with the technique. Yet, the concentration range where both IR and CD measurements can be made has only a small overlap. In this study, the IR and CD spectra obtained during the thermal denaturation of α-chymotrpysin (α-CT) in the overlapping concentration range of the two spectroscopy techniques, between 10mgmL[-1] to 40mgmL[-1], are used to extract more information about the denaturation process of the protein and its concentration dependence. To this end, the protein denaturation spectra from both methods between 20°C to 80°C are fused and analyzed using multivariate curve resolution-alternating least squares (MCR-ALS), a bilinear unmixing technique that provides thermal profiles and pure fingerprints of the protein conformations involved in the denaturation process. However, in these measurements, a large and information-dense part of the CD spectra found at the lowest UV wavelengths cannot be used due to the saturated signal linked to high protein concentration levels. A modified version of MCR-ALS is hence introduced to overcome this issue, which allows all available information to be used without sacrificing the quality of the fit. The prowess of the adapted MCR-ALS technique as a tool for data fusion was demonstrated by not only providing a better fit than the individual models (CD and IR spectra analyzed separately), but also by aiding in squeezing out information about a third protein conformation that forms during the denaturation of α-CT.},
}

@article {pmid41406304,
year = {2025},
author = {Geva, M and Goldberg, YP and Leitner, ML and Cruz-Herranz, A and Hand, R and Chen, K and Gershoni Emek, N and Tan, AM and Paganoni, S and Berry, JD and Macklin, EA and Shefner, JM and Cudkowicz, ME and Hayden, MR},
title = {Pridopidine treatment in ALS: subgroup analyses from the HEALEY ALS Platform trial.},
journal = {Amyotrophic lateral sclerosis & frontotemporal degeneration},
volume = {},
number = {},
pages = {1-13},
doi = {10.1080/21678421.2025.2597935},
pmid = {41406304},
issn = {2167-9223},
abstract = {Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with limited treatment options. Pridopidine, a selective sigma-1 receptor agonist, was evaluated in Regimen D of the HEALEY ALS Platform Trial. Although the primary endpoint (ALS Functional Rating Scale-Revised (ALSFRS-R) total score accounting for survival at 24 weeks) was not met, a predefined subgroup analysis suggested slowed disease progression in ALS patients with definite and early disease (<18 months from onset). This report presents an exploratory analysis that further investigates pridopidine in rapidly progressing participants with definite/probable ALS and early-disease, where treatment effects may be more pronounced. Methods: The randomized, double-blind, placebo-controlled phase 2 trial assigned participants to pridopidine 45 mg bid or placebo, and placebo patients were shared across four trial regimens. The primary outcome was ALSFRS-R total score, with secondary outcomes assessing respiratory, bulbar, and speech functions. Results: Of 163 participants randomized to Regimen D, 72 met subgroup criteria (pridopidine: n = 37; shared placebo: n = 35). At week 24, pridopidine slowed ALSFRS-R total score decline (32%; Δ2.90, p = 0.03) and slowed decline of ALSFRS-R respiratory function (62%; Δ1.20, p = 0.03) and dyspnea (88%; Δ0.85, p = 0.005). ALSFRS-R-Bulbar function stabilized, with articulation and speaking rate declines reduced by 93% (Δ0.43, p = 0.0007) and 70% (Δ0.43, p = 0.002), respectively. Pridopidine was well-tolerated, with a safety profile comparable to placebo. All p values are nominal. Conclusion: Post hoc subgroup analysis suggests therapeutic benefits of pridopidine in patients that had definite/probable ALS and with early-disease progression, supporting further evaluation in a Phase 3 trial.},
}

@article {pmid41405451,
year = {2025},
author = {Liampas, I and Kimiskidis, VK and Zouvelou, V and Veltsista, D and Moscholouri, A and Triantafyllou, E and Daponte, A and Xirou, S and Sterpi, AE and Salakou, S and Poulidou, V and Arnaoutoglou, M and Tsouris, Z and Ralli, S and Dardiotis, E and Papagiannopoulos, S and Zampetakis, A and Zaganas, Ι and Mitsias, P and Giannakis, A and Konitsiotis, S and Kefalas, F and Alexiou, E and Stoiloudis, P and Parissis, D and Kiamelidis, S and Terzoudi, A and Tsivgoulis, G and Rentzos, M and Chroni, E},
title = {Greek Registry for Amyotrophic Lateral Sclerosis (ALS-GR): An Observational Cohort of Individuals With ALS Across 11 Specialized Centers in Greece.},
journal = {European journal of neurology},
volume = {32},
number = {12},
pages = {e70403},
doi = {10.1111/ene.70403},
pmid = {41405451},
issn = {1468-1331},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/physiopathology/drug therapy/therapy ; Greece/epidemiology ; *Registries ; Male ; Middle Aged ; Female ; Aged ; Cohort Studies ; Disease Progression ; Adult ; Riluzole/therapeutic use ; },
abstract = {BACKGROUND: Epidemiological studies on amyotrophic lateral sclerosis (ALS) in Greece are scarce and outdated.

METHODS: We performed an observational cohort study in 11 specialized centres across Greece. Adult individuals with ALS diagnosed based on the Gold Coast criteria were recruited. Data were collected on socio-demographics, somatometrics, comorbidities, early life exposures, disease-related parameters, riluzole intake, motor and non-motor symptoms, as well as functional progression. Follow-up evaluations were scheduled on approximately 6-9-12-18-24 months. Our aim was to identify shortcomings in the monitoring of patients with ALS in specialized centers, delineate the course of the disease, and capture factors related to the earlier occurrence of ALS and potential diagnostic delays.

RESULTS: A total of 229 ALS patients were included in the present registry. The average age of diagnosis was 63.7 years, with an average 12.8-month interval between symptom onset and diagnosis. The presence of bulbar symptoms at onset was associated with shorter diagnostic delays. Systematic physical exercise was strongly linked to the earlier onset of symptoms. Disease progression was slower during the prediagnostic stage, more precipitous over the first year following diagnosis, and milder thereafter (~1-point monthly decline in ALSFRS-R on average, post-diagnosis). The majority of associated motor and non-motor symptoms accumulated over time. The overwhelming majority of patients were prescribed the liquid form of riluzole, which exhibited an excellent tolerability profile. Greek islands are probably the most underprivileged in terms of specialized monitoring of ALS cases.

CONCLUSIONS: The present observational cohort study mapped key aspects and shortcomings of ALS management in Greece.},
}

Humans
*Amyotrophic Lateral Sclerosis/epidemiology/diagnosis/physiopathology/drug therapy/therapy
Greece/epidemiology
*Registries
Male
Middle Aged
Female
Aged
Cohort Studies
Disease Progression
Adult
Riluzole/therapeutic use

@article {pmid41404692,
year = {2025},
author = {Żur-Wyrozumska, K},
title = {A case of an ALS patient with an SQSTM1 mutation - implications for the p62/NF-κB/Nrf2/autophagy pathways in the selection of individualised therapeutic strategies: a preliminary report.},
journal = {Folia medica Cracoviensia},
volume = {65},
number = {3},
pages = {173-183},
doi = {10.24425/fmc.2025.156692},
pmid = {41404692},
issn = {0015-5616},
mesh = {Humans ; *Amyotrophic Lateral Sclerosis/genetics/drug therapy ; *Sequestosome-1 Protein/genetics ; Middle Aged ; Female ; NF-E2-Related Factor 2/genetics/metabolism ; Autophagy/genetics ; NF-kappa B/genetics ; Mutation ; Signal Transduction ; },
abstract = {INTRODUCTION: Amyotrophic lateral sclerosis (ALS) represents a heterogeneous group of neurodegenerative disorders sharing a common ALS phenotype but arising from diverse genetic and molecular mechanisms. Among the genes implicated in ALS, SQSTM1, encoding the multifunctional protein p62, plays a pivotal role in maintaining neuronal homeostasis through the regulation of autophagy and the crosstalk between NF-κB and Nrf2 pathways. Disruption of these mechanisms contributes to oxidative stress, neuroinflammation, and protein aggregation in motor neurons.

MATERIAL AND METHODS: A comprehensive genetic analysis, including next-generation sequencing (NGS), whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA), was performed in a patient clinically diagnosed with ALS. Literature data regarding the role of SQSTM1, NF-κB/Nrf2 signaling, and autophagy modulation in ALS pathogenesis were reviewed to contextualize the findings.

CASE PRESENTATION: We describe a 49-year-old woman with a 12-month history of progressive - bulbar-onset ALS. Genetic testing revealed a heterozygous SQSTM1 c.1175C>T (p.Pro392Leu) variant inherited from her father, classified as likely pathogenic. The patient received dimethyl fumarate (Nrf2 activator), celecoxib (NF-κB inhibitor), and rapamycin (mTOR pathway modulator) as part of an individualized treatment strategy.

DISCUSSION: Mutations in SQSTM1 contribute to ALS pathogenesis through dysregulation of autophagy, impaired protein clearance, and excessive neuroinflammation mediated by NF-κB activation. The interplay between NF-κB and Nrf2 signaling pathways suggests that targeted therapeutic modulation may attenuate neurodegeneration. The patient's case illustrates the clinical and molecular heterogeneity of ALS and supports the concept of pathway-specific, precision medicine approaches.

CONCLUSIONS: This case highlights the relevance of SQSTM1-related pathogenic mechanisms within the heterogeneous ALS spectrum and underscores the importance of advanced genetic testing for identifying candidates for personalized therapy.},
}

Humans
*Amyotrophic Lateral Sclerosis/genetics/drug therapy
*Sequestosome-1 Protein/genetics
Middle Aged
Female
NF-E2-Related Factor 2/genetics/metabolism
Autophagy/genetics
NF-kappa B/genetics
Mutation
Signal Transduction

@article {pmid41404604,
year = {2025},
author = {Jilani, SB and Ashok, N and Bomble, YJ and Guss, AM and Olson, DG},
title = {Engineering Clostridium thermocellum for production of 2,3-butanediol from cellulose.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.11.28.691234},
pmid = {41404604},
issn = {2692-8205},
abstract = {Clostridium thermocellum is a promising host for consolidated bioprocessing due to its ability to directly ferment cellulose into fuels and chemicals. However, natural product formation in this organism is limited. Here, we report engineering C. thermocellum for the production of 2,3-butanediol (23BD), a valuable industrial chemical. We functionally expressed a thermophilic 23BD pathway in this organism resulting in a 23BD titer of 19.7 mM from cellulose, representing a metabolic yield of 24%. We used a cell-free systems biology approach to identify limiting steps in the 23BD pathway, revealing that exogenous 23BD dehydrogenase (BDH) activity was essential for production, while native acetolactate synthase (ALS) and acetolactate decarboxylase (ALDC) activities were present but limiting in the parent strain. This approach also revealed redox balance limitations. We demonstrated that this improved understanding of redox balance limitations could be used to increase 23BD titer in vivo, showing that adding acetate could be used to increase 23BD yield. This work establishes a foundation for developing C. thermocellum into a robust platform for 23BD production directly from cellulose and highlights the utility of cell-free systems for guiding metabolic engineering in non-model organisms.},
}

@article {pmid41403635,
year = {2025},
author = {Li, CY and Xie, WX and You, HP and Hu, HR and Chen, ZY},
title = {A multi-stage genomic approach to uncover druggable gene targets and neural pathways in postpartum depression.},
journal = {Archives of medical science : AMS},
volume = {21},
number = {5},
pages = {2047-2057},
pmid = {41403635},
issn = {1734-1922},
abstract = {INTRODUCTION: Postpartum depression (PPD) is a severe emotional disorder affecting women worldwide, with significant impacts on maternal and infant health. Its genetic contributors and biological mechanisms are poorly understood. Identifying druggable genes and clarifying their causal roles may offer insights for developing more effective treatments.

MATERIAL AND METHODS: We identified drug-related genes and screened gene expression quantitative trait loci (eQTL) from the eQTLGen consortium and genotype tissue expression (GTEx) v8 dataset, focusing on 13 brain tissues, along with Qi et al.'s meta-study on the cerebral cortex. Mendelian randomization (MR) analyses were used to investigate causal relationships between gene expression and PPD risk. Replication analyses in an independent PPD cohort validated initial findings, and meta-analysis combined MR results. Summary-data-based MR (SMR) and heterogeneity in dependent instruments (HEIDI) tests were also performed, followed by colocalization analyses to assess shared causal variants. Mediation analyses were conducted to explore how genetic effects may influence brain connectivity patterns.

RESULTS: From 5,883 druggable genes, 37 showed potential causal links to PPD. Replication analyses confirmed 9 of these genes, with 4 remaining significant in meta-analysis. SMR and HEIDI analyses focused on CLCN7, which showed robust evidence for causal involvement in PPD. Colocalization analyses suggested shared causal variants, and mediation analyses revealed that CLCN7's genetic risk is partially mediated by left- to right-hemisphere visual network white-matter structural connectivity.

CONCLUSIONS: Our analysis identified CLCN7 as a potential causal factor in PPD, with its effect mediated through brain connectivity. These findings offer targets for future studies and therapeutic strategies for PPD.},
}

@article {pmid41403093,
year = {2025},
author = {Ghaderi, S and Mohammadi, S and Kalra, S},
title = {Hippocampal Subfield Integrity and Age-Driven Neural Correlates of Appetite Loss in Amyotrophic Lateral Sclerosis.},
journal = {Journal of magnetic resonance imaging : JMRI},
volume = {},
number = {},
pages = {},
doi = {10.1002/jmri.70206},
pmid = {41403093},
issn = {1522-2586},
abstract = {BACKGROUND: Appetite loss is a non-motor symptom in amyotrophic lateral sclerosis (ALS) linked to poorer prognosis. While the hippocampus regulates "meal memory", a key cognitive modulator of eating behavior, its structural role in ALS-related appetite loss is unknown.

PURPOSE: To determine if hippocampal subfield integrity influences appetite dysregulation in ALS and to evaluate the strength of neuroanatomical versus demographic factors.

STUDY TYPE: Cross-sectional secondary analysis.

POPULATION: Thirty-two patients with ALS (mean age: 58.97 ± 8.91 years; 24 males) and 22 non-neurodegenerative controls (NNDc) (mean age: 53.86 ± 9.98 years; 16 males).

FIELD STRENGTH/SEQUENCE: 3T; 3D T1-weighted magnetization-prepared rapid gradient-echo (MP2RAGE) and 3D T2-weighted turbo spin-echo (T2-SPACE) sequences.

ASSESSMENT: Appetite was measured using the Council on Nutrition Appetite Questionnaire (CNAQ). Hippocampal subfield volumes (CA1, CA2/3, CA4/DG, stratum radiatum/lacunosum/moleculare [SRLM], subiculum) and asymmetry indices were segmented from T1w and T2w images using the HIPS automated pipeline.

STATISTICAL TESTS: Analysis of Covariance (ANCOVA) (adjusting for age, sex, body mass index (BMI), total intracranial volume (TIV), and subfield volumes/asymmetry) and hierarchical multiple regression analyses were used. Significance was set at p < 0.05.

RESULTS: Patients with ALS (adjusted mean: 29.51 ± 0.53) had significantly lower adjusted CNAQ scores compared to controls (adjusted mean: 31.98 ± 0.66; mean difference: -2.47, partial η[2] = 0.195). In the ANCOVA model, left SRLM volume was the only significant neuroanatomical covariate (F [1, 30] = 6.45, partial η[2] = 0.177). However, hierarchical regression revealed that age was the only consistent independent predictor of CNAQ scores (B = -0.158), explaining the largest variance (ΔR[2] = 0.165). Hippocampal volumes and asymmetry did not remain significant predictors after adjusting for age (left SRLM: p = 0.853; SRLM asymmetry: p = 0.868).

DATA CONCLUSION: Appetite loss is a non-motor symptom in ALS. While associated with lower left SRLM volume at the group level, appetite decline is more robustly and independently associated with advancing age.

EVIDENCE LEVEL: 3.

TECHNICAL EFFICACY: 3.},
}