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30 Nov 2020 at 01:32
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Bibliography on: Alzheimer Disease — Current Literature


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RJR: Recommended Bibliography 30 Nov 2020 at 01:32 Created: 

Alzheimer Disease — Current Literature

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. This bibliography runs a generic query on "Alzheimer" and then restricts the results to papers published in or after 2017.

Created with PubMed® Query: alzheimer[TIAB] and (2017[PDAT] OR [2018[PDAT] OR 2019[PDAT] OR 2020[PDAT]) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2020-11-29

Darrow JA, Calabro A, Gannon S, et al (2020)

Effect of Patient-Specific Preanalytic Variables on CSF Aβ1-42 Concentrations Measured on an Automated Chemiluminescent Platform.

The journal of applied laboratory medicine pii:6010325 [Epub ahead of print].

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly used to confirm the accuracy of a clinical diagnosis of mild cognitive impairment or dementia due to Alzheimer disease (AD). Recent evidence suggests that fully automated assays reduce the impact of some preanalytical factors on the variability of these measures. This study evaluated the effect of several preanalytical variables common in clinical settings on the variability of CSF β-amyloid 1-42 (Aβ1-42) concentrations.

METHODS: Aβ1-42 concentrations were measured using the LUMIPULSE G1200 from both freshly collected and frozen CSF samples. Preanalytic variables examined were: (1) patient fasting prior to CSF collection, (2) blood contamination of specimens, and (3) aliquoting specimens sequentially over the course of collection (i.e., CSF gradients).

RESULTS: Patient fasting did not significantly affect CSF Aβ1-42 levels. While assessing gradient effects, Aβ1-42 concentrations remained stable within the first 5 1-mL aliquots. However, there is evidence of a gradient effect toward higher concentrations over successive aliquots. Aβ1-42 levels were stable when fresh CSF samples were spiked with up to 2.5% of blood. However, in frozen CSF samples, even 0.25% blood contamination significantly decreased Aβ1-42 concentrations.

CONCLUSIONS: The preanalytical variables examined here do not have significant effects on Aβ1-42 concentrations if fresh samples are processed within 2 h. However, a gradient effect can be observed on Aβ1-42 concentrations after the first 5 mL of collection and blood contamination has a significant impact on Aβ1-42 concentrations once specimens have been frozen.

RevDate: 2020-11-27

Lu WH, Barreto PS, Rolland Y, et al (2020)

Biological and Neuroimaging Markers as Predictors of 5-year Incident Frailty in Older Adults: a Secondary Analysis of the MAPT study.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:6007777 [Epub ahead of print].

BACKGROUND: This study aims to investigate the predictive value of biological and neuroimaging markers to determine incident frailty among older people over 5 years.

METHODS: We included 1,394 adults ≥70 years from the Multidomain Alzheimer Preventive Trial (MAPT), who were not frail at baseline (according to Fried's criteria) and who had at least one post-baseline measurement of frailty. Participants who progressed to frailty during the 5-year follow-up were categorized as "incident frailty" and those who remained non-frail were categorized as "without frailty". The differences of baseline biochemical factors (25-hydroxyvitamin D, homocysteine, omega-3 index, C-reactive protein - CRP), other biological markers (Apolipoprotein E genotypes, amyloid-β deposits) and neuroimaging data (grey matter volume, hippocampal volume, white matter hyperintensities) were compared between groups. Cox proportional hazard model was used to evaluate the associations between biomarkers and incident frailty.

RESULTS: A total of 195 participants (14.0%) became frail over 5 years. Although 25-hydroxyvitamin D deficiency, homocysteine levels, low-grade inflammation (persistently increased CRP 3-10 mg/L), grey matter and hippocampal volume were significantly associated with incident frailty in unadjusted models, these associations disappeared after adjustment for age, sex, and other confounders. Omega-3 index was the sole marker that presented a trend of association with incident frailty (HR: 0.92; 95% CI: 0.83-1.01; p=0.082).

CONCLUSION: This study failed to identify biomarkers able to predict frailty incidence in community-dwelling older adults over 5 years. Further longitudinal research with multiple measurements of biomarkers and frailty is needed to evaluate the long-term relationships between changes in biomarkers levels and frailty evolution.

RevDate: 2020-11-27

Almaliki WH, Alzahrani A, Mahmoud El-Daly ME, et al (2020)

The emerging potential of SIRT-3 in oxidative stress-inflammatory axis associated increased neuroinflammatory component for metabolically impaired neural cell.

Chemico-biological interactions pii:S0009-2797(20)31756-7 [Epub ahead of print].

People suffering from conditions like epilepsy, where there is an excess of neuron excitement, stroke, and cardiac arrest, where there are oxygen and glucose deprivation, Alzheimer, Parkinson, and Huntington's disease that causes metabolic and also oxidative stress-inflammatory axis; are known to be more vulnerable to disturbances in the metabolism, and there is a lot of inadequacy in defining the inflammation's mechanistic connections, as well as neurodegeneration and the bioenergetic deficiencies in the CNS. We retrieved relevant studies from PubMed/ScienceDirect/Medline/Public library of science/Mendeley/Springer link as well as Google Scholar. We used various keywords both individually and in combination with the literature search. 'Epidemiology of neurodegenerative disorders', 'neurodegenerative diseases associated hyper inflammation', 'Mechanism of inflammation in neuronal cell', 'Involvement of SIRTin inflammation', 'Pathogenesis of mitochondrial associated metabolic impairment in neurons', 'Reactive oxygen species-mediated mitochondrial dysfunction' were a few of the keywords used for the search. PINCH, which is a chronic neuro-inflammatory component that cannot be detected in matured neurons which are healthy, though expressed in oxidative stress inflammatory axis related tauopathy and diseases that cause neurodegeneration. We attempted to study the regulatory mechanisms that cause changes in the bioenergetics and its neuronal defects and mitochondrial subcellular localization that are PINCH protein-mediated on the other handSIRT1, the most intensively studied sirtuin, in oxidative stress-mediated inflammatory consequence for many diseases but very few research data explore the role of SIRT-3 for correction of the chronic neuroinflammatory component. Thus, in this review, we investigate the very recently identified molecules involving in the pathogenesis during stimulated oxidative stress-inflammatory axis in the excitatory neuronal cell which changes brain metabolism. Simultaneously, in CNS neurons of diseases with a component of chronic neuroinflammation which exhibit neuroprotective response, the consequences (mechanistic and biological) of SIRT-3, could be emerging future targets for neurodegenerative disorder treatment with impaired metabolisms.

RevDate: 2020-11-27

Sánchez-Sarasúa S, Ribes-Navarro A, Beltrán-Bretones MT, et al (2020)

AAV delivery of shRNA against IRS1 in GABAergic neurons in rat hippocampus impairs spatial memory in females and male rats.

Brain structure & function pii:10.1007/s00429-020-02155-x [Epub ahead of print].

Brain insulin resistance is a major factor leading to impaired cognitive function and it is considered as the onset of Alzheimer´s disease. Insulin resistance is intimately linked to inflammatory conditions, many studies have revealed how pro-inflammatory cytokines lead to insulin resistance, by inhibiting IRS1 function. Thus, the dysfunction of insulin signaling is concomitant with inflammatory biomarkers. However, the specific effect of IRS1 impaired function in otherwise healthy brain has not been dissected out. So, we decided in our study, to study the specific role of IRS1 in the hippocampus, in the absence of comorbidities. To that end, shRNA against rat and human IRS1 was designed and tested in cultured HEK cells to evaluate mRNA levels and specificity. The best candidate sequence was encapsulated in an AAV vector (strain DJ8) under the control of the cytomegalovirus promoter and together with the green fluorescent protein gene as a reporter. AAV-CMV-shIRS1-EGFP and control AAV-CMV-EGFP were inoculated into the dorsal hippocampus of female and male Wistar rats. One month later, animals undertook a battery of behavioral paradigms evaluating spatial and social memory and anxiety. Our results suggest that females displayed increased susceptibility to AAV-shIRS1 in the novel recognition object paradigm; whereas both females and males show impaired performance in the T maze when infected with AAV-shIRS1 compared to control. Anxiety parameters were not affected by AAV-shIRS1 infection. We observed specific fluorescence within the hilum of the dentate gyrus, in immuno-characterized parvalbumin and somatostatin neurons. AAV DJ8 did not enter astrocytes. Intense green fibers were found in the fornix, mammillary bodies, and in the medial septum indicating that hippocampal efferent had been efficiently targeted by the AAV DJ8 infection. We observed that AAV-shIRS1 reduced significantly synaptophysin labeling in hippocampal-septal projections compared to controls. These results support that, small alterations in the insulin/IGF1 pathway in specific hippocampal circuitries can underlie alterations in synaptic plasticity and affect behavior, in the absence of inflammatory conditions.

RevDate: 2020-11-27

Villarejo-Galende A, González-Sánchez M, Blanco-Palmero VA, et al (2020)

Non-steroidal anti-inflammatory drugs as candidates for the prevention or treatment of Alzheimer's disease: Do they still have a role?.

Current Alzheimer research pii:CAR-EPUB-111922 [Epub ahead of print].

PURPOSE OF REVIEW: to provide an updated analysis of the possible use of non-steroidal anti-inflammatory drugs (NSAIDs) as treatments for Alzheimer´s disease (AD).

RECENT FINDINGS: Neuroinflammation in AD is an active field of research, with increasing evidence from basic and clinical studies for an involvement of innate or adaptive immune responses in the pathophysiology of AD. Few clinical trials with anti-inflammatory drugs have been performed in the last decade, with negative results.

SUMMARY: Besides the information gathered from basic research, epidemiological studies have provided conflicting findings, with most case-control or prevalence studies suggesting an inverse relationship between NSAIDs use and AD, but divided results in prospective population-based incident cohort studies. Clinical trials with different NSAIDs are almost unanimous in reporting an absence of clear benefit in AD.

CONCLUSION: the modulation of inflammatory responses is a promising therapeutic strategy in AD. After three decades of research, it seems that conventional NSAIDs are not the best pharmacological option, both for their lack of clear effects and for an unfavorable side-effect profile in long-term treatment. The development of other anti-inflammatory drugs as candidate treatments in AD may benefit from the knowledge acquired with NSAIDs.

RevDate: 2020-11-27

Fu X, Shea MK, Dolnikowski GG, et al (2020)

Vitamin D and Vitamin K Concentrations in Human Brain Tissue Are Influenced by Freezer Storage Time: The Memory and Aging Project.

The Journal of nutrition pii:6007429 [Epub ahead of print].

BACKGROUND: Vitamins D and K, which are present in human brain, may have a role in neurodegenerative disease.

OBJECTIVES: Given the interest in measuring nutrient concentrations in archived brain samples, it is important to evaluate whether freezer storage time affects these concentrations. Therefore, we evaluated differences in vitamin D and vitamin K concentrations in human brain samples stored for various lengths of time.

METHODS: Postmortem brain samples were obtained from 499 participants in the Rush Memory and Aging Project (mean age 92 y, 72% female). Concentrations of vitamins D and K and their metabolites were measured in 4 regions (midtemporal cortex, midfrontal cortex, cerebellum, anterior watershed white matter) using LC-MS/MS and HPLC, respectively. The predominant forms were 25-hydroxycholecalciferol [25(OH)D3] and menaquinone-4 (MK4). ANOVA was used to determine if concentrations differed according to storage time.

RESULTS: The geometric mean of the mean 25(OH)D3 concentration (across 4 regions) in brains stored for 1.1 to 6.0 y did not differ from that in brains stored ≤1.0 y (all P ≥ 0.37), whereas 25(OH)D3 in brains stored >6.0 y was 31-40% lower (P ≤ 0.003). MK4 had similar results, with the geometric mean MK4 concentration in the brains stored ≥9.0 y being 48-52% lower than those in brains stored ≤1.0 y (P ≤ 0.012). The 25(OH)D3 and MK4 concentrations were positively correlated across all 4 regions (all Spearman ρ ≥ 0.79, P < 0.001).

CONCLUSIONS: 25(OH)D3 and MK4 appear to be stable in brain tissue from older adults stored at -80°C for up to 6 and 9 y, respectively, but not longer. Freezer storage time should be considered in the design and interpretation of studies using archived brain tissue.

RevDate: 2020-11-27

Angioni D, Macaron T, Takeda C, et al (2020)

Can We Distinguish Age-Related Frailty from Frailty Related to Diseases ? Data from the MAPT Study.

The journal of nutrition, health & aging, 24(10):1144-1151.

BACKGROUND: No study has tried to distinguish subjects that become frail due to diseases (frailty related to diseases) or in the absence of specific medical events; in this latter case, it is possible that aging process would act as the main frailty driver (age-related frailty).

OBJECTIVES: To classify subjects according to the origin of physical frailty: age-related frailty, frailty related to diseases, frailty of uncertain origin, and to compare their clinical characteristics.

MATERIALS AND METHODS: We performed a secondary analysis of the Multidomain Alzheimer Preventive Trial (MAPT), including 195 subjects ≥70 years non-frail at baseline who became frail during a 5-year follow-up (mean age 77.8 years ± 4.7; 70% female). Physical frailty was defined as presenting ≥3 of the 5 Fried criteria: weight loss, exhaustion, weakness, slowness, low physical activity. Clinical files were independently reviewed by two different clinicians using a standardized assessment method in order to classify subjects as: "age-related frailty", "frailty related to diseases" or "frailty of uncertain origin". Inconsistencies among the two raters and cases of uncertain frailty were further assessed by two other experienced clinicians.

RESULTS: From the 195 included subjects, 82 (42%) were classified as age-related frailty, 53 (27%) as frailty related to diseases, and 60 (31%) as frailty of uncertain origin. Patients who became frail due to diseases did not differ from the others groups in terms of functional, cognitive, psychological status and age at baseline, however they presented a higher burden of comorbidity as measured by the Cumulative Illness Rating Scale (CIRS) (8.20 ± 2.69; vs 6.22 ± 2.02 frailty of uncertain origin; vs. 3.25 ± 1.65 age-related frailty). Time to incident frailty (23.4 months ± 12.1 vs. 39.2 ± 19.3 months) and time spent in a pre-frailty condition (17.1 ± 11.4 vs 26.6 ± 16.6 months) were shorter in the group of frailty related to diseases compared to age-related frailty. Orthopedic diseases (n=14, 26%) were the most common pathologies leading to frailty related to diseases, followed by cardiovascular diseases (n=9, 17%) and neurological diseases (n = 8, 15%).

CONCLUSION: People classified as age-related frailty and frailty related to diseases presented different frailty-associated indicators. Future research should target the underlying biological cascades leading to these two frailty classifications, since they could ask for distinct strategies of prevention and management.

RevDate: 2020-11-27

Krauss JK, Lipsman N, Aziz T, et al (2020)

Technology of deep brain stimulation: current status and future directions.

Nature reviews. Neurology pii:10.1038/s41582-020-00426-z [Epub ahead of print].

Deep brain stimulation (DBS) is a neurosurgical procedure that allows targeted circuit-based neuromodulation. DBS is a standard of care in Parkinson disease, essential tremor and dystonia, and is also under active investigation for other conditions linked to pathological circuitry, including major depressive disorder and Alzheimer disease. Modern DBS systems, borrowed from the cardiac field, consist of an intracranial electrode, an extension wire and a pulse generator, and have evolved slowly over the past two decades. Advances in engineering and imaging along with an improved understanding of brain disorders are poised to reshape how DBS is viewed and delivered to patients. Breakthroughs in electrode and battery designs, stimulation paradigms, closed-loop and on-demand stimulation, and sensing technologies are expected to enhance the efficacy and tolerability of DBS. In this Review, we provide a comprehensive overview of the technical development of DBS, from its origins to its future. Understanding the evolution of DBS technology helps put the currently available systems in perspective and allows us to predict the next major technological advances and hurdles in the field.

RevDate: 2020-11-27

Pillai JA, Larvie M, Chen J, et al (2020)

Spatial patterns of correlation between cortical amyloid and cortical thickness in a tertiary clinical population with memory deficit.

Scientific reports, 10(1):20717 pii:10.1038/s41598-020-77503-2.

To estimate regional Alzheimer disease (AD) pathology burden clinically, analysis methods that enable tracking brain amyloid or tau positron emission tomography (PET) with magnetic resonance imaging (MRI) measures are needed. We therefore developed a robust MRI analysis method to identify brain regions that correlate linearly with regional amyloid burden in congruent PET images. This method was designed to reduce data variance and improve the sensitivity of the detection of cortical thickness-amyloid correlation by using whole brain modeling, nonlinear image coregistration, and partial volume correction. Using this method, a cross-sectional analysis of 75 tertiary memory clinic AD patients was performed to test our hypothesis that regional amyloid burden and cortical thickness are inversely correlated in medial temporal neocortical regions. Medial temporal cortical thicknesses were not correlated with their regional amyloid burden, whereas cortical thicknesses in the lateral temporal, lateral parietal, and frontal regions were inversely correlated with amyloid burden. This study demonstrates the robustness of our technique combining whole brain modeling, nonlinear image coregistration, and partial volume correction to track the differential correlation between regional amyloid burden and cortical thinning in specific brain regions. This method could be used with amyloid and tau PET to assess corresponding cortical thickness changes.

RevDate: 2020-11-26

Grande G, Vetrano DL, Mazzoleni F, et al (2020)

Detection and Prediction of Incident Alzheimer Dementia over a 10-Year or Longer Medical History: A Population-Based Study in Primary Care.

Dementia and geriatric cognitive disorders pii:000509379 [Epub ahead of print].

BACKGROUND: Despite the crucial role played by general practitioners in the identification and care of people with cognitive impairment, few data are available on how they may improve the early recognition of patients with Alzheimer dementia (AD), especially those with long (i.e., 10 years and longer) medical history.

AIMS: To investigate the occurrence and the predictors of AD during a 10-year or longer period prior AD diagnosis in primary care patients aged 60 years or older.

MATERIALS AND METHODS: A cohort study with a nested case-control analysis has been conducted. Data were extracted from the Italian Health Search Database (HSD), an Italian database with primary care data. AD cases have been defined in accordance with the International Classification of Diseases, ninth edition (ICD-9-CM) codes and coupled with the use of anti-dementia drugs. Prevalence and incidence rates of AD have been calculated. To test the association between candidate predictors, being identified in a minimum period of 10 years, and incident cases of AD, we used a multivariate conditional logistic regression model.

RESULTS: As recorded in the primary care database, AD prevalence among patients aged 60 years or older was 0.8% during 2016, reaching 2.4% among nonagenarians. Overall, 1,889 incident cases of AD have been identified, with an incidence rate as high as 0.09% person-year. Compared with 18,890 matched controls, history of hallucinations, agitation, anxiety, aberrant motor behavior, and memory deficits were positively associated with higher odds of AD (p < 0.001 for all) diagnosis. A previous diagnosis of depression and diabetes and the use of low-dose aspirin and non-steroidal anti-inflammatory drugs were associated with higher odds of AD (p < 0.05 for all).

CONCLUSION: Our findings show that, in accordance with primary care records, 1% of patients aged 60 years and older have a diagnosis of AD, with an incident AD diagnosis of 0.1% per year. AD is often under-reported in primary care settings; yet, several predictors identified in this study may support general practitioners to early identify patients at risk of AD.

RevDate: 2020-11-26

Arancio O (2020)

What Does the APP Family Do in the Brain?.

Neuron, 108(4):583-585.

Amyloid-β precursor protein (APP) is overshadowed by its degradation product, the Alzheimer protein Aβ. Lee et al. now find a role for the APP family in neuronal excitability, synaptic plasticity, and memory in adulthood, despite the lack of requirement for neuronal survival.

RevDate: 2020-11-26

Lim B, Prassas I, EP Diamandis (2020)

Alzheimer Disease Pathogenesis: The Role of Autoimmunity.

The journal of applied laboratory medicine pii:6006391 [Epub ahead of print].

BACKGROUND: In addition to deposits of amyloid β (Aβ) plaques and neurofibrillary tangles, growing evidence demonstrates that complex and multifaceted biological processes can arise during Alzheimer disease (AD) pathogenesis. The recent failures of clinical trials based on the amyloid hypothesis and the presence of Aβ plaques in cognitively healthy elderly persons without AD point toward a need to explore novel pathobiological mechanisms of AD.

CONTENT: In the search for alternative AD mechanisms, numerous genome-wide association studies and mechanistic discoveries suggest a potential immunologic component of the disease. However, new experimental tools are needed to uncover these immunogenic components. The current methods, such as ELISAs or protein microarrays, have limitations of low throughput and/or sensitivity and specificity. In this article, we briefly discuss evidence of potential autoimmune contributions to AD pathobiology, describe the current methods for identifying autoantibodies in patient fluids, and outline our own efforts to develop new techniques for novel autoantibody biomarker discovery.

SUMMARY: Uncovering the putative autoimmune components of AD may be crucial in paving the way to new concepts for pathogenesis, diagnosis, and therapy.

IMPACT STATEMENT: In addition to deposits of amyloid β plaques and neurofibrillary tangles, growing evidence demonstrates that complex and multifaceted biological processes can arise during Alzheimer disease (AD) pathogenesis. Numerous research directions, including genome-wide association, clinical correlation, and mechanistic studies, have pointed to a potential autoimmunologic contribution to AD pathology. We present research suggesting the association between autoimmunity and AD and demonstrate the need for new laboratory techniques to further characterize potential brain antigen-specific autoantibodies. Uncovering the putative autoimmune components of AD may be crucial in paving the way to new concepts for pathogenesis, diagnosis, and therapy.

RevDate: 2020-11-26

Slachevsky A, Zitko P, Martínez-Pernía D, et al (2020)

GERO Cohort Protocol, Chile, 2017-2022: Community-based Cohort of Functional Decline in Subjective Cognitive Complaint elderly.

BMC geriatrics, 20(1):505 pii:10.1186/s12877-020-01866-4.

BACKGROUND: With the global population aging and life expectancy increasing, dementia has turned a priority in the health care system. In Chile, dementia is one of the most important causes of disability in the elderly and the most rapidly growing cause of death in the last 20 years. Cognitive complaint is considered a predictor for cognitive and functional decline, incident mild cognitive impairment, and incident dementia. The GERO cohort is the Chilean core clinical project of the Geroscience Center for Brain Health and Metabolism (GERO). The objective of the GERO cohort is to analyze the rate of functional decline and progression to clinical dementia and their associated risk factors in a community-dwelling elderly with subjective cognitive complaint, through a population-based study. We also aim to undertake clinical research on brain ageing and dementia disorders, to create data and biobanks with the appropriate infrastructure to conduct other studies and facilitate to the national and international scientific community access to the data and samples for research.

METHODS: The GERO cohort aims the recruitment of 300 elderly subjects (> 70 years) from Santiago (Chile), following them up for at least 3 years. Eligible people are adults not diagnosed with dementia with subjective cognitive complaint, which are reported either by the participant, a proxy or both. Participants are identified through a household census. The protocol for evaluation is based on a multidimensional approach including socio-demographic, biomedical, psychosocial, neuropsychological, neuropsychiatric and motor assessments. Neuroimaging, blood and stool samples are also obtained. This multidimensional evaluation is carried out in a baseline and 2 follow-ups assessments, at 18 and 36 months. In addition, in months 6, 12, 24, and 30, a telephone interview is performed in order to keep contact with the participants and to assess general well-being.

DISCUSSION: Our work will allow us to determine multidimensional risks factors associated with functional decline and conversion to dementia in elderly with subjective cognitive complain. The aim of our GERO group is to establish the capacity to foster cutting edge and multidisciplinary research on aging in Chile including basic and clinical research.

TRIAL REGISTRATION: NCT04265482 in ClinicalTrials.gov. Registration Date: February 11, 2020. Retrospectively Registered.

RevDate: 2020-11-25

Li S, Liu C, Zhang Y, et al (2020)

On-line coupling pressurised liquid extraction with two-dimensional counter current chromatography for isolation of natural acetylcholinesterase inhibitors from Astragalus membranaceus.

Phytochemical analysis : PCA [Epub ahead of print].

INTRODUCTION: Radix Astragali, the dried root of Astragalus membranaceus (Fish.) Bge. (family Fabaceae), which is known as Huangqi in China, has been proven to be an immunostimulant, diuretic, antidiabetic, analgesic, and it has also been used as a health food supplement in some Asian populations and also serves as a lead herb in many traditional Chinese medicine formulations as well as in Chinese ethnic tonifying soups.

OBJECTIVE: Screening and purification of bioactive compounds from natural products is challenging work due to their complexity. We present the first report on the use of pressurised liquid extraction and on-line two-dimensional counter current chromatography as an efficient medium for scaled-up extraction and separation of six bioactive compounds from Astragalus membranaceus.

METHOD: We applied the established method with ultrafiltration-liquid chromatography to screen acetylcholinesterase inhibitors, which were then evaluated and confirmed for anti-Alzheimer activity using PC12 cell model.

RESULTS: Six major compounds, namely, calycosin-7-O-β-d-glucoside, pratensein-7-O-β-d-glucoside, formononetin-7-O-β-d-glucoside, calycosin, genistein, and formononetin, with acetylcholinesterase binding affinities were identified and isolated from the raw plant materials via two sets of n-hexane/ethyl acetate/0.2% acetic acid (first-stage counter current chromatography) and n-hexane/ethyl acetate/methanol/water (second-stage counter current chromatography) solvent systems: 1.87:1.0:1.33 and 5.62:1.0:2.42:5.25, v/v/v/v, which were optimised by a mathematical model.

CONCLUSION: Therefore, a useful platform for the large-scale production of bioactive and nutraceutical ingredients was developed herein. With the on-line system developed here, we present a feasible, selective, and effective strategy for rapid screening and identification of enzyme inhibitors from complex mixtures.

RevDate: 2020-11-25

Gopalan D, Pandey A, Alex A, et al (2020)

Nanoconstructs as a Versatile Tool for Detection and Diagnosis of Alzheimer Biomarkers.

Nanotechnology [Epub ahead of print].

The current review focuses towards the advancements made in the past decade in the field of nanotechnology for the early diagnosis of Alzheimer's disease (AD). This review includes the application of nanomaterials and nanosensors for the early detection of the main AD biomarkers (such as amyloid beta, phosphorylated tau, APO-E4, microRNAs and cholesterol) in biological fluids, to detect the biomarkers at a very low concentration ranging in pico, femto and even atto molar concentrations. The field of drug development has always aimed and is constantly working on developing disease modifying drugs, but these drugs will only succeed when given in the early disease stages. Thus, developing efficient diagnostic tools is of vital importance. Various nanomaterials such as liposomes; dendrimers; polymeric nanoparticles; coordination polymers; inorganic nanoparticles such as silica, manganese oxide, zinc oxide, iron oxide, super paramagnetic iron oxides; quantum dots, silver nanoparticles, gold nanoparticles, and carbon based nanostructures (carbon nanotubes, graphene oxide, nanofibres, nanodiamonds, carbon dots); Up-conversion nanoparticles; 2-D nanomaterials; and radioactive nanoprobes have been used in constructing and improving efficiency of nano-sensors for AD biosensing at an early stage of diagnosis.

RevDate: 2020-11-25

Álvarez I, Diez-Fairen M, Aguilar M, et al (2020)

Added value of CSF multi-marker analysis in diagnosis and progression of dementia.

European journal of neurology [Epub ahead of print].

Recently, some emerging cerebrospinal fluid (CSF) markers have been proposed as biomarkers for Alzheimer disease (AD) that can have an effect on disease progression. We analyze the accuracy of these CSF markers for diagnosis of AD in reference to brain Amyloid-PET. We also investigated whether they help in differentiating AD from other dementias and examine their influence in tracing the progression to dementia. Amyloid-β (Aβ) 1-42, total tau (t-tau), phosphorylated tau, Aβ40 , Aβ38 , Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1), neurogranin (ng), phosphorylated-heavy-chain neurofilament, and α-synuclein (α-syn) CSF levels were analyzed in 319 subjects, among whom 57 also underwent an Amyloid-PET scan. We also analyzed longitudinal clinical data from 239 subjects. Emerging CSF markers, especially ng/BACE-1 ratio (AUC=0.77) and their combinations with core-AD CSF markers (all AUCs > 0.85), showed high accuracy to discriminate Amyloid-PET positivity. Subjects with AD had higher CSF BACE-1, ng and α-syn levels than those with non-AD dementia. Interestingly, CSF t-tau/α-syn ratio was higher in subjects with dementia with Lewy bodies than in those with frontotemporal dementia. Most emerging/core-AD ratios predicted a faster conversion from MCI stage to AD and appeared to be helpful when core-AD CSF markers were discordant. In addition, the rate of cognitive decline was associated with all CSF core-AD biomarkers, several emerging/core-AD two-marker ratios and CSF ng levels. These results suggest that emerging biomarkers in conjunction with core-AD markers improve diagnosis of AD, are associated with the conversion from MCI into AD and predict a faster progression of dementia.

RevDate: 2020-11-24

Maddox M (2020)

Alzheimer Aubade.

JAMA, 324(20):2108.

RevDate: 2020-11-24

Das G, Dubey S, Sinharoy U, et al (2020)

Clinical and radiological profile of posterior cortical atrophy and comparison with a group of typical Alzheimer disease and amnestic mild cognitive impairment.

Acta neurologica Belgica pii:10.1007/s13760-020-01547-4 [Epub ahead of print].

Posterior cortical atrophy (PCA) is a rare dementia affecting higher visual processing and other posterior cortical functions with atrophy and hypometabolism in occipito-parieto-temporal areas, more on right side. The objective of the study was to explore the clinical, neuropsychological, and radiological features of PCA patients and to compare them with typical multi-domain amnestic Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) patients. Four out of 9 patients of PCA fulfilling the criteria of Tang-Wai et al. (2004), 10 patients each of AD and aMCI fulfilling NIA-AA criteria were chosen. Patients were assessed clinically by experienced neurologists. Neuropsychological assessment was performed with standardized validated tests. Each patient underwent an MRI. FDG-PET was done for all PCA and six AD patients. PCA patients were younger, cognitively more impaired with rapid progression showing predominant visuospatial deficits consistent with the damage to the upstream of visual processing. AD patients presented predominantly with amnestic symptoms, with visuospatial dysfunction in some and aMCI had mild memory loss. Marked atrophy and hypometabolism in occipital, parietal and temporal areas in PCA, atrophy and hypometabolism in medial temporal areas in AD and minimal non-localized atrophy in MRI in aMCI were seen. Two PCA patients showed hypometabolism extending to the medial temporal and one to the frontal cortex. The clinical and imaging features of PCA are consistent with the damage predominantly to the upstream of visual processing. The difference between PCA and typical AD suggests involvement of AD pathology at different sites within a common disease-relevant network of brain regions.

RevDate: 2020-11-24

Durairajan SSK, Li M, Chung SK, et al (2020)

Modified Huang-Lian-Jie-Du-Tang and its combination with memantine for Alzheimer disease: an in vivo study (abridged secondary publication).

Hong Kong medical journal = Xianggang yi xue za zhi, 26 Suppl 7(6):33-36.

RevDate: 2020-11-24

Ng RCL, Jian M, Bunting M, et al (2020)

Small molecule of adiponectin receptor agonist-AdipoRon-for Alzheimer disease: abridged secondary publication.

Hong Kong medical journal = Xianggang yi xue za zhi, 26 Suppl 7(6):29-32.

RevDate: 2020-11-24

Chan AML, Baum L, Chang RCC, et al (2020)

Targeted drug discovery for Alzheimer disease: abridged secondary publication.

Hong Kong medical journal = Xianggang yi xue za zhi, 26 Suppl 7(6):20-22.

RevDate: 2020-11-24

Baum L, Chow AHL, Wang YX, et al (2020)

Nanoparticles to identify Alzheimer disease by magnetic resonance imaging: abridged secondary publication.

Hong Kong medical journal = Xianggang yi xue za zhi, 26 Suppl 7(6):17-19.

RevDate: 2020-11-24

Karceski S (2020)

How a buildup of abnormal proteins in the brain may be the key to understanding Alzheimer disease.

Neurology, 95(21):e2951-e2953.

RevDate: 2020-11-24

Richardson K, Loke YK, Fox C, et al (2020)

Adverse effects of Z-drugs for sleep disturbance in people living with dementia: a population-based cohort study.

BMC medicine, 18(1):351 pii:10.1186/s12916-020-01821-5.

BACKGROUND: Sleep disturbance is common in dementia and often treated with Z-drugs (zopiclone, zaleplon, and zolpidem). While some observational studies suggest that Z-drugs are associated with adverse events such as falls and fracture risks in older people, this has not been studied in dementia.

METHODS: We used data from 27,090 patients diagnosed with dementia between January 2000 and March 2016 from the Clinical Practice Research Datalink linked to Hospital Episodes Statistics data in England. We compared adverse events for 3532 patients newly prescribed Z-drugs by time-varying dosage to (1) 1833 non-sedative-users with sleep disturbance; (2) 10,214 non-sedative-users with proximal GP consultation matched on age, sex, and antipsychotic use; and (3) 5172 patients newly prescribed benzodiazepines. We defined higher dose Z-drugs and benzodiazepines as prescriptions equivalent to ≥ 7.5 mg zopiclone or > 5 mg diazepam daily. Cox regression was used to estimate hazard ratios (HRs) for incident fracture, hip fracture, fall, mortality, acute bacterial infection, ischaemic stroke/transient ischaemic attack, and venous thromboembolism over a 2-year follow-up, adjusted for demographic- and health-related covariates.

RESULTS: The mean (SD) age of patients was 83 (7.7) years, and 16,802 (62%) were women. Of 3532 patients prescribed Z-drugs, 584 (17%) were initiated at higher doses. For patients prescribed higher dose Z-drugs relative to non-users with sleep disturbance, the HRs (95% confidence interval) for fractures, hip fractures, falls, and ischaemic stroke were 1.67 (1.13-2.46), 1.96 (1.16-3.31), 1.33 (1.06-1.66), and 1.88 (1.14-3.10), respectively. We observed similar associations when compared to non-sedative-users with proximal GP consultation. Minimal or inconsistent excess risks were observed at ≤ 3.75 mg zopiclone or equivalent daily, and for mortality, infection, and venous thromboembolism. We observed no differences in adverse events for Z-drugs compared to benzodiazepines, except lower mortality rates with Z-drugs (HR [95% confidence interval] of 0.73 [0.64-0.83]).

CONCLUSIONS: Higher dose Z-drug use in dementia is associated with increased fracture and stroke risks, similar or greater to that for higher dose benzodiazepines. Higher dose Z-drugs should be avoided, if possible, in people living with dementia, and non-pharmacological alternatives preferentially considered. Prescriptions for higher dose Z-drugs in dementia should be regularly reviewed.

TRIAL REGISTRATION: ENCePP e-register of studies, EUPAS18006.

RevDate: 2020-11-23

Lemoine L, Ledreux A, Mufson EJ, et al (2020)

Regional binding of tau and amyloid PET tracers in Down syndrome autopsy brain tissue.

Molecular neurodegeneration, 15(1):68 pii:10.1186/s13024-020-00414-3.

INTRODUCTION: Tau pathology is a major age-related event in Down syndrome with Alzheimer's disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PIB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD.

METHODS: Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo.

RESULTS: The two Tau tracers showed a significant correlation with each other and with AT8, suggesting that both tracers were binding to Tau deposits. 3H-MK6240 Tau binding correlated with AT8 immunostaining but to a lesser degree than the 3H-THK5117 tracer, suggesting differences in binding sites between the two Tau tracers. 3H-THK5117, 3H-MK6240 and 3H-PIB displayed dense laminar binding in the HIPP and MFG in adult DS brains. A regional difference in Tau binding between adult DS and AD was observed suggesting differential regional Tau deposition in adult DS compared to AD, with higher THK binding density in the MFG in adult with DS compared to AD. No significant correlation was found between 3H-PIB and Amylo-Glo staining in adult DS brains suggesting that the amyloid PIB tracer binds to additional sites.

CONCLUSIONS: This study provides new insights into the regional binding distribution of a first-generation and a second-generation Tau tracer in limbic and neocortical regions in adults with DS, as well as regional differences in Tau binding in adult with DS vs. those with AD. These findings provide new information about the binding properties of two Tau radiotracers for the detection of Tau pathology in adults with DS in vivo and provide valuable data regarding Tau vs. amyloid binding in adult DS compared to AD.

RevDate: 2020-11-23

Yue C, Shan Z, Tan Y, et al (2020)

His-Rich Domain of Selenoprotein P Ameliorates Neuropathology and Cognitive Deficits by Regulating TrkB Pathway and Zinc Homeostasis in an Alzheimer Model of Mice.

ACS chemical neuroscience [Epub ahead of print].

Selenoproteins are a family of special proteins that contain the 21st amino acid, selenocysteine (Sec), in their sequence. Selenoprotein P has 10 Sec residues and modulates selenium homeostasis and redox balance in the brain. Previously, we found that the Sec-devoid His-rich motif of selenoprotein P (Selenop-H) suppressed metal-induced aggregation and neurotoxicities of both Aβ and tau in vitro. To investigate the intervening capacity of Selenop-H on the neuropathology and cognitive deficits of triple transgenic AD (3 × Tg-AD) mice, the Selenop-H gene packaged in rAAV9 was delivered into the hippocampal CA3 regions of mice via stereotaxic injection. Four months later, we demonstrated that Selenop-H (1) improved the spatial learning and memory deficits, (2) alleviated neuron damage and synaptic protein loss, (3) inhibited both tau pathology and amyloid beta protein (Aβ) aggregation, (4) activated both BDNF- and Src-mediated TrkB signaling, and (5) increased MT3 and ZnT3 levels and restored Zn2+ homeostasis in the mice model of AD. The study revealed that Selenop-H is potent in ameliorating AD-related neuropathology and cognitive deficits by modulating TrkB signaling and Zn2+ homeostasis.

RevDate: 2020-11-23

Tobys D, Kowalski LM, Cziudaj E, et al (2020)

Inhibition of clathrin-mediated endocytosis by knockdown of AP-2 leads to alterations in the plasma membrane proteome.

Traffic (Copenhagen, Denmark) [Epub ahead of print].

In eukaryotic cells, clathrin-mediated endocytosis (CME) is a central pathway for the internalization of proteins from the cell surface, thereby contributing to the maintenance of the plasma membrane protein composition. A key component for the formation of endocytic clathrin-coated vesicles (CCVs) is AP-2, as it sequesters cargo membrane proteins, recruits a multitude of other endocytic factors and initiates clathrin polymerization. Here, we inhibited CME by depletion of AP-2 and explored the consequences for the plasma membrane proteome. Quantitative analysis revealed accumulation of major constituents of the endosomal-lysosomal system reflecting a block in retrieval by compensatory CME. The noticeable enrichment of integrins and blockage of their turnover resulted in severely impaired cell migration. Rare proteins such as the anti-cancer drug target CA9 and tumor markers (CD73, CD164, CD302) were significantly enriched. The AP-2 knockdown attenuated the global endocytic capacity, but clathrin-independent entry pathways were still operating, as indicated by persistent internalization of specific membrane-spanning and GPI-anchored receptors (PVR, IGF1R, CD55, TNAP). We hypothesize that blocking AP-2 function and thus inhibiting CME may be a novel approach to identify new druggable targets, or to increase their residence time at the plasma membrane, thereby increasing the probability for efficient therapeutic intervention. This article is protected by copyright. All rights reserved.

RevDate: 2020-11-23

Pereira JB (2020)

Detecting early changes in Alzheimer's disease with graph theory.

Brain communications, 2(2):fcaa129 pii:fcaa129.

This scientific commentary refers to 'Single-subject grey matter network trajectories over the disease course of autosomal dominant Alzheimer disease', by Vermunt et al. (https://doi.org/10.1093/braincomms/fcaa102).

RevDate: 2020-11-23

Reitz C, Rogaeva E, GW Beecham (2020)

Late-onset vs nonmendelian early-onset Alzheimer disease: A distinction without a difference?.

Neurology. Genetics, 6(5):e512 pii:NG2020013862.

There is mounting evidence that only a small fraction of early-onset Alzheimer disease cases (onset <65 years) are explained by known mutations. Even multiplex families with early onset often also have late-onset cases, suggesting that the commonly applied categorization of Alzheimer disease into early- and late-onset forms may not reflect distinct underlying etiology. Nevertheless, this categorization continues to govern today's research and the design of clinical trials. The aim of this review is to evaluate this categorization by providing a comprehensive, critical review of reported clinical, neuropathologic, and genomic characteristics of both onset-based subtypes and explore potential overlap between both categories. The article will lay out the need to comprehensively assess the phenotypic, neuropathologic, and molecular variability in Alzheimer disease and identify factors explaining the observed significant variation in onset age in persons with and without known mutations. The article will critically review ongoing large-scale genomic efforts in Alzheimer disease research (e.g., Alzheimer Disease Sequencing Project, Dominantly Inherited Alzheimer Network, Alzheimer Disease Neuroimaging Initiative) and their shortcomings to disentangle the delineation of unexplained nonmendelian early-onset from late-onset and mendelian forms of Alzheimer disease. In addition, it will outline specific approaches including epigenetic research through which a comprehensive characterization of this delineation can be achieved.

RevDate: 2020-11-23

Pavisic IM, Nicholas JM, O'Connor A, et al (2020)

Disease duration in autosomal dominant familial Alzheimer disease: A survival analysis.

Neurology. Genetics, 6(5):e507 pii:NG2020014597.

Objective: To use survival modeling to estimate disease duration in autosomal dominant familial Alzheimer disease (ADAD) and ascertain whether factors influencing age at onset also affect survival.

Methods: Symptomatic mutation carriers (201 presenilin 1 [PSEN1] and 55 amyloid precursor protein [APP]) from ADAD families referred to the Dementia Research Centre, between 1987 and 2019, were included. Survival was assessed with respect to age at onset, year of birth, APOE ε4 status, cognitive presentation, and sex using multilevel mixed-effects Weibull survival models. The contribution of mutation and family to variance in age at onset and duration was also assessed.

Results: Estimated mean survival was 11.6 (10.4-12.9) years and was similar for APP and PSEN1 mutations. Sixty-seven percent of the variance in age at onset was explained by mutation and 72% by mutation and family together. In contrast, only 6% of the variance in disease duration was explained by mutation specificity and 18% by family membership. Irrespective of gene, survival appeared longer for successive generations and in individuals with atypical presentations. Older age at onset was associated with longer duration within PSEN1 and shorter duration within APP mutation carriers. No differences in survival time were found between sexes or between mutations located before or beyond codon 200 within PSEN1.

Conclusions: Survival is influenced by mutation to a much lesser extent than age at onset. Survival time has increased over time and is longer in atypical presentations. These insights may inform the interpretation of disease-modifying therapy trials in ADAD.

RevDate: 2020-11-23

Zamanian-Azodi M, Rezaei-Tavirani M, M Rezaei-Tavirani (2020)

Investigating the Effects of Ibuprofen on the Gene Expression Profile in Hippocampus of Mice Model of Alzheimer's Disease through Bioinformatics Analysis.

Iranian journal of pharmaceutical research : IJPR, 19(2):352-359.

Non-steroidal anti-inflammatory drugs (NSAIDs) are identified as effective in many diseases. One of which is neurodegenerative diseases including Alzheimer disease (AD). In this study gross alteration of gene expression in AD mice by ibuprofen treatment is investigated via Protein-protein interaction network (PPI) analysis. Expression profiling of microarray dataset GSE67306 was retrieved from GEO database and analyzed via GEO2R tool. PPI analysis was performed via Cytoscape 3.7.0. and its plug-ins including Network Analyzer, Gene MANIA, and CluePedia. Numbers of 10 central genes including Htr1a, Sstr2, Drd2, Htr1b, Penk, Pomc, Oprm1, Npy, Sst, and Chrm2 were identified as potential biomarkers. However, the role of Penk gene was highlighted. The finding indicates that ibuprofen changes gene expression level of several genes that are involved in AD.

RevDate: 2020-11-23

Kocakaya SO, Ertas A, Yener I, et al (2020)

Selective in-vitro Enzymes' Inhibitory Activities of Fingerprints Compounds of Salvia Species and Molecular Docking Simulations.

Iranian journal of pharmaceutical research : IJPR, 19(2):187-198.

Recently Nutrition and Food Chemistry researches have been focused on plants and their products or their secondary metabolites having anti-alzheimer, anti-cancer, anti-aging, and antioxidant properties. Among these plants Salvia L. (Lamiaceae) species come into prominence with their booster effects due to high antioxidant contents, which have over 900 species in the world and 98 in Turkey. Some Salvia species are already in use as herbal treatment of vessel stiffness, Dementia like problems and cancer. Recently some species of Salvia are of extensive research topic. In this study, inhibitory potentials of secondary metabolites, rosmarinic acid, salvigenin, salvianolic acid A and B, tanshinone I and IIA, cyrtotanshinone, dihydrotanshinone I, carnosic acid, carnosol, and danshensu sodium salt were investigated against acetylcholinesterase, butyrylcholinesterase, urease and tyrosinase enzymes both in-vitro and in slico in detail. Elevated inhibitory effects on acetyl- and butyryl-cholinesterase of dihydrotanshinone I (IC50: 1.50 ± 0.02 and 0.50 ± 0.01 µg/mL, respectively), carnasol (IC50: 11.15 ± 0.05 ve 3.92 ± 0.03 µg/mL) and carnosic acid (IC50: 31.83 ± 0.65 ve 4.12±0.04 µg/mL) were observed. Furthermore, all other secondary metabolites were active against butyrylcholinesterase. Anti-urease (42.41 ± 0.85%) and anti-tyrosinase (39.82 ± 1.16%) activities of tanshinone I were also observed. Potential inhibitory effects of these molecules on target proteins were investigated using DOCK and molecular dynamics calculations. Dock score analysis and Lipinski parameters were demonstrated that these ligands are potential inhibitors against relevant enzymes. Our findings suggest that Salvia species can be utilized as a ptential source of anti-alzheimer active compounds for designing novel products.

RevDate: 2020-11-23

Berlanga-Acosta J, Guillén-Nieto G, Rodríguez-Rodríguez N, et al (2020)

Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review.

Frontiers in endocrinology, 11:560375.

Insulin plays a major neuroprotective and trophic function for cerebral cell population, thus countering apoptosis, beta-amyloid toxicity, and oxidative stress; favoring neuronal survival; and enhancing memory and learning processes. Insulin resistance and impaired cerebral glucose metabolism are invariantly reported in Alzheimer's disease (AD) and other neurodegenerative processes. AD is a fatal neurodegenerative disorder in which progressive glucose hypometabolism parallels to cognitive impairment. Although AD may appear and progress in virtue of multifactorial nosogenic ingredients, multiple interperpetuative and interconnected vicious circles appear to drive disease pathophysiology. The disease is primarily a metabolic/energetic disorder in which amyloid accumulation may appear as a by-product of more proximal events, especially in the late-onset form. As a bridge between AD and type 2 diabetes, activation of c-Jun N-terminal kinase (JNK) pathway with the ensued serine phosphorylation of the insulin response substrate (IRS)-1/2 may be at the crossroads of insulin resistance and its subsequent dysmetabolic consequences. Central insulin axis bankruptcy translates in neuronal vulnerability and demise. As a link in the chain of pathogenic vicious circles, mitochondrial dysfunction, oxidative stress, and peripheral/central immune-inflammation are increasingly advocated as major pathology drivers. Pharmacological interventions addressed to preserve insulin axis physiology, mitochondrial biogenesis-integral functionality, and mitophagy of diseased organelles may attenuate the adjacent spillover of free radicals that further perpetuate mitochondrial damages and catalyze inflammation. Central and/or peripheral inflammation may account for a local flood of proinflammatory cytokines that along with astrogliosis amplify insulin resistance, mitochondrial dysfunction, and oxidative stress. All these elements are endogenous stressor, pro-senescent factors that contribute to JNK activation. Taken together, these evidences incite to identify novel multi-mechanistic approaches to succeed in ameliorating this pandemic affliction.

RevDate: 2020-11-23

Bargagli A, Fontanelli E, Zanca D, et al (2020)

Neurophthalmologic and Orthoptic Ambulatory Assessments Reveal Ocular and Visual Changes in Patients With Early Alzheimer and Parkinson's Disease.

Frontiers in neurology, 11:577362.

Patients with Alzheimer's disease (AD) and Parkinson's disease (PD) develop a progressive decline of visual function. This condition aggravates overall cognitive and motor abilities, is a risk factor for developing hallucinations, and can have a significant influence on general quality of life. Visual problems are common complaints of patients with PD and AD in the early stages of the disease, but they also occur during normal aging, making it difficult to differentiate between normal and pathological conditions. In this respect, their real incidence has remained largely underestimated, and no rehabilitative approaches have been standardized. With the aim to increase awareness for ocular and visual disorders, we collected the main neurophthalmologic and orthoptic parameters, including optical coherence tomography (OCT), in six patients with a diagnosis of PD, six patients with a diagnosis of early AD, and eight control subjects in an easily assessable outpatient setting. We also evaluated the patient's ability to recognize changes in facial expression. Our study demonstrates that visual problems, including blurred vision, diplopia, reading discomfort, photophobia, and glare, are commonly reported in patients with PD and AD. Moreover, abnormal eye alignment and vergence insufficiency were documented in all patients during examination. Despite the small size of the sample, we demonstrated greater ganglion cell and retinal nerve fibers layer (RNFL) damage and a defect of facial emotion recognition in AD/PD patients with respect to a comparable group of normal elderly persons, with peculiarities depending upon the disease. Ocular defects or visual discomfort could be correctly evaluated in these patients and possibly corrected by means of lens, orthoptic exercises, and visual rehabilitation. Such a practical approach may help to ameliorate motor autonomy, reading ability, and may also reduce the risk of falls, with a positive impact in daily living activities.

RevDate: 2020-11-23

Machado M, Wilson TM, Sousa DER, et al (2020)

Uraemic Encephalopathy in a Persian Cat with Chronic Kidney Disease.

Journal of comparative pathology, 180:100-104.

Uraemic encephalopathy (UE) is rarely associated with acute kidney injury or chronic kidney disease in domestic animals, and we now report the first case in a cat. The animal presented with hypothermia, apathy, lethargy, depression, severe dehydration, uraemic breath, elevated serum urea nitrogen and creatine concentrations, and eventual seizures and coma prior to death. Gross necropsy findings included severe bilateral renal scarring, ulcerative stomatitis and glossitis, and uraemic gastropathy. Microscopic lesions of diffuse interstitial fibrosis, multifocal mineralization and lymphoplasmacytic interstitial nephritis were seen in the kidneys. There was symmetrical, bilateral spongy vacuolation of the white matter of the basal nuclei and cerebellum and Alzheimer type II astrocytes in the cerebral cortex and hippocampus. Glial fibrillary acid protein immunolabelling was absent or faint in astrocytes of the cerebral grey matter. UE should be included in the differential diagnosis in animals with chronic kidney disease and neurological signs.

RevDate: 2020-11-22

Chadha S, Behl T, Sehgal A, et al (2020)

Exploring the Role of Mitochondrial Proteins as Molecular Target in Alzheimer's Disease.

Mitochondrion pii:S1567-7249(20)30215-4 [Epub ahead of print].

Brain is a fully differentiated organ and is sensitive towards oxidative damage of various compounds including lipids, proteins, and DNA that occurs during process of normal aging and is mainly due to its high energy metabolism and reduced activity of anti-oxidative defense mechanism. Mitochondria are dynamic ATP-generating organelles which constitutes cellular functions such as regulation of intracellular calcium, bio-energetic processes, and reduction-oxidation of cells. Such functioning is negatively affected due to the presence of amyloid β peptide (Aβ) which is involved in pathogenesis of Alzheimer disease (AD). Aβ interacts with mitochondria and leads to mitochondrial dysfunction. Mitochondrial dysfunction, abnormal interactions, oxidative stress, and mis-folding of synaptic proteins inside nervous system are explored and regarded as primary or initial features in insurgence of pathology (AD and other neurological disease). The major histopathological hallmarks of AD are characterized by presence of these hallmarks intracellularly, its further progression and exacerbation which leads to excessive accumulation of oligomeric as well as fibrillar-β-amyloid peptides (present extracellularly) and accumulation of neurofibrillary tangles intracellularly. The current review will focus on alterations and variation in mitochondria/mitochondrial DNA (mtDNA) and the rationale for involvement of related abnormalities in pathogenesis of AD.

RevDate: 2020-11-21

Lindgren M, Gustafsson C, Shirani H, et al (2020)

Deciphering the Electronic Transitions of Thiophene-Based Donor-Acceptor-Donor Pentameric Ligands Utilized for Multimodal Fluorescence Microscopy of Protein Aggregates.

Chemphyschem : a European journal of chemical physics and physical chemistry [Epub ahead of print].

Anionic pentameric thiophene acetates can be used for fluorescence detection and diagnosis of protein amyloid aggregates. Replacing the central thiophene unit by benzothiadiazole (BTD) or quinoxaline (QX) leads to large emission shifts and basic spectral features have been reported [Chem. Eur. J.2015, 21, 15133-13137]. Here we present new detailed experimental results of solvent effects, time-resolved fluorescence and examples employing multi-photon microscopy and lifetime imaging. Quantum chemical response calculations elucidate how the introduction of the BTD/QX groups changes the electronic states and emissions. The dramatic red-shift follows an increased conjugation and quinoid character of the π-electrons of the thiophene backbone. An efficient charge transfer in the excited states S1 and S2 compared to the all-thiophene analogue makes these more sensitive to the polarity and quenching by the solvent. Taken together, the results guide in the interpretation of images of stained Alzheimer disease brain sections employing advanced fluorescence microscopy and lifetime imaging, and can guide to optimize future fluorescent ligand development.

RevDate: 2020-11-21

Benenati S, Canale C, De Marzo V, et al (2020)

Atrial fibrillation and Alzheimer disease: a conundrum.

European journal of clinical investigation [Epub ahead of print].

During ageing, the prevalence of Alzheimer's disease (AD) and of cardiovascular disease CVD) increases. Our aim is to investigate the relationship between AD and CVD and its risk factors, with a view to explaining the underlying mechanisms of this association. This review is based on the material obtained via MEDLINE (PubMed), EMBASE and Clinical Trials databases, from January 1980 until May 2019. The search term used was "Alzheimer's disease", combined with "cardiovascular disease", "hypertension", "dyslipidaemia", "diabetes mellitus", "atrial fibrillation", "coronary artery disease", "heart valve disease", "heart failure". Out of the 1,328 papers initially retrieved, 431 duplicates and 216 records in languages other than English were removed; thus, only 98 papers were included in our research material. We have found that AD and CVD are frequently associated, while both of them, alone may be considered deleterious to health, the study of their combination constitutes a clinical challenge. Further research will help to clarify the real impact of CVD and its risk factors on AD, in order to better comprehend the effects of subclinical and clinical cardiovascular diseases on the brain. It may be hypothesized that there are various mechanisms underlying the association between AD and CVD, the main ones being: hypoperfusion and emboli, atherosclerosis, furthermore in both the heart and brain of AD patients, amyloid deposits may be present, thus causing damage to these organs. We need to clarify the real impact of these underlying hypothesized mechanisms and to investigate gender issues.

RevDate: 2020-11-21

Fyfe I (2020)

Brain organoids shed light on APOE genotype and Alzheimer disease pathology.

Nature reviews. Neurology pii:10.1038/s41582-020-00437-w [Epub ahead of print].

RevDate: 2020-11-21

Lei P, Ayton S, AI Bush (2020)

The Essential Elements of Alzheimer's Disease.

The Journal of biological chemistry pii:REV120.008207 [Epub ahead of print].

Treatments for Alzheimer's disease (AD) directed against the prominent amyloid plaque neuropathology have yet to prove effective despite many phase 3 clinical trials. There are several other neurochemical abnormalities that occur in the Alzheimer's disease brain that warrant renewed emphasis as potential therapeutic targets for this disease. Among those are the elementomic signatures of iron, copper, zinc, and selenium. Here we review these essential elements of Alzheimer's disease for their broad potential to contribute to Alzheimer's pathophysiology, and we also highlight more recent attempts to translate these findings into therapeutics. A reinspection of large bodies of discovery in the AD field, such as this, may inspire new thinking about pathogenesis and therapeutic targets.

RevDate: 2020-11-20

Guerville F, De Souto Barreto P, Coley N, et al (2020)

Kidney Function and Cognitive Decline in Older Adults: Examining the Role of Neurodegeneration.

Journal of the American Geriatrics Society [Epub ahead of print].

BACKGROUND/OBJECTIVES: Cognitive decline associated with impaired kidney function might involve neurodegeneration. Our objectives were to evaluate the longitudinal association between kidney function and cognitive decline in older adults and to assess the involvement of cortical beta-amyloid and hippocampal atrophy (features of Alzheimer's disease (AD)) in this association.

DESIGN: Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial (MAPT).

SETTINGS: Thirteen memory centers (France and Monaco, 2008-2016).

PARTICIPANTS: A total of 1,334 community-dwellers >70 years old without dementia at baseline.

MEASUREMENTS: We estimated glomerular filtration rate (eGFR) from serum creatinine using CKD-Epi equation. Cognition was assessed at baseline, 6, 12, 24, 36, 48, and 60 months using a composite Z-score designed for MAPT. The Clinical Dementia Rating (CDR) score was used to assess cognition and functional independence. We examined the association between eGFR and (1) evolution of the composite cognitive Z-score using mixed-effect models and (2) progression on CDR using Cox models and mixed-effect models. Adjustments were made for age, sex, education, ApoE genotype, cardiovascular risk factors and disease, hippocampal volume (measured with magnetic resonance), and cortical beta-amyloid (measured with positron emission tomography).

RESULTS: Median (IQR) eGFR was 73(60-84) mL/min/1.73 m2 . Two hundred sixty-nine participants experienced progression on CDR score during follow-up. eGFR<60 was significantly associated with progression on CDR score (adjusted hazard ratio (aHR) = 1.35, 95% CI 1.01-1.80) and with both the cognitive and functional independence components of CDR, but not with the evolution of the composite cognitive Z-score (adjusted β-coefficient -0.004, 95% CI -0.014; 0.006). Associations were not modified after further adjustment for beta-amyloid (subsample: n = 252) and hippocampal volume (subsample: n = 270).

CONCLUSIONS: We did not find a mild to moderate renal insufficiency to be associated with brain imaging features of AD, and our results do not support the involvement of AD mechanisms in the incidence of cognitive impairment and functional decline associated with chronic kidney disease.

RevDate: 2020-11-20

Ogunlade B, Fidelis OP, Afolayan OO, et al (2020)


Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association pii:S0278-6915(20)30752-3 [Epub ahead of print].

INTRODUCTION: Cuprizone is a neurotoxicant causing neurodegeneration through enzymes inhibition and oxidative stress. D-Ribose-L-Cysteine (DRLC) is a powerful antioxidant with neuroprotective properties. This study explored the antioxidant response of DRLC against cuprizone-induced behavioral alterations, biochemical imbalance and hippocampal neuronal damage in adult wistar rats.

MATERIALS AND METHODS: Thirty two (32) adult male wistar rats (150- 200g) were divided into four groups (n=8). Group A received normal saline only as placebo; Group B received 0.5% cuprizone diet only; Group C received a combination of 0.5% cuprizone diet and 100mg/kg bw of DRLC and Group D received 100mg/kg bw of DRLC only. The administration was done through oral gavage once daily for 45 days. After the last treatment, neurobehavioral tests (Morris Water Maze and Y maze) was conducted; animals sacrificed and brain harvested for histological analysis and biochemical estimations of levels of antioxidants, oxidative stress markers, neurotransmitters and enzyme activitties.

RESULTS: The results showed significant memory decline, hippocampal alterations, decrease levels of antioxidant markers, enzyme and neurotransmitters activities with concomitant increase in norepinephrine and oxidative stress markers in cuprizone induced rats relative to normal but was attenuated with DRLC administration.

CONCLUSION: Cuprizone causes cognitive impairment and neurodegeneration through oxidative stress; however, administration of DRLC ameliorated neuropathological alteration induced by cuprizone.

RevDate: 2020-11-20

Funnell C, Feldman HH, Mackenzie IRA, et al (2020)

Applying the Alzheimer Disease ATN Diagnostic Framework in Atypical Dementia.

Alzheimer disease and associated disorders, 34(4):357-359.

Cerebrospinal fluid (CSF) biomarkers amyloid-β and tau have been validated for the antemortem diagnosis of Alzheimer disease (AD) and are included in the AT(N) research framework for AD. Recently, an AT(N) CSF profile has been described for dementia with Lewy bodies (DLB), a disorder which is difficult to distinguish clinically from AD, particularly early in the disease course. Herein we describe a 71-year old male who presented with an atypical dementia syndrome including years of stability after an initial abrupt decline, marked visuospatial dysfunction, and relative sparing of memory. CSF biomarkers combined with the pattern of cognitive symptoms made AD unlikely and were consistent with DLB. This classification was confirmed clinically, with the emergence of classic DLB symptoms, and at postmortem pathologic examination. This case highlights the role for AD CSF biomarkers in facilitating earlier diagnosis of non-Alzheimer neurodegenerative dementias.

RevDate: 2020-11-19

Rosa JM, Camargo A, Wolin IAV, et al (2020)

Physical exercise prevents amyloid β1-40-induced disturbances in NLRP3 inflammasome pathway in the hippocampus of mice.

Metabolic brain disease pii:10.1007/s11011-020-00646-8 [Epub ahead of print].

Amyloid beta (Aβ), one of the main hallmarks of Alzheimer's Disease (AD), may stimulate pattern recognition receptors (PRR) such as the NLRP3 inflammasome, inducing a pro-inflammatory state in the brain that contributes to disease development. Physical exercise can have multiple beneficial effects on brain function, including anti-inflammatory and neuroprotective roles. The objective of this study was to investigate the prophylactic effect of moderate treadmill exercise for 4 weeks on inflammatory events related to NLRP3 signaling in the hippocampus of mice after intracerebroventricular Aβ1-40 administration. Our results show that Aβ1-40 administration (400 pmol/mouse, i.c.v.) significantly increased the immunocontent Iba-1 (a microglial reactivity marker), NLRP3, TXNIP, and caspase-1 in the hippocampus of mice. However, physical exercise prevented the hippocampal increase in Iba-1, TXNIP, and activation of the NLRP3 inflammasome pathway caused by Aβ1-40. Moreover, physical exercise per se reduced the TXNIP and caspase-1 immunocontent in the hippocampus. No alterations were observed on the immunocontent of GFAP, ASC, and IL-1β in the hippocampus after Aβ1-40 and/or physical exercise. These results reinforce the role of NLRP3 inflammasome pathway in AD and point to physical exercise as a possible non-pharmacological strategy to prevent inflammatory events triggered by Aβ1-40 in mice.

RevDate: 2020-11-19

Gu Y, Beato JM, Amarante E, et al (2020)

Assessment of Leisure Time Physical Activity and Brain Health in a Multiethnic Cohort of Older Adults.

JAMA network open, 3(11):e2026506 pii:2773103.

Importance: Results from longitudinal studies suggest that regular leisure time physical activity (LTPA) is associated with reduced risk of dementia or Alzheimer disease. Data on the association between LTPA and brain magnetic resonance imaging (MRI) measures remain scarce and inconsistent.

Objective: To examine the association of LTPA and MRI-assessed brain aging measures in a multiethnic elderly population.

This cross-sectional study included 1443 older (≥65 years) adults without dementia who were participants of the Washington/Hamilton Heights-Inwood Columbia Aging Project study. LTPA, from self-reported questionnaire, was calculated as metabolic equivalent of energy expenditure. Both moderate to vigorous LTPA, assessed as meeting Physical Activity Guidelines for Americans (≥150 minutes/week) or not, and light-intensity LTPA were also examined.

Exposures: LTPA.

Main Outcomes and Measures: Primary outcomes included total brain volume (TBV), cortical thickness, and white matter hyperintensity volume, all derived from MRI scans with established methods and adjusted for intracranial volume when necessary. We examined the association of LTPA with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors.

Results: The 1443 participants of the study had a mean (SD) age of 77.2 (6.4) years; 921 (63.8%) were women; 27.0%, 34.4%, and 36.3% were non-Hispanic White, non-Hispanic African American, and Hispanic individuals, respectively; and 27.3% carried the apolipoprotein E (APOE) ɛ4 allele. Compared with the LTPA of nonactive older adults, those with the most LTPA had larger (in cm3) TBV (β [SE], 13.17 [4.42] cm3; P = .003; P for trend = .006) and greater cortical thickness (β [SE], 0.016 [0.008] mm; P = .05; P for trend = .03). The effect size comparing the highest LTPA level with the nonactive group was equivalent to approximately 3 to 4 years of aging (β for 1 year older, -3.06 and -0.005 for TBV and cortical thickness, respectively). A dose-response association was found and even the lowest LTPA level had benefits (eg, TBV: β [SE], 9.03 [4.26] cm3; P = .03) compared with the nonactive group. Meeting Physical Activity Guidelines for Americans (TBV: β [SE], 18.82 [5.14] cm3; P < .001) and light-intensity LTPA (TBV: β [SE], 9.26 [4.29] cm3; P = .03) were also associated with larger brain measures. The association between LTPA and TBV was moderated by race/ethnicity, sex, and APOE status, but generally existed in all subgroups. The results remained similar after excluding participants with mild cognitive impairment.

Conclusions and Relevance: In this study, more physical activity was associated with larger brain volume in older adults. Longitudinal studies are warranted to explore the potential role of physical activity in brain health among older individuals.

RevDate: 2020-11-19

Winand L, Sester A, M Nett (2020)

Bioengineering of Antiinflammatory Natural Products.

ChemMedChem [Epub ahead of print].

Inflammatory processes occur as generic response of the immune system and can be triggered by various factors, e.g. infection with pathogenic microorganisms or damaged tissue. Due to the complexity of the inflammation process and its role in common diseases, as asthma, cancer, skin disorders or Alzheimer, antiinflammatory drugs are of high pharmaceutical interest. Nature is a rich source for compounds with antiinflammatory properties. Several studies focused on the structural optimization of natural products to improve their pharmacological properties. As derivatization through total synthesis is often laborious with low yields and limited stereoselectivity, the use of biosynthetic, i.e. enzyme-driven reactions is an attractive alternative for synthesizing and modifying complex bioactive molecules. In this minireview, we present an outline of biotechnological methods used for the derivatization of antiinflammatory natural products, including precursor-directed biosynthesis, mutasynthesis, combinatorial biosynthesis, as well as whole cell and in vitro biotransformation.

RevDate: 2020-11-18

Bougea A, Anagnostouli M, Angelopoulou E, et al (2020)

Psychosocial and Trauma-Related Stress and Risk of Dementia: A Meta-Analytic Systematic Review of Longitudinal Studies.

Journal of geriatric psychiatry and neurology [Epub ahead of print].

Stress has deleterious effects on brain health and yet, the prognostic value of psychosocial stress regarding the most common types of dementias, including Alzheimer disease, is still unclear. The primary aim of this systematic review was to explore the association between psychosocial stress and late onset dementia. We classified 24articles from Medline, PsycINFO, CINAHL, and Web of Science, as pertaining toxic categories of psychosocial and trauma-related stress (low socio-economic status [SES] related inequalities, marital status, posttraumatic stress disorder, work stress, "vital exhaustion" [VE], and, combined stressors). Using the Quality of Prognosis Studies in Systematic Reviews tool, we judged the quality of evidence to be low. This systematic review provided some non-robust, yet suggestive evidence that the above psychosocial types of stress are associated with increased risk of dementia in later life. Future robust, longitudinal studies with repeated validated measures of psychosocial stress and dementiaare required to strengthen or refute these findings.

RevDate: 2020-11-19

Rosas HD, Hsu E, Mercaldo ND, et al (2020)

Alzheimer-related altered white matter microstructural integrity in Down syndrome: A model for sporadic AD?.

Alzheimer's & dementia (Amsterdam, Netherlands), 12(1):e12040.

Introduction: Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD)-associated neuropathology by the age of 40, with risk for dementia increasing from the early 50s. White matter (WM) pathology has been reported in sporadic AD, including early demyelination, microglial activation, loss of oligodendrocytes and reactive astrocytes but has not been extensively studied in the at-risk DS population.

Methods: Fifty-six adults with DS (35 cognitively stable adults, 11 with mild cognitive impairment, 10 with dementia) underwent diffusion-weighted magnetic resonance imaging (MRI), amyloid imaging, and had assessments of cognition and functional abilities using tasks appropriate for persons with intellectual disability.

Results: Early changes in late-myelinating and relative sparing of early-myelinating pathways, consistent with the retrogenesis model proposed for sporadic AD, were associated with AD-related cognitive deficits and with regional amyloid deposition.

Discussion: Our findings suggest that quantification of WM changes in DS could provide a promising and clinically relevant biomarker for AD clinical onset and progression.

RevDate: 2020-11-17

Wang ZT, Shen XN, Ma YH, et al (2020)

Associations of the Rate of Change in Geriatric Depression Scale with Amyloid and Cerebral Glucose Metabolism in Cognitively Normal Older Adults: A Longitudinal Study.

Journal of affective disorders, 280(Pt A):77-84 pii:S0165-0327(20)32935-9 [Epub ahead of print].

BACKGROUND: Depression is considered a psychological risk factor for Alzheimer's disease (AD). We sought to examine the differential associations of depression severity with cognitive decline, clinical progression to mild cognitive impairment (MCI) or AD, and neuroimaging markers of AD in cognitively normal older adults.

METHODS: A total of 522 cognitively normal (CN) participants who underwent assessments for depression (longitudinal geriatric depression scale [GDS]) and cognitive assessments were included from the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort. The cross-sectional and longitudinal associations of the rate of change in GDS with amyloid-β (Aβ)-positron emission tomography (PET), tau-PET, and 18F-fluorodeoxyglucose (FDG)-PET were explored. Kaplan-Meier survival curves of clinical progression and Aβ accumulation were plotted based on mean annual changes in GDS. Mediation analyses were utilized to explore the mediation effects of AD markers.

RESULTS: Higher rate of increase in GDS was associated with faster cognitive decline and higher risk of progression to MCI or AD. Moreover, the rate of change in GDS was significantly associated with Aβ accumulation and cerebral glucose metabolism. The influences of the rate of change in GDS on cognition and clinical progression were partially mediated by Aβ accumulation and cerebral glucose metabolism.

LIMITATIONS: GDS is a self-reported questionnaire and not the same as a clinical diagnosis of depression.

CONCLUSIONS: The cognitive and clinical consequences of changes in depressive symptoms partly stem from Aβ accumulation and cerebral glucose metabolism, which increases our understanding of how depressive symptoms may increase vulnerability to dementia.

RevDate: 2020-11-17

Lee J, Jang H, Kang SH, et al (2020)

Cerebrospinal Fluid Biomarkers for the Diagnosis and Classification of Alzheimer's Disease Spectrum.

Journal of Korean medical science, 35(44):e361 pii:35.e361.

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers are increasingly used in clinical practice for the diagnosis of Alzheimer's disease (AD). We aimed to 1) determine cutoff values of CSF biomarkers for AD, 2) investigate their clinical utility by estimating a concordance with amyloid positron emission tomography (PET), and 3) apply ATN (amyloid/tau/neurodegeneration) classification based on CSF results.

METHODS: We performed CSF analysis in 51 normal controls (NC), 23 mild cognitive impairment (MCI) and 65 AD dementia (ADD) patients at the Samsung Medical Center in Korea. We attempted to develop cutoff of CSF biomarkers for differentiating ADD from NC using receiver operating characteristic analysis. We also investigated a concordance between CSF and amyloid PET results and applied ATN classification scheme based on CSF biomarker abnormalities to characterize our participants.

RESULTS: CSF Aβ42, total tau (t-tau) and phosphorylated tau (p-tau) significantly differed across the three groups. The area under curve for the differentiation between NC and ADD was highest in t-tau/Aβ42 (0.994) followed by p-tau/Aβ42 (0.963), Aβ42 (0.960), t-tau (0.918), and p-tau (0.684). The concordance rate between CSF Aβ42 and amyloid PET results was 92%. Finally, ATN classification based on CSF biomarker abnormalities led to a majority of NC categorized into A-T-N-(73%), MCI as A+T-N-(30%)/A+T+N+(26%), and ADD as A+T+N+(57%).

CONCLUSION: CSF biomarkers had high sensitivity and specificity in differentiating ADD from NC and were as accurate as amyloid PET. The ATN subtypes based on CSF biomarkers may further serve to predict the prognosis.

RevDate: 2020-11-17

Uhlmann RE, Rother C, Rasmussen J, et al (2020)

Acute targeting of pre-amyloid seeds in transgenic mice reduces Alzheimer-like pathology later in life.

Nature neuroscience pii:10.1038/s41593-020-00737-w [Epub ahead of print].

Amyloid-β (Aβ) deposits are a relatively late consequence of Aβ aggregation in Alzheimer's disease. When pathogenic Aβ seeds begin to form, propagate and spread is not known, nor are they biochemically defined. We tested various antibodies for their ability to neutralize Aβ seeds before Aβ deposition becomes detectable in Aβ precursor protein-transgenic mice. We also characterized the different antibody recognition profiles using immunoprecipitation of size-fractionated, native, mouse and human brain-derived Aβ assemblies. At least one antibody, aducanumab, after acute administration at the pre-amyloid stage, led to a significant reduction of Aβ deposition and downstream pathologies 6 months later. This demonstrates that therapeutically targetable pathogenic Aβ seeds already exist during the lag phase of protein aggregation in the brain. Thus, the preclinical phase of Alzheimer's disease-currently defined as Aβ deposition without clinical symptoms-may be a relatively late manifestation of a much earlier pathogenic seed formation and propagation that currently escapes detection in vivo.

RevDate: 2020-11-17

Ren S, Breuillaud L, Yao W, et al (2020)

TNF-α-mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer's disease pathology in young Trem2R47H rats.

The Journal of biological chemistry pii:RA120.016395 [Epub ahead of print].

Alzheimer's disease is a neurodegenerative dementia associated with deposition in the central nervous system (CNS) of amyloid plaques and neurofibrillary tangles, formed by Aβ peptides and phosphor-tau, respectively. ~2% of AD cases are due to familial mutations (FAD); ~98% of cases are sporadic (SAD). FAD animal models are commonly used to study SAD pathogenesis. Because mechanisms leading to FAD and SAD may be distinct, to study SAD pathogenesis we generated Trem2R47H knock-in rats, which carry the SAD risk factor p.R47H variant of the microglia gene Triggering Receptor Expressed on Myeloid Cells 2 (TREM2). Trem2R47H rats produce human-Aβ from a humanized-App rat allele because human-Aβ is more toxic than rodent-Aβ and the pathogenic role of the p.R47H TREM2 variant has been linked to human-Aβ-clearing deficits. Using peri-adolescent Trem2R47H rats, we previously demonstrated that supraphysiological TNF-α boosts glutamatergic transmission, which is excitatory, and suppresses long-term potentiation (LTP), a surrogate of learning and memory. Here, we tested the effect of the p.R47H variant on the inhibitory neurotransmitter GABA. We report that GABAergic transmission is decreased in Trem2R47H/R47H rats. This decrease is due to acute and reversible action of TNF-α and is not associated with increased human-Aβ levels and AD-pathology. Thus, the p.R47H variant changes the excitatory/inhibitory balance, favoring excitation. This imbalance could potentiate glutamate excitotoxicity and contribute to neuronal dysfunction, enhanced neuronal death and neurodegeneration. Future studies will determine whether this imbalance represents an early, Aβ-independent pathway leading to dementia and may reveal the AD-modifying therapeutic potential of TNF-α inhibition in the CNS.

RevDate: 2020-11-17

Arsenault D, Tremblay C, Emond V, et al (2020)

Sex-dependent alterations in the physiology of entorhinal cortex neurons in old heterozygous 3xTg-AD mice.

Biology of sex differences, 11(1):63 pii:10.1186/s13293-020-00337-0.

While the higher prevalence of Alzheimer's disease (AD) in women is clear, studies suggest that biological sex may also influence AD pathogenesis. However, mechanisms behind these differences are not clear. To investigate physiological differences between sexes at the cellular level in the brain, we investigated the intrinsic and synaptic properties of entorhinal cortex neurons in heterozygous 3xTg-AD mice of both sexes at the age of 20 months. This brain region was selected because of its early association with AD symptoms. First, we found physiological differences between male and female non-transgenic mice, providing indirect evidence of axonal alterations in old females. Second, we observed a transgene-dependent elevation of the firing activity, post-burst afterhyperpolarization (AHP), and spontaneous excitatory postsynaptic current (EPSC) activity, without any effect of sex. Third, the passive properties and the hyperpolarization-activated current (Ih) were altered by transgene expression only in female mice, whereas the paired-pulse ratio (PPR) of evoked EPSC was changed only in males. Fourth, both sex and transgene expression were associated with changes in action potential properties. Consistent with previous work, higher levels of Aβ neuropathology were detected in 3xTg-AD females, whereas tau deposition was similar. In summary, our results support the idea that aging and AD neuropathology differentially alter the physiology of entorhinal cortex neurons in males and females.

RevDate: 2020-11-16

Montal V, Vilaplana E, Pegueroles J, et al (2020)

Biphasic cortical macro- and microstructural changes in autosomal dominant Alzheimer's disease.

Alzheimer's & dementia : the journal of the Alzheimer's Association [Epub ahead of print].

INTRODUCTION: A biphasic model for brain structural changes in preclinical Alzheimer's disease (AD) could reconcile some conflicting and paradoxical findings in observational studies and anti-amyloid clinical trials.

METHODS: In this study we tested this model fitting linear versus quadratic trajectories and computed the timing of the inflection points vertexwise of cortical thickness and cortical diffusivity-a novel marker of cortical microstructure-changes in 389 participants from the Dominantly Inherited Alzheimer Network.

RESULTS: In early preclinical AD, between 20 and 15 years before estimated symptom onset, we found increases in cortical thickness and decreases in cortical diffusivity followed by cortical thinning and cortical diffusivity increases in later preclinical and symptomatic stages. The inflection points 16 to 19 years before estimated symptom onset are in agreement with the start of tau biomarker alterations.

DISCUSSION: These findings confirm a biphasic trajectory for brain structural changes and have direct implications when interpreting magnetic resonance imaging measures in preventive AD clinical trials.

RevDate: 2020-11-16

Jin J, Wu Y, Li S, et al (2020)

Effect of 1 Year of Qigong Exercise on Cognitive Function Among Older Chinese Adults at Risk of Cognitive Decline: A Cluster Randomized Controlled Trial.

Frontiers in psychology, 11:546834.

Background: The rapidly aging Chinese population is showing an increase in age-related illnesses, including mild cognitive impairment and Alzheimer disease. The best types of physical activity for the improvement of cognition remain unknown. This study aimed to compare the effectiveness of a tailored qigong exercise with that of stretching exercise in the maintenance of cognitive abilities in Chinese elders at risk of cognitive decline. Methods: Seventy-four community-dwelling adults aged ≥60 years were screened for eligibility. Using a randomized control group design, participants with scores ≥19 on the Chinese version of the Montreal Cognitive Assessment-Basic (MoCA) were allocated to a 1-year qigong intervention (n = 33) and a stretching control exercise group (n = 33). The primary outcome was the MoCA score, as a measure of global cognitive function, and secondary outcomes were globe cognition and five domain scores on the Chinese version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The MoCA and RBANS were administered at baseline and 1 year after intervention to assess the effect of the exercises on cognitive decline. Results: Twenty-five of 33 (75.8%) participants in the qigong group and 26 of 33 (78.8%) participants in the control group completed the 1-year exercise programs. A bivariate test revealed strong correlation between MoCA and RBANS total scores after the intervention (r = 0.517, p < 0.01). Generalized estimating equations revealed a lower risk of progression of cognitive decline at 1 year in the qigong group than in the control group (odds ratio, 0.314; 95% confidence interval, 0.103-0.961; p = 0.04). Two-way repeated-measures ANOVA followed by post hoc t tests with Bonferroni corrections indicated that MoCA and RBANS scores were significantly higher in the qigong group than in the control group (MoCA and RBANS global cognition, memory, visuospatial/constructional ability, and language, all p < 0.01), with the exception of RBANS attention score (p > 0.05). Conclusions: One year of qigong practice was significantly superior to stretching exercise not only for the prevention of cognitive decline progression, but also for the improvement of several cognitive functions, among older Chinese adults at risk of cognitive decline.

RevDate: 2020-11-16

van Maurik IS, Bakker ED, van den Buuse S, et al (2020)

Psychosocial Effects of Corona Measures on Patients With Dementia, Mild Cognitive Impairment and Subjective Cognitive Decline.

Frontiers in psychiatry, 11:585686.

Background: The recent COVID-19 pandemic is not only a major healthcare problem in itself, but also poses enormous social challenges. Though nursing homes increasingly receive attention, the majority of people with cognitive decline and dementia live at home. We aimed to explore the psychosocial effects of corona measures in memory clinic (pre-)dementia patients and their caregivers. Methods: Between April 28th and July 13th 2020, n = 389 patients of Alzheimer center Amsterdam [n = 121 symptomatic (age = 69 ± 6, 33%F, MMSE = 23 ± 5), n = 268 cognitively normal (age = 66 ± 8, 40% F, MMSE = 29 ± 1)] completed a survey on psychosocial effects of the corona measures. Questions related to social isolation, worries for faster cognitive decline, behavioral problems and discontinuation of care. In addition, n = 147 caregivers of symptomatic patients completed a similar survey with additional questions on caregiver burden. Results: Social isolation was experienced by n = 42 (35%) symptomatic and n = 67 (25%) cognitively normal patients and two third of patients [n = 129 (66%); n = 58 (75%) symptomatic, n = 71 (61%) cognitively normal] reported that care was discontinued. Worries for faster cognitive decline were existed in symptomatic patients [n = 44 (44%)] and caregivers [n = 73 (53%)], but were also reported by a subgroup of cognitively normal patients [n = 27 (14%)]. Both patients [n = 56 (46%) symptomatic, n = 102 (38%) cognitively normal] and caregivers [n = 72 (48%)] reported an increase in psychological symptoms. More than three quarter of caregivers [n = 111(76%)] reported an increase in patients' behavioral problems. A higher caregiver burden was experienced by n = 69 (56%) of caregivers and n = 43 (29%) of them reported that a need for more support. Discontinuation of care (OR = 3.3 [1.3-7.9]), psychological (OR = 4.0 [1.6-9.9]) and behavioral problems (OR = 3.0 [1.0-9.0]) strongly related to experiencing a higher caregiver burden. Lastly, social isolation (OR = 3.2 [1.2-8.1]) and psychological symptoms (OR = 8.1 [2.8-23.7]) were red flags for worries for faster cognitive decline. Conclusion: Not only symptomatic patients, but also cognitively normal patients express worries for faster cognitive decline and psychological symptoms. Moreover, we identified patients who are at risk of adverse outcomes of the corona measures, i.e., discontinued care, social isolation, psychological and behavioral problems. This underlines the need for health care professionals to provide ways to warrant the continuation of care and support (informal) networks surrounding patients and caregivers to mitigate the higher risk of negative psychosocial effects.

RevDate: 2020-11-16

Alonso-Lana S, Marquié M, Ruiz A, et al (2020)

Cognitive and Neuropsychiatric Manifestations of COVID-19 and Effects on Elderly Individuals With Dementia.

Frontiers in aging neuroscience, 12:588872.

The coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide and has had unprecedented effects in healthcare systems, economies and society. COVID-19 clinical presentation primarily affects the respiratory system causing bilateral pneumonia, but it is increasingly being recognized as a systemic disease, with neurologic manifestations reported in patients with mild symptoms but, most frequently, in those in a severe condition. Elderly individuals are at high risk of developing severe forms of COVID-19 due to factors associated with aging and a higher prevalence of medical comorbidities and, therefore, they are more vulnerable to possible lasting neuropsychiatric and cognitive impairments. Several reports have described insomnia, depressed mood, anxiety, post-traumatic stress disorder and cognitive impairment in a proportion of patients after discharge from the hospital. The potential mechanisms underlying these symptoms are not fully understood but are probably multifactorial, involving direct neurotrophic effect of SARS-CoV-2, consequences of long intensive care unit stays, the use of mechanical ventilation and sedative drugs, brain hypoxia, systemic inflammation, secondary effects of medications used to treat COVID-19 and dysfunction of peripheral organs. Chronic diseases such as dementia are a particular concern not only because they are associated with higher rates of hospitalization and mortality but also because COVID-19 further exacerbates the vulnerability of those with cognitive impairment. In patients with dementia, COVID-19 frequently has an atypical presentation with mental status changes complicating the early identification of cases. COVID-19 has had a dramatical impact in long-term care facilities, where rates of infection and mortality have been very high. Community measures implemented to slow the spread of the virus have forced to social distancing and cancelation of cognitive stimulation programs, which may have contributed to generate loneliness, behavioral symptoms and worsening of cognition in patients with dementia. COVID-19 has impacted the functioning of Memory Clinics, research programs and clinical trials in the Alzheimer's field, triggering the implementation of telemedicine. COVID-19 survivors should be periodically evaluated with comprehensive cognitive and neuropsychiatric assessments, and specific mental health and cognitive rehabilitation programs should be provided for those suffering long-term cognitive and psychiatric sequelae.

RevDate: 2020-11-16

Ávila-Villanueva M, Gómez-Ramírez J, Maestú F, et al (2020)

The Role of Chronic Stress as a Trigger for the Alzheimer Disease Continuum.

Frontiers in aging neuroscience, 12:561504.

RevDate: 2020-11-16

Guo R, Li L, Su J, et al (2020)

Pharmacological Activity and Mechanism of Tanshinone IIA in Related Diseases.

Drug design, development and therapy, 14:4735-4748 pii:266911.

Salvia miltiorrhiza: (Danshen) is a significant (traditional Chinese medication) natural remedy, enhancing blood circulation and clear blood stasis. In this view, it is widely used against several heart diseases, eg, cardiomyopathy, arrhythmia, and congenital heart defects. Tanshinone IIA (tan-IIA) is the main fat-soluble component of Salvia miltiorrhiza. Modern pharmacological study shows that tan-IIA has anti-inflammatory and anti-oxidant activities. Tan-IIA induces remarkable cardioprotective effects via enhancing angiogenesis which may serve as an effective treatment against cardiovascular diseases (CVD). There is also evidence that tan-IIA has extensive immunomodulatory effects and plays a significant role in the development and function of immune cells. Tan-IIA reduces the production of inflammatory mediators and restores abnormal signaling pathways via regulating the function and activation of immune cells. It can also regulate signal transduction pathways, ie, TLR/NF-κB pathway and MAPKs/NF-κB pathway, thereby tan-IIA has an anti-inflammatory, anticoagulant, antithrombotic and neuroprotective role. It plays a protective role in the pathogenesis of cardiovascular disorders (ie, atherosclerosis, hypertension) and Alzheimer's disease. It has also been revealed that tan-IIA has an anti-tumor role by killing various tumor cells, inducing differentiation and apoptosis, and has potential activity against carcinoma progression. In the review of this fact, the tan-IIA role in different diseases and its mechanism have been summarized while its clinical applications are also explored to provide a new perspective of Salvia miltiorrhiza. An extensive study on the mechanism of action of tan-IIA is of great significance for the effective use of Chinese herbal medicine and the promotion of its status and influence on the world.

RevDate: 2020-11-16

Hemonnot-Girard AL, Valverde AJ, Hua J, et al (2020)

Analysis of CX3CR1 haplodeficiency in male and female APPswe/PSEN1dE9 mice along Alzheimer disease progression.

Brain, behavior, and immunity pii:S0889-1591(20)32371-0 [Epub ahead of print].

Microglia, the resident immune cells of the brain, have recently emerged as key players in Alzheimer Disease (AD) pathogenesis, but their roles in AD remain largely elusive and require further investigation. Microglia functions are readily altered when isolated from their brain environment, and microglia reporter mice thus represent valuable tools to study the contribution of these cells to neurodegenerative diseases such as AD. The CX3CR1+/eGFP mice is one of the most popular microglia reporter mice, and has been used in numerous studies to investigate in vivo microglial functions, including in the context of AD research. However, until now, the impact of CX3CR1 haplodeficiency on the typical features of Alzheimer Disease has not been studied in depth. To fill this gap, we generated APPswe/PSEN1dE9:CX3CR1+/eGFP mice and analyzed these mice for Alzheimer's like pathology and neuroinflammation hallmarks. More specifically, using robust multifactorial statistical and multivariate analyses, we investigated the impact of CX3CR1 deficiency in both males and females, at three typical stages of the pathology progression: at early stage when Amyloid-β (Aβ) deposition just starts, at intermediate stage during Aβ accumulation phase and at more advanced stages when Aβ plaque number stabilizes. We found that CX3CR1 haplodeficiency had little impact on the progression of the pathology in the APPswe/PSEN1dE9 model and demonstrated that the APPswe/PSEN1dE9:CX3CR1+/eGFP line is a relevant and useful model to study the role of microglia in Alzheimer Disease. In addition, although Aβ plaques density is higher in females compared to age-matched males, we show that their glial reaction, inflammation status and memory deficits are not different.

RevDate: 2020-11-15

Santos-Bezerra DP, Cavaleiro AM, Santos AS, et al (2020)

Alcohol Use Disorder is Associated with Upregulation of MicroRNAs-34a and -34c in Hippocampal Postmortem Tissue.

Alcoholism, clinical and experimental research [Epub ahead of print].

BACKGROUND: In order to investigate epigenetic mechanisms potentially involved in the cognitive decline associated with chronic alcohol intake, we evaluated the expressions of three micro-RNAs (miRs -34a, -34b and -34c) highly expressed in the hippocampus and involved in neuronal physiology and pathology. MiR-34a participates in functioning and survival of mature neurons; miR-34b is associated with Alzheimer-like disorders and miR-34c is implicated in the memory impairment of Alzheimer disease in rodents and humans.

METHODS: A total of 69 cases were selected from the Biobank for Aging Studies (BAS) and categorized according to the absence (n=50) or presence (n=19) of alcohol use disorder (AUD). Cases presenting neuropathological diagnosis of dementias were excluded. Total RNA was extracted from hippocampal paraffinized slices, complementary DNA was synthesized from miRs, and qRT-PCR was performed with Taqman® assays.

RESULTS: Higher expressions of miR-34a and miR-34c, but not of miR-34b, were found in the group with AUD in comparison to the group without AUD after adjustment for potential confounders (age, sex, body mass index, presence of hypertension, diabetes mellitus, smoking and physical inactivity).

CONCLUSIONS: Hippocampal upregulation of miRs-34a and miRs-34c may be involved in the cognitive decline associated with chronic alcohol consumption.

RevDate: 2020-11-15

Liu Z, Zhang B, Xia S, et al (2020)

ROS-responsive and multifunctional anti-Alzheimer prodrugs: Tacrine-ibuprofen hybrids via a phenyl boronate linker.

European journal of medicinal chemistry pii:S0223-5234(20)30969-7 [Epub ahead of print].

Current drugs available in clinic for Alzheimer's disease (AD) treatment can only alleviate disease symptoms without clearly curing or delaying the process of AD. And some AD drugs failed in Phase III clinical trials are only focused on targeting amyloid-β (Aβ). Therefore, an alternative strategy in AD drug design is meaningful to be involved in the multiple pathogenic factors which can affect each other at multiple levels. Herein, we report a series of ROS-responsive prodrugs based on multi-target-directed ligands (MTDLs) approach, which can specifically release tacrine derivatives and ibuprofen under oxidation of ROS and show acetylcholinesterase (AChE)-inhibiting, neuron-protective and anti-inflammatory effects in extracellular or intracellular assays. Related biological study illustrated that compound 22 was able to permeate blood-brain-barrier (BBB) showing little hepatotoxicity in comparison to tacrine. Besides, 22 hinted a therapeutic clue in AD-treatment by regulating proinflammatory factors (IL-1β and TNF-α) and apoptosis related proteins (Bax, Bcl-2 and cleaved caspase-3). Further spatial memory assays in Aβ-induced AD model showed that 22 enhanced the ability of learning and memory. Our study proves that the strategy of ROS-responsive prodrugs has promise for AD treatments in future and offers a way for AD drug development.

RevDate: 2020-11-15

Singleton EH, Pijnenburg YAL, Sudre CH, et al (2020)

Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer disease.

Alzheimer's research & therapy, 12(1):148 pii:10.1186/s13195-020-00717-z.

BACKGROUND: We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer's disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers.

METHODS: We retrospectively included 150 participants, including 29 bvAD, 28 "typical" amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [18F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy.

RESULTS: bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvADbvFTD, area under the curve [AUC] range 0.85-0.91, all p < 0.001). The top-3 for bvAD vs. tAD were amygdalar volume (bvAD>tAD), MRI anterior-DMN-ratios (bvAD
CONCLUSIONS: Subtle frontoinsular hypometabolism and anterior DMN involvement may underlie the prominent behavioral phenotype in bvAD.

RevDate: 2020-11-14

Leskinen HM, Tringham M, Karjalainen H, et al (2020)

APOE Genotype Disclosure and Lifestyle Advice in a Randomized Intervention Study with Finnish Participants.

The Journal of nutrition pii:5981720 [Epub ahead of print].

BACKGROUND: The APOE ε4 allele is associated with higher risks of cardiovascular diseases and Alzheimer disease than ε3 and ε2.

OBJECTIVES: We studied the effectiveness of dietary and lifestyle guidance and personal genetic risk information [ε4 carrier (ε4+); ε4 noncarrier (ε4-)] as motivators for a healthier lifestyle.

METHODS: A total of 188 healthy Finnish volunteers (82.4% women; mean ± SD age: 51.0 ± 5.6 y; BMI: 26.0 ± 3.6 kg/m2; total cholesterol: 5.2 ± 0.9 mmol/L) participated in our randomized intervention study. The participants were genotyped for APOE and divided into intervention (INT; INTε4+, n = 33; INTε4-, n = 57) and control groups (CTRL; CTRLε4+, n = 36; CTRLε4-, n = 62). Blood samples, measured observations, and questionnaire data were obtained at baseline and at 1 and 1.5 y. INT participants received their ε4 carrier status at baseline. Monthly Internet-based guidance based on the Finnish Dietary guidelines was provided for all.

RESULTS: The proportion of SFAs in plasma over time fluctuated less in INTε4+ than in the other groups (P-interaction < 0.05; primary outcome). The lifestyle guidance increased vegetable consumption from 3.5 to 3.6 portions/d, improved the dietary fat quality score by 5.3%, increased the plasma n-3 (ω-3) FA proportion by 7.3%, and decreased the consumption of high-fat/high-sugar foods from 7.3 to 6.5 portions/wk and total- and LDL-cholesterol concentrations by 4.3% and 6.1%, respectively, in the entire participant population (P < 0.05; secondary outcome). Compared with the ε4- participants, ε4+ participants had 2.4% higher plasma n-6 (ω-6) FA, lower C-peptide (3.9 compared with 4.2 nmol/L × h) and sensitive C-reactive protein values, and decreased plasma malondialdehyde concentrations over time (P < 0.05; secondary outcome).

CONCLUSIONS: Lifestyle guidance given to healthy Finnish participants yielded small but beneficial changes. The INTε4+ group did not seem markedly more responsive to the guidance than the other groups.This trial was registered at clinicaltrials.gov as NCT03794141.

RevDate: 2020-11-16

Mielech A, Puścion-Jakubik A, Markiewicz-Żukowska R, et al (2020)

Vitamins in Alzheimer's Disease-Review of the Latest Reports.

Nutrients, 12(11): pii:nu12113458.

Alzheimer's disease (AD) is the most common form of dementia, and the aging of the population means that the number of cases is successively increasing. The cause of the disease has not been established, but it is suggested that many factors affect it, including nutritional aspects. As part of the work, the PubMed database has been searched, beginning from 2005, for terms related to key nutritional aspects. A diet rich in antioxidant vitamins can improve the cognitive functions of patients. Thanks to an adequate intake of B vitamins, homocysteine levels are reduced, which indirectly protects against the development of the disease. A properly balanced diet, as well as the use of appropriate supplementation, can contribute to improving the clinical condition of patients with AD.

RevDate: 2020-11-16

Ospina-Romero M, Glymour MM, Hayes-Larson E, et al (2020)

Association Between Alzheimer Disease and Cancer With Evaluation of Study Biases: A Systematic Review and Meta-analysis.

JAMA network open, 3(11):e2025515 pii:2772918.

Importance: Observational studies consistently report inverse associations between cancer and Alzheimer disease (AD). Shared inverse etiological mechanisms might explain this phenomenon, but a systematic evaluation of methodological biases in existing studies is needed.

Objectives: To systematically review and meta-analyze evidence on the association between cancer and subsequent AD, systematically identify potential methodological biases in studies, and estimate the influence of these biases on the estimated pooled association between cancer and AD.

Data Sources: All-language publications were identified from PubMed, Embase, and PsycINFO databases through September 2, 2020.

Study Selection: Longitudinal cohort studies and case-control studies on the risk of AD in older adults with a history of any cancer type, prostate cancer, breast cancer, colorectal cancer, or nonmelanoma skin cancer, relative to those with no cancer history.

Data Extraction and Synthesis: Two reviewers independently abstracted the data and evaluated study biases related to confounding, diagnostic bias, competing risks, or survival bias. Random-effects meta-analysis was used to provide pooled estimates of the association between cancer and AD. Metaregressions were used to evaluate whether the observed pooled estimate could be attributable to each bias. The study was designed and conducted according to the Preferring Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

Main Outcomes and Measures: Incidence, hazard, or odds ratios for AD comparing older adults with vs without a previous cancer diagnosis.

Results: In total, 19 cohort studies and 3 case-control studies of the associations between any cancer type (n = 13), prostate cancer (n = 5), breast cancer (n = 1), and nonmelanoma skin cancer (n = 3) with AD were identified, representing 9 630 435 individuals. In all studies combined, cancer was associated with decreased AD incidence (cohort studies: random-effects hazard ratio, 0.89; 95% CI, 0.79-1.00; case-control studies: random-effects odds ratio, 0.75; 95% CI, 0.61-0.93). Studies with insufficient or inappropriate confounder control or greater likelihood of AD diagnostic bias had mean hazard ratios closer to the null value, indicating that these biases could not explain the observed inverse association. Competing risks bias was rare. Studies with greater likelihood of survival bias had mean hazard ratios farther from the null value.

Conclusions and Relevance: The weak inverse association between cancer and AD may reflect shared inverse etiological mechanisms or survival bias but is not likely attributable to diagnostic bias, competing risks bias, or insufficient or inappropriate control for potential confounding factors.

RevDate: 2020-11-13

Singh A, Allen D, Fracassi A, et al (2020)

Functional Integrity of Synapses in the Central Nervous System of Cognitively Intact Individuals with High Alzheimer's Disease Neuropathology is Associated with Absence of Synaptic Tau Oligomers.

Journal of Alzheimer's disease : JAD pii:JAD200716 [Epub ahead of print].

BACKGROUND: Certain individuals, here referred to as Non-Demented with Alzheimer Neuropathology (NDAN), do not show overt neurodegeneration (N -) and remain cognitively intact despite the presence of plaques (A+) and tangles (T+) that would normally be consistent with fully symptomatic Alzheimer's disease (AD).

OBJECTIVE: The existence of NDAN (A + T +N -) subjects suggests that the human brain utilizes intrinsic mechanisms that can naturally evade cognitive decline normally associated with the symptomatic stages of AD (A + T +N +). Deciphering the underlying mechanisms would prove relevant to develop complementing therapeutics to prevent progression of AD-related cognitive decline.

METHODS: Previously, we have reported that NDAN present with preserved neurogenesis and synaptic integrity paralleled by absence of amyloid oligomers at synapses. Using postmortem brain samples from age-matched control subjects, demented AD patients and NDAN individuals, we performed immunofluorescence, western blots, micro transplantation of synaptic membranes in Xenopus oocytes followed by twin electrode voltage clamp electrophysiology and fluorescence assisted single synaptosome-long term potentiation studies.

RESULTS: We report decreased tau oligomers at synapses in the brains of NDAN subjects. Furthermore, using novel approaches we report, for the first time, that such absence of tau oligomers at synapses is associated with synaptic functional integrity in NDAN subjects as compared to demented AD patients.

CONCLUSION: Overall, these results give further credence to tau oligomers as primary actors of synaptic destruction underscoring cognitive demise in AD and support their targeting as a viable therapeutic strategy for AD and related tauopathies.

RevDate: 2020-11-13

de Barros Viana M, Rosário BDA, de Fátima Santana de Nazaré M, et al (2020)

COVID-19 in age-related neurodegenerative diseases: is there a role for vitamin D3 as a possible therapeutic strategy?.

Reviews in the neurosciences pii:/j/revneuro.ahead-of-print/revneuro-2020-0074/revneuro-2020-0074.xml [Epub ahead of print].

The coronavirus disease (COVID-19), identified in Wuhan, China, on December 2019, was declared a pandemic by the World Health Organization, on March, 2020. Since then, efforts have been gathered to describe its clinical course and to determine preventive measures and treatment strategies. Adults older than 65 years of age are more susceptible to serious clinical symptoms and present higher mortality rates. Angiotensin-converting enzyme 2 (ACE2) is a major receptor for some coronavirus infection, including SARS-COV-2, but is also a crucial determinant in anti-inflammation processes during the renin-angiotensin system (RAS) functioning - converting angiotensin II to angiotensin 1-7. The decline in ACE2 expression that occurs with aging has been associated to the higher morbidity and mortality rates in older adults. These observations highlight the importance of investigating the association between COVID-19 and age-related neurodegenerative disorders, i.e., Parkinson's and Alzheimer's diseases. A possible option to reduce the risk of COVID-19 is vitamin D supplementation, due to its anti-inflammatory and immune-system-modulating effects. It has also been suggested that vitamin D supplementation plays a role in slowing progression of Parkinson and Alzheimer. The present study is a literature review of articles published on the theme COVID-19, Parkinson and Alzheimer's diseases, and the role played by vitamin D. PUBMED, MEDLINE, and EMBASE databases were consulted. Results confirm neurodegenerative and neuroinflammatory effects of COVID-19, aggravated in Parkinson's and Alzheimer's patients, and the important role of vitamin D as a possible therapeutic strategy. Nevertheless, randomized controlled trials and large population studies are still warranted.

RevDate: 2020-11-16

Lussier M, Aboujaoudé A, Couture M, et al (2020)

Using Ambient Assisted Living to Monitor Older Adults With Alzheimer Disease: Single-Case Study to Validate the Monitoring Report.

JMIR medical informatics, 8(11):e20215 pii:v8i11e20215.

BACKGROUND: Many older adults choose to live independently in their homes for as long as possible, despite psychosocial and medical conditions that compromise their independence in daily living and safety. Faced with unprecedented challenges in allocating resources, home care administrators are increasingly open to using monitoring technologies known as ambient assisted living (AAL) to better support care recipients. To be effective, these technologies should be able to report clinically relevant changes to support decision making at an individual level.

OBJECTIVE: The aim of this study is to examine the concurrent validity of AAL monitoring reports and information gathered by care professionals using triangulation.

METHODS: This longitudinal single-case study spans over 490 days of monitoring a 90-year-old woman with Alzheimer disease receiving support from local health care services. A clinical nurse in charge of her health and social care was interviewed 3 times during the project. Linear mixed models for repeated measures were used to analyze each daily activity (ie, sleep, outing activities, periods of low mobility, cooking-related activities, hygiene-related activities). Significant changes observed in data from monitoring reports were compared with information gathered by the care professional to explore concurrent validity.

RESULTS: Over time, the monitoring reports showed evolving trends in the care recipient's daily activities. Significant activity changes occurred over time regarding sleep, outings, cooking, mobility, and hygiene-related activities. Although the nurse observed some trends, the monitoring reports highlighted information that the nurse had not yet identified. Most trends detected in the monitoring reports were consistent with the clinical information gathered by the nurse. In addition, the AAL system detected changes in daily trends following an intervention specific to meal preparation.

CONCLUSIONS: Overall, trends identified by AAL monitoring are consistent with clinical reports. They help answer the nurse's questions and help the nurse develop interventions to maintain the care recipient at home. These findings suggest the vast potential of AAL technologies to support health care services and aging in place by providing valid and clinically relevant information over time regarding activities of daily living. Such data are essential when other sources yield incomplete information for decision making.

RevDate: 2020-11-12

Seaks CE, DM Wilcock (2020)

Infectious hypothesis of Alzheimer disease.

PLoS pathogens, 16(11):e1008596 pii:PPATHOGENS-D-19-02193.

RevDate: 2020-11-12

Armstrong GW, Kim LA, Vingopoulos F, et al (2020)

Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms.

JAMA ophthalmology pii:2772810 [Epub ahead of print].

Importance: Individuals with autosomal dominant mutations for Alzheimer disease are valuable in determining biomarkers present prior to the onset of cognitive decline, improving the ability to diagnose Alzheimer disease as early as possible. Optical coherence tomography (OCT) has surfaced as a potential noninvasive technique capable of analyzing central nervous system tissues for biomarkers of Alzheimer disease.

Objective: To evaluate whether OCT can detect early retinal alterations in carriers of the presenilin 1 (PSEN1 [OMIM 104311]) E280A mutation who are cognitively unimpaired.

A cross-sectional imaging study conducted from July 13, 2015, to September 16, 2020, included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired and 10 healthy noncarrier family members, all leveraged from a homogenous Colombian kindred. Statistical analysis was conducted from September 9, 2017, to September 16, 2020.

Main Outcomes and Measures: Mixed-effects multiple linear regression was performed to compare the thickness values of the whole retina and individual retinal layers on OCT scans between mutation carriers and noncarriers. Simple linear-effects and mixed-effects multiple linear regression models were used to assess whether age was an effect modifier for PSEN1 mutation of amyloid β levels and retinal thickness, respectively. Fundus photographs were used to compare the number of arterial and venous branch points, arterial and venous tortuosity, and fractal dimension.

Results: This study included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired (7 women [70%]; mean [SD] age, 36.3 [8.1] years) and 10 healthy noncarrier family members (7 women [70%]; mean [SD] age, 36.4 [8.2] years). Compared with noncarrier controls, PSEN1 mutation carriers who were cognitively unimpaired had a generalized decrease in thickness of the whole retina as well as individual layers detected on OCT scans, with the inner nuclear layer (outer superior quadrant, β = -3.06; P = .007; outer inferior quadrant, β = -2.60; P = .02), outer plexiform layer (outer superior quadrant, β = -3.44; P = .03), and outer nuclear layer (central quadrant, β = -8.61; P = .03; inner nasal quadrant, β = -8.39; P = .04; inner temporal quadrant, β = -9.39; P = .02) showing the greatest amount of statistically significant thinning. Age was a significant effect modifier for the association between PSEN1 mutation and amyloid β levels in cortical regions (β = 0.03; P = .001) but not for the association between PSEN1 mutation and retinal thickness. No statistical difference was detected in any of the vascular parameters studied.

Conclusions and Relevance: These findings suggest that OCT can detect functional and morphologic changes in the retina of carriers of familial Alzheimer disease who are cognitively unimpaired several years before clinical onset, suggesting that OCT findings and retinal vascular parameters may be biomarkers prior to the onset of cognitive decline.

RevDate: 2020-11-12

Liu F, Zhao Q, Liu S, et al (2020)

Revealing the Pharmacological Mechanism of Acorus tatarinowii in the Treatment of Ischemic Stroke Based on Network Pharmacology.

Evidence-based complementary and alternative medicine : eCAM, 2020:3236768.

Aim: Stroke is the second significant cause for death, with ischemic stroke (IS) being the main type threatening human being's health. Acorus tatarinowii (AT) is widely used in the treatment of Alzheimer disease, epilepsy, depression, and stroke, which leads to disorders of consciousness disease. However, the systemic mechanism of AT treating IS is unexplicit. This article is supposed to explain why AT has an effect on the treatment of IS in a comprehensive and systematic way by network pharmacology.

Methods and Materials: ADME (absorbed, distributed, metabolized, and excreted) is an important property for screening-related compounds in AT, which were screening out of TCMSP, TCMID, Chemistry Database, and literature from CNKI. Then, these targets related to screened compounds were predicted via Swiss Targets, when AT-related targets database was established. The gene targets related to IS were collected from DisGeNET and GeneCards. IS-AT is a common protein interactive network established by STRING Database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analysed by IS-AT common target genes. Cytoscape software was used to establish a visualized network for active compounds-core targets and core target proteins-proteins interactive network. Furthermore, we drew a signal pathway picture about its effect to reveal the basic mechanism of AT against IS systematically.

Results: There were 53 active compounds screened from AT, inferring the main therapeutic substances as follows: bisasaricin, 3-cyclohexene-1-methanol-α,α,4-trimethyl,acetate, cis,cis,cis-7,10,13-hexadecatrienal, hydroxyacoronene, nerolidol, galgravin, veraguensin, 2'-o-methyl isoliquiritigenin, gamma-asarone, and alpha-asarone. We obtained 398 related targets, 63 of which were the same as the IS-related genes from targets prediction. Except for GRM2, remaining 62 target genes have an interactive relation, respectively. The top 10 degree core target genes were IL6, TNF, IL1B, TLR4, NOS3, MAPK1, PTGS2, VEGFA, JUN, and MMP9. There were more than 20 terms of biological process, 7 terms of cellular components, and 14 terms of molecular function through GO enrichment analysis and 13 terms of signal pathway from KEGG enrichment analysis based on P < 0.05.

Conclusion: AT had a therapeutic effect for ischemic via multicomponent, multitarget, and multisignal pathway, which provided a novel research aspect for AT against IS.

RevDate: 2020-11-12

Wang F, Kream RM, GB Stefano (2020)

Long-Term Respiratory and Neurological Sequelae of COVID-19.

Medical science monitor : international medical journal of experimental and clinical research, 26:e928996 pii:928996.

Since the initial reports of coronavirus disease 2019 (COVID-19) in China in late 2019, infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have spread rapidly, resulting in a global pandemic that has caused millions of deaths. Initially, the large number of infected people required the direction of global healthcare resources to provide supportive care for the acutely ill population in an attempt to reduce mortality. While clinical trials for safe and effective antiviral agents are ongoing, and vaccine development programs are being accelerated, long-term sequelae of SARS-CoV-2 infection have become increasingly recognized and concerning. Although the upper and lower respiratory tracts are the main sites of entry of SARS-CoV-2 into the body, resulting in COVID-19 pneumonia as the most common presentation, acute lung damage may be followed by pulmonary fibrosis and chronic impairment of lung function, with impaired quality of life. Also, increasing reports have shown that SARS-CoV-2 infection involves the central nervous system (CNS) and the peripheral nervous system (PNS) and directly or indirectly damages neurons, leading to long-term neurological sequelae. This review aims to provide an update on the mechanisms involved in the development of the long-term sequelae of SARS-CoV-2 infection in the 3 main areas of lung injury, neuronal injury, and neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and multiple sclerosis, and highlights the need for patient monitoring following the acute stage of infection with SARS-CoV-2 to provide a rationale for the prevention, diagnosis, and management of these potential long-term sequelae.

RevDate: 2020-11-12

Kim YJ, Han KD, Baek MS, et al (2020)

Association between physical activity and conversion from mild cognitive impairment to dementia.

Alzheimer's research & therapy, 12(1):136 pii:10.1186/s13195-020-00707-1.

BACKGROUND: Physical activity has been suggested to prevent the conversion of mild cognitive impairment (MCI) to dementia in patients. We investigated the association between the continuance and regularity of physical activity and the risk of developing dementia in patients with MCI.

METHODS: We analyzed 6-year followed up data for 247,149 individuals in the National Health Insurance Service (NHIS) cohort of Korea who were enrolled between January 1, 2009, and December 31, 2015. The patients were divided into four groups: those who did not engage in physical activity consistently (Never-PA group), those who initiated physical activity (Initiation-PA group), those who ceased physical activity (Withdrawal-PA group), and those who performed physical activity consistently (Maintenance-PA group). We also divided the patients into two groups: those who engaged in physical activity irregularly (Irregular-PA) and those who undertook physical activity regularly (Regular-PA).

RESULTS: When the risk for the Never-PA group was set as the benchmark (ref = 1), the Maintenance-PA group had the lowest incidence of dementia of the Alzheimer type (DAT) compared to the other groups (HR = 0.82, 95% CI 0.79-0.86). The DAT risk of the Initiation-PA group (HR = 0.89, 95% CI 0.85-0.93) was lower than the Never-PA group. In addition, compared to the Irregular-PA group, the Regular-PA group had a 15% reduced risk for developing DAT.

CONCLUSIONS: Although no causal inference could be made, continued regular physical activity in patients with MCI is associated with a protective effect against developing DAT. Moreover, ceasing physical activity could halt this protective effect.

RevDate: 2020-11-12

Ramírez-Expósito MJ, Martínez-Martos JM, Cantón-Habas V, et al (2020)

Putative Involvement of Endocrine Disruptors in the Alzheimer's disease Via the Insulin-Regulated Aminopeptidase / GLUT4 Pathway.

Current neuropharmacology pii:CN-EPUB-111381 [Epub ahead of print].

It has been well established that there is a connection between type II diabetes (DMTII) and Alzheimer's disease (AD). In fact, the increase in AD incidence may be an emerging complication of DMTII. Both pathologies are related to estradiol (E2) exposure; on the one hand, estrogen receptors (ER) are emerging as important modulators of glucose homeostasis through ß-pancreatic cell function; on the other hand, brain bioenergetic and cognitive deficits have been related to the down regulation of brain ERs, contributing to women ageing and AD susceptibility, both related to the reduction in estradiol levels and the deficits in brain metabolism. Here we discuss that environmental contaminants with estrogenic capacity such as bisphenol A (BPA) could develop pharmacological effects similar to those of E2, which could affect ß-pancreatic cell function by increasing the biosynthesis of glucose-induced insulin after extranuclear ER binding. BPA-induced hyperinsulinemia would promote the translocation of glucose transporter 4 (GLUT4) which is located next to insulin-regulated aminopeptidase (IRAP) in intracellular vesicles. In insulin-responsive tissues, IRAP and GLUT 4 are routed together to the cell surface after insulin stimulation. IRAP is also the angiotensin IV (AngIV) receptor, and AngIV associates the brain reninangiotensin system (bRAS) with AD, since AngIV is related to learning, memory, emotional responses, and processing of sensory information not only through its inhibitory effect on IRAP but also through the stimulation of glucose uptake by increasing the presence of IRAP/GLUT4 at the cell surface. Thus, the IRAP/GLUT4 pathway is an emerging target for the pharmacological intervention against AD.

RevDate: 2020-11-11

Chen Y, Strickland MR, Soranno A, et al (2020)

Apolipoprotein E: Structural Insights and Links to Alzheimer Disease Pathogenesis.

Neuron pii:S0896-6273(20)30776-5 [Epub ahead of print].

Apolipoprotein E (ApoE) is of great interest due to its role as a cholesterol/lipid transporter in the central nervous system (CNS) and as the most influential genetic risk factor for Alzheimer disease (AD). Work over the last four decades has given us important insights into the structure of ApoE and how this might impact the neuropathology and pathogenesis of AD. In this review, we highlight the history and progress in the structural and molecular understanding of ApoE and discuss how these studies on ApoE have illuminated the physiology of ApoE, receptor binding, and interaction with amyloid-β (Aβ). We also identify future areas of study needed to advance our understanding of how ApoE influences neurodegeneration.

RevDate: 2020-11-11

Deng Y, Wu S, H Fan (2020)

Genome-wide pathway-based quantitative multiple phenotypes analysis.

PloS one, 15(11):e0240910 pii:PONE-D-20-04125.

For complex diseases, genome-wide pathway association studies have become increasingly promising. Currently, however, pathway-based association analysis mainly focus on a single phenotype, which may insufficient to describe the complex diseases and physiological processes. This work proposes a combination model to evaluate the association between a pathway and multiple phenotypes and to reduce the run time based on asymptotic results. For a single phenotype, we propose a semi-supervised maximum kernel-based U-statistics (mSKU) method to assess the pathway-based association analysis. For multiple phenotypes, we propose the fisher combination function with dependent phenotypes (FC) to transform the p-values between the pathway and each marginal phenotype individually to achieve pathway-based multiple phenotypes analysis. With real data from the Alzheimer Disease Neuroimaging Initiative (ADNI) study and Human Liver Cohort (HLC) study, the FC-mSKU method allows us to specify which pathways are specific to a single phenotype or contribute to common genetic constructions of multiple phenotypes. If we only focus on single-phenotype tests, we may miss some findings for etiology studies. Through extensive simulation studies, the FC-mSKU method demonstrates its advantages compared with its counterparts.

RevDate: 2020-11-12

Shehzad A, Rockwood K, Stanley J, et al (2020)

Use of Patient-Reported Symptoms from an Online Symptom Tracking Tool for Dementia Severity Staging: Development and Validation of a Machine Learning Approach.

Journal of medical Internet research, 22(11):e20840 pii:v22i11e20840.

BACKGROUND: SymptomGuide Dementia (DGI Clinical Inc) is a publicly available online symptom tracking tool to support caregivers of persons living with dementia. The value of such data are enhanced when the specific dementia stage is identified.

OBJECTIVE: We aimed to develop a supervised machine learning algorithm to classify dementia stages based on tracked symptoms.

METHODS: We employed clinical data from 717 people from 3 sources: (1) a memory clinic; (2) long-term care; and (3) an open-label trial of donepezil in vascular and mixed dementia (VASPECT). Symptoms were captured with SymptomGuide Dementia. A clinician classified participants into 4 groups using either the Functional Assessment Staging Test or the Global Deterioration Scale as mild cognitive impairment, mild dementia, moderate dementia, or severe dementia. Individualized symptom profiles from the pooled data were used to train machine learning models to predict dementia severity. Models trained with 6 different machine learning algorithms were compared using nested cross-validation to identify the best performing model. Model performance was assessed using measures of balanced accuracy, precision, recall, Cohen κ, area under the receiver operating characteristic curve (AUROC), and area under the precision-recall curve (AUPRC). The best performing algorithm was used to train a model optimized for balanced accuracy.

RESULTS: The study population was mostly female (424/717, 59.1%), older adults (mean 77.3 years, SD 10.6, range 40-100) with mild to moderate dementia (332/717, 46.3%). Age, duration of symptoms, 37 unique dementia symptoms, and 10 symptom-derived variables were used to distinguish dementia stages. A model trained with a support vector machine learning algorithm using a one-versus-rest approach showed the best performance. The correct dementia stage was identified with 83% balanced accuracy (Cohen κ=0.81, AUPRC 0.91, AUROC 0.96). The best performance was seen when classifying severe dementia (AUROC 0.99).

CONCLUSIONS: A supervised machine learning algorithm exhibited excellent performance in identifying dementia stages based on dementia symptoms reported in an online environment. This novel dementia staging algorithm can be used to describe dementia stage based on user-reported symptoms. This type of symptom recording offers real-world data that reflect important symptoms in people with dementia.

RevDate: 2020-11-11

Yang S, Lim KH, Kim SH, et al (2020)

Molecular landscape of long noncoding RNAs in brain disorders.

Molecular psychiatry pii:10.1038/s41380-020-00947-5 [Epub ahead of print].

According to current paradigms, various risk factors, such as genetic mutations, oxidative stress, neural network dysfunction, and abnormal protein degradation, contribute to the progression of brain disorders. Through the cooperation of gene transcripts in biological processes, the study of noncoding RNAs can lead to insights into the cause and treatment of brain disorders. Recently, long noncoding RNAs (lncRNAs) which are longer than 200 nucleotides in length have been suggested as key factors in various brain disorders. Accumulating evidence suggests the potential of lncRNAs as diagnostic or prognostic biomarkers and therapeutic targets. High-throughput screening-based sequencing has been instrumental in identification of lncRNAs that demand new approaches to understanding the progression of brain disorders. In this review, we discuss the recent progress in the study of lncRNAs, and addresses the pathogenesis of brain disorders that involve lncRNAs and describes the associations of lncRNAs with neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and neurodevelopmental disorders. We also discuss potential targets of lncRNAs and their promise as novel therapeutics and biomarkers in brain disorders.

RevDate: 2020-11-12

Zhang X, Wei M, Fan J, et al (2020)

Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons.

Autophagy [Epub ahead of print].

Macroautophagy/autophagy is vital for neuronal homeostasis and functions. Accumulating evidence suggest that autophagy is impaired during cerebral ischemia, contributing to neuronal dysfunction and neurodegeneration. However, the outcomes after transient modification in autophagy machinery are not fully understood. This study investigated the effects of ischemic stress on autophagy and synaptic structures using a rat model of oxygen-glucose deprivation (OGD) in hippocampal neurons and a mouse model of middle cerebral artery occlusion (MCAO). Upon acute ischemia, an initial autophagy modification occurred in an upregulation manner. Following, the number of lysosomes increased, as well as lysosomal volume, indicating dysfunctional lysosomal storage. These changes were prevented by inhibiting autophagy via 3-methyladenine (3-MA) treatment or ATG7 (autophagy related 7) knockdown, or were mimicked by rapamycin (RAPA), a known activator of autophagy. This suggests that dysfunctional lysosomal storage is associated with the early burst of autophagy. Dysfunctional lysosomal storage contributed to autophagy dysfunction because the basal level of MTOR-dependent lysosomal biogenesis in the reperfusion was not sufficient to clear undegraded cargoes after transient autophagy upregulation. Further investigation revealed that impairment of synaptic ultra-structures, accompanied by dysfunctional lysosomal storage, may result from a failure in dynamic turnover of synaptic proteins. This indicates a vital role of autophagy-lysosomal machinery in the maintenance of synaptic structures. This study supports previous evidence that dysfunctional lysosomal storage may occur following the upregulation of autophagy in neurons. Appropriate autophagosome-lysosomal functioning is vital for maintenance of neuronal synaptic function and impacts more than the few known synaptic proteins. Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AD: Alzheimer disease; ALR: autophagic lysosome reformation; ATG7: autophagy related 7; CTSB: cathepsin B; CTSD: cathepsin D; DAPI: 4',6-diamidino-2-phenylindole; DEGs: differentially expressed genes; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; GO: Gene Ontology; HBSS: Hanks' balanced salt solution; HPCA: hippocalcin; i.c.v: intracerebroventricular; KEGG: kyoto encyclopedia of genes and genomes; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; LSDs: lysosomal storage disorders; MAP2: microtubule-associated protein 2; MCAO: middle cerebral artery occlusion; mCTSB: mature CTSB; mCTSD: mature CTSD; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; OGD/R: oxygen-glucose deprivation/reoxygenation; PBS: phosphate-buffered saline; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; proCTSD: pro-cathepsin D; RAPA: rapamycin; RNA-seq: RNA sequencing; RPS6KB/p70S6K: ribosomal protein S6 kinase; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SIM: Structured Illumination Microscopy; SNAP25: synaptosomal-associated protein 25; SQSTM1/p62: sequestosome 1; SYN1: synapsin I; SYT1: synaptotagmin I; TBST: tris-buffered saline Tween-20; TEM: transmission electron microscopy; TFEB: transcription factor EB; tMCAO: transient middle cerebral artery occlusion; TTC: 2,3,5-triphenyltetrazolium chloride; TUBB3: tubulin, beta 3 class III.

RevDate: 2020-11-07

Tan S, Baggio D, Shortt J, et al (2020)

Cardiovascular Safety of Nilotinib in Alzheimer Disease.

RevDate: 2020-11-10

Sheline YI, Snider BJ, Beer JC, et al (2020)

Effect of escitalopram dose and treatment duration on CSF Aβ levels in healthy older adults: A controlled clinical trial.

Neurology, 95(19):e2658-e2665.

OBJECTIVE: To determine whether treatment with escitalopram compared with placebo would lower CSF β-amyloid 42 (Aβ42) levels.

RATIONALE: Serotonin signaling suppresses Aβ42 in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram.

METHODS: Using lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aβ42 was used as the primary outcome in subsequent analyses.

RESULTS: An overall 9.4% greater reduction in CSF Aβ42 was found in escitalopram-treated compared with placebo-treated groups (p < 0.001, 95% confidence interval [CI] 4.9%-14.2%, d = 0.81). Positive baseline Aβ status (CSF Aβ42 levels <250 pg/mL) was associated with smaller Aβ42 reduction (p = 0.006, 95% CI -16.7% to 0.5%, d = -0.52) compared with negative baseline amyloid status (CSF Aβ42 levels >250 pg/mL).

CONCLUSIONS: Short-term longitudinal doses of escitalopram decreased CSF Aβ42 in cognitively normal older adults, the target group for AD prevention.


CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aβ42.

RevDate: 2020-11-10

Jahn T, Clark C, Kerksiek A, et al (2020)

Cholesterol metabolites and plant sterols in cerebrospinal fluid are associated with Alzheimer´s cerebral pathology and clinical disease progression.

The Journal of steroid biochemistry and molecular biology pii:S0960-0760(20)30310-1 [Epub ahead of print].

BACKGROUND AND PURPOSE: Altered cholesterol metabolism is associated with increased risk of neurodegeneration and in particular with the development of Alzheimer's disease (AD). Here, we investigate whether non-cholesterol sterols and oxysterols in the central nervous system are associated with (i) the presence of cerebral AD pathology, (ii) distinct aspects of AD pathology, i.e. amyloid pathology, neuronal injury, and tau pathology, and (iii) cognitive decline over time.

EXPERIMENTAL APPROACH: One hundred forty-two elder subjects with normal cognition, mild cognitive impairment, or mild dementia participating in a cohort study on cognitive decline and AD were included. Clinical and neuropsychological assessments were performed at inclusion and repeated at follow-up visits at 18 and 36 months. Concentrations of cholesterol, non-cholesterol sterols, and cholesterol metabolites were measured in cerebrospinal fluid (CSF), along with CSF beta-amyloid (Aβ)1-42; Aβ1-42/Aβ1-40 ratio, total-tau (tau), and tau phosphorylated at threonine 181 (p-tau) as markers of amyloid pathology, neuronal injury and tau pathology, respectively. Cognitive decline was assessed by changes in Mini-Mental State Examination and Clinical Dementia Rating sum of boxes at follow-up visits.

KEY RESULTS: CSF 24S-hydroxycholesterol (24S-OHC) and the 24S-OHC/27-OHC ratio were higher in subjects with AD pathology. CSF desmosterol correlated with Aβ1-42 levels. The 24S-OHC levels, the 24S-OHC/27-OHC ratio and the plant sterols campesterol and sitosterol were associated with the tau and p-tau levels. Both plant sterol concentrations along with the 24S-OHC/27-OHC ratio at baseline predicted cognitive decline at follow-up visits.

CONCLUSIONS AND IMPLICATIONS: We show the importance of CSF levels of several non-cholesterol sterols and oxysterols to AD and core AD biomarkers. The plant sterols campesterol and sitosterol appear to be involved in tau pathology and neurodegeneration. CSF desmosterol level indicates CNS cholesterol synthesis and might be of relevance for clinical disease severity. Therefore these non-cholesterol sterols may represent intervention targets to slow down disease progression.

RevDate: 2020-11-10

Franceschi AM, Clifton MA, Naser-Tavakolian K, et al (2020)

FDG PET/MRI for Visual Detection of Crossed Cerebellar Diaschisis in Patients With Dementia.

AJR. American journal of roentgenology [Epub ahead of print].

OBJECTIVE: Depressed regional metabolism and cerebellar blood flow may be caused by dysfunction in anatomically separate but functionally related regions, presumably related to disruption of the corticopontine-cerebellar pathway. The purpose of this study was to evaluate the prevalence of crossed cerebellar diaschisis (CCD) in patients undergoing 18F-FDG PET/MRI for suspected neurodegenerative disease.

MATERIALS AND METHODS: In total, 75 patients (31 men, 44 women; mean age, 74 years) underwent hybrid FDG PET/MRI for clinical workup of neurodegenerative disease. Images were obtained with an integrated 3-T PET/MRI system. PET surface maps, fused T1-weighted magnetization-prepared rapid acquisition gradient echo and axial FLAIR/PET images were generated with postprocessing software. Two board-certified neuroradiologists and a nuclear medicine physician blinded to patient history evaluated for pattern of neurodegenerative disease and CCD.

RESULTS: Qualitative assessment showed that 10 of 75 (7.5%) patients had decreased FDG activity in the cerebellar hemisphere contralateral to the supratentorial cortical hypometabolism consistent with CCD. Six of the 10 patients had characteristic imaging findings of frontotemporal dementia (three behavioral variant frontotemporal dementia, two semantic primary progressive aphasia, and one logopenic primary progressive aphasia), three had suspected corticobasal degeneration, and one had Alzheimer dementia.

CONCLUSION: Our study results suggest that CCD occurs most commonly in frontotemporal dementia, particularly the behavioral variant, and in patients with cortico-basal degeneration. Careful attention to cerebellar metabolism may assist in the clinical evaluation of patients with cognitive impairment undergoing FDG PET/MRI as part of their routine dementia workup.

RevDate: 2020-11-10

Kiani AK, Miggiano GAD, Aquilanti B, et al (2020)

Food supplements based on palmitoylethanolamide plus hydroxytyrosol from olive tree or Bacopa monnieri extracts for neurological diseases.

Acta bio-medica : Atenei Parmensis, 91(13-S):e2020007.

Neurological disorders like Parkinson disease and Alzheimer disease, spinal cord injury and stroke have some recurrent characteristics such as abnormal protein aggregation, oxidative stress induction, apoptosis, excitotoxicity, perturbation of intracellular Ca2+ homeostasis and inflammation. To date, there are few effective treatments available and the drugs currently used to manage the symptoms have important side effects. Therefore, research studies are focusing on natural phytochemicals present in diet as bioactive molecules potentially useful against neurodegenerative diseases. In this review, we will discuss the neuroprotective role of palmitoylethanolamide, hydroxytyrosol, and Bacopa monnieri extracts against neuroinflammation and neurodegeneration, thereby revealing their remarkable potential as novel therapeutic options for the treatment of neurodegenerative disorders.

RevDate: 2020-11-10

Suárez-Calvet M, Karikari TK, Ashton NJ, et al (2020)

Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected.

EMBO molecular medicine [Epub ahead of print].

In Alzheimer's disease (AD), tau phosphorylation in the brain and its subsequent release into cerebrospinal fluid (CSF) and blood is a dynamic process that changes during disease evolution. The main aim of our study was to characterize the pattern of changes in phosphorylated tau (p-tau) in the preclinical stage of the Alzheimer's continuum. We measured three novel CSF p-tau biomarkers, phosphorylated at threonine-181 and threonine-217 with an N-terminal partner antibody and at threonine-231 with a mid-region partner antibody. These were compared with an automated mid-region p-tau181 assay (Elecsys) as the gold standard p-tau measure. We demonstrate that these novel p-tau biomarkers increase more prominently in preclinical Alzheimer, when only subtle changes of amyloid-β (Aβ) pathology are detected, and can accurately differentiate Aβ-positive from Aβ-negative cognitively unimpaired individuals. Moreover, we show that the novel plasma N-terminal p-tau181 biomarker is mildly but significantly increased in the preclinical stage. Our results support the idea that early changes in neuronal tau metabolism in preclinical Alzheimer, likely in response to Aβ exposure, can be detected with these novel p-tau assays.

RevDate: 2020-11-10

Won SY, Park YW, Park M, et al (2020)

Quality Reporting of Radiomics Analysis in Mild Cognitive Impairment and Alzheimer's Disease: A Roadmap for Moving Forward.

Korean journal of radiology pii:21.e167 [Epub ahead of print].

OBJECTIVE: To evaluate radiomics analysis in studies on mild cognitive impairment (MCI) and Alzheimer's disease (AD) using a radiomics quality score (RQS) system to establish a roadmap for further improvement in clinical use.

MATERIALS AND METHODS: PubMed MEDLINE and EMBASE were searched using the terms 'cognitive impairment' or 'Alzheimer' or 'dementia' and 'radiomic' or 'texture' or 'radiogenomic' for articles published until March 2020. From 258 articles, 26 relevant original research articles were selected. Two neuroradiologists assessed the quality of the methodology according to the RQS. Adherence rates for the following six key domains were evaluated: image protocol and reproducibility, feature reduction and validation, biologic/clinical utility, performance index, high level of evidence, and open science.

RESULTS: The hippocampus was the most frequently analyzed (46.2%) anatomical structure. Of the 26 studies, 16 (61.5%) used an open source database (14 from Alzheimer's Disease Neuroimaging Initiative and 2 from Open Access Series of Imaging Studies). The mean RQS was 3.6 out of 36 (9.9%), and the basic adherence rate was 27.6%. Only one study (3.8%) performed external validation. The adherence rate was relatively high for reporting the imaging protocol (96.2%), multiple segmentation (76.9%), discrimination statistics (69.2%), and open science and data (65.4%) but low for conducting test-retest analysis (7.7%) and biologic correlation (3.8%). None of the studies stated potential clinical utility, conducted a phantom study, performed cut-off analysis or calibration statistics, was a prospective study, or conducted cost-effectiveness analysis, resulting in a low level of evidence.

CONCLUSION: The quality of radiomics reporting in MCI and AD studies is suboptimal. Validation is necessary using external dataset, and improvements need to be made to feature reproducibility, feature selection, clinical utility, model performance index, and pursuits of a higher level of evidence.

RevDate: 2020-11-10

Muñoz IC, Cueva LT, Fábrega JCR, et al (2020)

Pet-amyloid after inconclusive cerebrospinal fluid biomarkers in clinical practice. is it necessary to duplicate procedures?.

Current Alzheimer research pii:CAR-EPUB-111269 [Epub ahead of print].

INTRODUCTION: In the absence of a gold standard for in vivo Alzheimer disease (AD) diagnosis, AD biomarkers such as cerebrospinal fluid biomarkers (CSF-B) and PET-Amyloid are considered diagnostically useful in clinical practice guidelines and have consensual appropriate use criteria (AUC). However, little evidence has been published on their utilization in the clinical setting or on approaches to mismatched results. The objective of this work was to evaluate the use of AD biomarkers in clinical practice, focusing on the implementation of PET-Amyloid in cases of inconclusive CSF-B.

METHODS: This naturalistic, ambispective case series included patients fulfilling AUC for CSF-B and PET-Amyloid whose CSF-B results were non-diagnostic (target population), analyzing the diagnostic certainty, the treatment approach, and the relationship between CSF-B and PET-Amyloid results.

RESULTS: Out of 2373 eligible patients, AD biomarkers were studied in 417 (17.6%), most frequently due to cognitive impairment in under 65-year-olds, using CSF-B in 311 patients and PET-Amyloid in 150. CSF-B results were non-diagnostic for 44 patients (52.3% male; aged 60.9±6.6 years), who then underwent PET-Amyloid study, which was positive in 31. A 'k' coefficient of 0.108 was obtained between CSF-B and PET-amyloid (54.5% concordance). In multivariate regression analysis, Aβ42 was the only significant predictor (p= 0.018) of a positive PET-Amyloid result. In the target population, PET-Amyloid increased diagnostic confidence by 53.7% (p <0.001) and modified the therapeutic approach in 36.4% of cases.

CONCLUSION: These findings support the duplication of AD biomarkers and demonstrate that the implementation of PETAmyloid provides an early and certain diagnosis to guide appropriate treatment.

RevDate: 2020-11-10

Camarda C, Torelli P, Pipia C, et al (2020)

APOE Genotypes and Brain Imaging Classes in Normal Cognition, Mild Cognitive Impairment, and Alzheimer's Disease: a Longitudinal Study.

Current Alzheimer research pii:CAR-EPUB-111270 [Epub ahead of print].

OBJECTIVE: To evaluate in 419 stroke-free cognitively normal subjects (CN) aged 45-82 years covering during a long prospective study (11.54 ± 1.47 years), the preclinical to dementia spectrum: 1) the distribution of small vessel disease (V) and brain atrophy (A) aggregated as following: V-/A-, V-/A+, V+/A-, V+/A+; 2) the relationship of these imaging classes with individual apolipoprotein E (APOE) genotypes; 3) the risk of progression to Alzheimer Disease (AD) of the individual APOE genotypes.

METHODS: Participants underwent one baseline (t0), and 4 clinical and neuropsychological assessments (t1,t2,t3, and t4). Brain MRI was performed in all subjects at t0, t2, t3 and t4.. White matter hyperintensities were assessed through two visual rating scales. Lacunes were also rated. Subcortical and global brain atrophy were determined through the bicaudate and the lateral ventricle to brain ratio, respectively. APOE genotypes were determined at t0 in all subjects. Cox proportional hazard model was used to evaluate the risk of progression to AD.

RESULTS: The imaging class of mixed type was very common in AD, and in non amnestic mild cognitive impaired APOE ε4 non carriers. In these subjects, frontal and parieto-occipital regions were most affected by small vessel disease.

CONCLUSION: Our findings suggest that the APOE ε3 allele is probably linked to the brain vascular pathology.

RevDate: 2020-11-09

Wang G, Dong Q, Wu J, et al (2020)

Developing univariate neurodegeneration biomarkers with low-rank and sparse subspace decomposition.

Medical image analysis, 67:101877 pii:S1361-8415(20)30241-3 [Epub ahead of print].

Cognitive decline due to Alzheimer's disease (AD) is closely associated with brain structure alterations captured by structural magnetic resonance imaging (sMRI). It supports the validity to develop sMRI-based univariate neurodegeneration biomarkers (UNB). However, existing UNB work either fails to model large group variances or does not capture AD dementia (ADD) induced changes. We propose a novel low-rank and sparse subspace decomposition method capable of stably quantifying the morphological changes induced by ADD. Specifically, we propose a numerically efficient rank minimization mechanism to extract group common structure and impose regularization constraints to encode the original 3D morphometry connectivity. Further, we generate regions-of-interest (ROI) with group difference study between common subspaces of Aβ+AD and Aβ-cognitively unimpaired (CU) groups. A univariate morphometry index (UMI) is constructed from these ROIs by summarizing individual morphological characteristics weighted by normalized difference between Aβ+AD and Aβ-CU groups. We use hippocampal surface radial distance feature to compute the UMIs and validate our work in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. With hippocampal UMIs, the estimated minimum sample sizes needed to detect a 25% reduction in the mean annual change with 80% power and two-tailed P=0.05are 116, 279 and 387 for the longitudinal Aβ+AD, Aβ+mild cognitive impairment (MCI) and Aβ+CU groups, respectively. Additionally, for MCI patients, UMIs well correlate with hazard ratio of conversion to AD (4.3, 95% CI = 2.3-8.2) within 18 months. Our experimental results outperform traditional hippocampal volume measures and suggest the application of UMI as a potential UNB.

RevDate: 2020-11-09

Koszewiczz M, Jaroch J, Brzecka A, et al (2020)

Dysbiosis is one of the risk factor for stroke and cognitive impairment and potential target for treatment.

Pharmacological research pii:S1043-6618(20)31585-1 [Epub ahead of print].

Above 50 millions people have different forms of cognitive impairment basically caused by neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, and cerebrovascular diseases, mostly stroke. Often these coexistence and exacerbate one another. The damaged area in the post-stroke dementia may lead to the additional neurodegenerative lesions. Gut microbiome functions like an endocrine organ by generating bioactive metabolites, can directly or indirectly impact human physiology. An alteration in the composition and function of intestinal flora, i.e. gut dysbiosis, is involved in neurodegenerative and cerebrovascular diseases. Additionally, gut dysbiosis may accelerate the progression of the cognitive impairment in the course of these diseases. Dysbiosis may result from obesity; metabolic, cardiovascular, and sleep disorders; or lack of physical activity. They may coexist in various patterns in older people, enhancing the risk, incidence, and progression of cerebrovascular lesions, neurodegenerative disorders, and cognitive impairment, creating a vicious circle. Recently, several metabolites produced by gut microbiota from dietary metabolism, e.g. trimethylamine,/trimethylamine N-oxide, short-chain fatty acids, secondary bile acids have been linked to neurodegenerative and cerebrovascular diseases. New treatment modalities, including prebiotic and probiotics, may normalize the gut microbiota composition, change the brain-gut barrier and decrease the risk of the pathology development. Fecal microbiota transplantation, sometimes with combination with other methods, is used for remodeling and replenishing the symbiotic gut microbiome. The promising field of research is associated with basic findings of bidirectional communication between body organs and gut microbiota that open the possibilities of pharmacological treatments of many clinical situations. The authors present the role of gut microbiota in physiology, and the novel therapeutic targets in modulation of intestinal microbiota Personalized therapies based on their personal genome make up could offer benefits by modulating microbiota cross-talk with brain and cardiovascular system. A healthy lifestyle, including pre and probiotic nutrition is generally recommended. Prevention may also be enhanced by correcting gut dysbiosis resulting a reduced risk of post-stroke cognitive impairment including dementia.

RevDate: 2020-11-09

Livinț Popa L, Dragoș HM, Strilciuc Ș, et al (2020)

Added Value of QEEG for the Differential Diagnosis of Common Forms of Dementia.

Clinical EEG and neuroscience [Epub ahead of print].

INTRODUCTION: Quantitative electroencephalography (QEEG) has been documented as a helpful tool in the differential diagnosis of Alzheimer's disease (AD) with common forms of dementia. The main objective of the study was to assess the role of QEEG in AD differential diagnosis with other forms of dementia: Lewy body dementia (LBD), Parkinson's disease dementia (PDD), frontotemporal dementia (FTD), and vascular dementia (VaD).

METHODS: We searched PubMed, Embase, and PsycNET, for articles in English published in peer-reviewed journals from January 1, 1980 to April 23, 2019 using adapted search strategies containing keywords quantitative EEG and Alzheimer. The risk of bias was assessed by applying the QUADAS tool. The systematic review was conducted in line with the PRISMA methodology.

RESULTS: We identified 10 articles showcasing QEEG features used in diagnosing dementia, EEG slowing phenomena in AD and PDD, coherence changes in AD and VaD, the role of LORETA in dementia, and the controversial QEEG pattern in FTD. Results vary significantly in terms of sociodemographic features of the studied population, neuropsychological assessment, signal acquisition and processing, and methods of analysis.

DISCUSSION: This article provides a comparative synthesis of existing evidence on the role of QEEG in diagnosing dementia, highlighting some specific features for different types of dementia (eg, the slow-wave activity has been remarked in both AD and PDD, but more pronounced in PDD patients, a diminution in anterior and posterior alpha coherence was noticed in AD, and a lower alpha coherence in the left temporal-parietal-occipital regions was observed in VaD).

CONCLUSION: QEEG may be a useful investigation for settling the diagnosis of common forms of dementia. Further research of quantitative analyses is warranted, particularly on the association between QEEG, neuropsychological, and imaging features. In conjunction, these methods may provide superior diagnostic accuracy in the diagnosis of dementia.

RevDate: 2020-11-09

Thijssen EH, GD Rabinovici (2020)

Rapid Progress Toward Reliable Blood Tests for Alzheimer Disease.

JAMA neurology pii:2772862 [Epub ahead of print].

RevDate: 2020-11-10

Brendel M, Barthel H, van Eimeren T, et al (2020)

Assessment of 18F-PI-2620 as a Biomarker in Progressive Supranuclear Palsy.

JAMA neurology, 77(11):1408-1419.

Importance: Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis.

Objective: To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP.

In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019.

Main Outcomes and Measures: Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex.

Results: Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP-non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP-non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region.

Conclusions and Relevance: This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.

RevDate: 2020-11-09

Janelidze S, Berron D, Smith R, et al (2020)

Associations of Plasma Phospho-Tau217 Levels With Tau Positron Emission Tomography in Early Alzheimer Disease.

JAMA neurology pii:2772866 [Epub ahead of print].

Importance: There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes.

Objective: To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology.

This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-β (Aβ)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans.

Main Outcomes and Measures: Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures.

Results: Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P = .02).

Conclusions and Relevance: In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology.

RevDate: 2020-11-10

Tural R, Altan N, Irkec C, et al (2020)

The probable role of insulin resistance and SIRT1 proteins in the Alzheimer's disease.

Bratislavske lekarske listy, 121(11):812-816.

OBJECTIVE: Recent evidence suggests that insulin resistance may play an important role in the pathogenesis of Alzheimer's disease (AD). In this study, the probable role of insulin resistance in the pathogenesis of AD was investigated in patients with Type 2 Diabetes Mellitus (T2DM).

METHODS: Serum amyloid beta (Aβ) (1-42), insulin like growth factor-1 (IGF-1), sirtuin1 (SIRT1) and leptin protein levels were measured in serum samples of control (n = 26), probable AD (n = 26), and probable AD+T2DM patients (n = 12) using ELISA method. Mini mental state examination (MMSE) was performed to the patient and control groups.

RESULT: Serum IGF-1 significantly increased in the probable AD+T2DM group as compared to the control and probable AD groups (p ˂ 0.05). The levels of serum leptin significantly decreased in the probable AD and AD+T2DM groups as compared to the control (p ˂ 0.05). There were no statistically significant differences in serum Aβ (1-42) and SIRT1 levels among groups (p > 0.05).

CONCLUSION: The significant decrease in serum leptin levels in AD patients may indicate that it may be a therapeutic marker in AD. The level of serum Aβ peptide and SIRT1 proteins can vary depending on the stage of the disease. Therefore, this study should be supported by more comprehensive studies in terms of the number of patients in advanced stage (Tab. 1, Fig. 4, Ref. 29).

RevDate: 2020-11-10

Hendrix RD, Ou Y, Davis JE, et al (2020)

Alzheimer amyloid-β- peptide disrupts membrane localization of glucose transporter 1 in astrocytes: implications for glucose levels in brain and blood.

Neurobiology of aging, 97:73-88 pii:S0197-4580(20)30310-9 [Epub ahead of print].

Alzheimer's disease (AD) is associated with disturbances in blood glucose regulation, and type-2 diabetes elevates the risk for dementia. A role for amyloid-β peptide (Aβ) in linking these age-related conditions has been proposed, tested primarily in transgenic mouse lines that overexpress mutated amyloid precursor protein (APP). Because APP has its own impacts on glucose regulation, we examined the BRI-Aβ42 line ("Aβ42-tg"), which produces extracellular Aβ1-42 in the CNS without elevation of APP. We also looked for interactions with diet-induced obesity (DIO) resulting from a high-fat, high-sucrose ("western") diet. Aβ42-tg mice were impaired in both spatial memory and glucose tolerance. Although DIO induced insulin resistance, Aβ1-42 accumulation did not, and the impacts of DIO and Aβ on glucose tolerance were merely additive. Aβ42-tg mice exhibited no significant differences from wild-type in insulin production, body weight, lipidemia, appetite, physical activity, respiratory quotient, an-/orexigenic factors, or inflammatory factors. These negative findings suggested that the phenotype in these mice arose from perturbation of glucose excursion in an insulin-independent tissue. To wit, cerebral cortex of Aβ42-tg mice had reduced glucose utilization, similar to human patients with AD. This was associated with insufficient trafficking of glucose transporter 1 to the plasma membrane in parenchymal brain cells, a finding also documented in human AD tissue. Together, the lower cerebral metabolic rate of glucose and diminished function of parenchymal glucose transporter 1 indicate that aberrant regulation of blood glucose in AD likely reflects a central phenomenon, resulting from the effects of Aβ on cerebral parenchyma, rather than a generalized disruption of hypothalamic or peripheral endocrinology. The involvement of a specific glucose transporter in this deficit provides a new target for the design of AD therapies.

RevDate: 2020-11-07

Ali A, Shah SA, Zaman N, et al (2020)

Vitamin D Exerts Neuroprotection via SIRT1/Nrf-2/ NF-kB Signaling Pathways against D-Galactose-induced Memory Impairment in Adult Mice.

Neurochemistry international pii:S0197-0186(20)30284-9 [Epub ahead of print].

Vitamin D (Vt. D) is one of the vital hormone having multiple functions in various tissues, including brain. Several evidences reported that Vt. D plays a significant part in memory and cognition as its inadequate amount may accelerate cognitive impairment. This study shows for the first time the antioxidant potential of Vt. D against D-Galactose (D-gal) induced oxidative stress mediated Alzheimer disease (AD) pathology in male adult albino mice. The result reveals that the mice exposed to D-gal (120 mg/kg) for eight weeks have pre-and post-synaptic dysfunction and impaired memory investigated through Morris water maze and Y-maze tests. This is followed by the suppressed Nuclear factor erythroid 2-related factor 2 (NRF2), Heme Oxygenase-1 (HO-1) and elevated expressions of Nuclear Factor kappa B (NF-kB), Tumor Necrosis Factor alpha (TNF-α) and Interleukin 1 beta (IL-1β) proteins in the brain homogenates evaluated through western blotting technique. On the other hand Vt. D (100 μg/kg) administration (three times a week for 4 weeks) activated Silent mating type information regulation 2 homolog 1 (SIRT1) and significantly improved both the neuronal synapse and memory, reduced oxidative stress by upregulating NRF-2 and HO-1 and downregulating NF-kB, TNF-α and IL-1β proteins expression. Most importantly, Vt. D significantly abrogate the amyloidogenic pathway of amyloid beta (Aβ) production against D-gal in the brains of adult male albino mice. These results reveal that Vt. D being an antioxidant agent plays a vital role in reducing the AD pathophysiology in D-gal induced animal model of aging, therefore act as a potential drug candidate in neurodegenerative diseases.

RevDate: 2020-11-07

Mohamed TM, Youssef MAM, Bakry AA, et al (2020)

Alzheimer's disease improved through the activity of mitochondrial chain complexes and their gene expression in rats by boswellic acid.

Metabolic brain disease pii:10.1007/s11011-020-00639-7 [Epub ahead of print].

The foremost neurodegenerative disease is Alzheimer's (AD), which is characterized as a gradual decrease in memory, cognitive function, and also personal changes occurred. This study aims to assess the role of boswellic bioactive component in control Alzheimer's disease through enhancing mitochondrial electron transport chain complexes in the rat model. Rats were divided into five equal groups: the control group (G1), boswellic acid control group (G2), AD disease group (G3), boswellic acid -pre-treated group (G4) and boswellic acid-treated group (G5). At the end of the experiment, blood glucose level, tau protein, different neurochemicals parameters (dopamine, acetylcholine), L-malondialdehyde (MDA) levels, and superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities was determined. Also, GLUT2 and mitochondrial electron transport chain complexes were evaluated. As a result, an increase in hippocampus glucose, tau protein expression, MDA and GLUT2 in the AD group (G3) compared to control groups (G1 and G2) has been recorded. These parameters were declined after pre (G4) and treated (G5) by boswellic acid. The neurochemicals, antioxidants parameters, four mitochondrial chain complexes activities and their gene expression in the hippocampus of the AD group were decreased compared to the control groups (G1 and G2). In contrast, pre and treated groups by boswellic acid (G4 and G5, respectively) have shown an increase in antioxidants parameters, and the activities of four mitochondrial complexes, with the best improvement in the pre-treated group (G4), then treated group (G5). In conclusion; the boswellic acid improved the antioxidant and mitochondrial complexes in Alzheimer's disease.

RevDate: 2020-11-09

Li WH, Wei ZW, XF Liu (2020)

Clinical efficacy of sertraline in the treatment of depression caused by Alzheimer disease: A protocol of systematic review.

Medicine, 99(45):e23076.

BACKGROUND: This study will appraise the clinical efficacy of sertraline in the treatment of depression caused by Alzheimer disease (AD).

METHODS: Comprehensive searches in PUBMED, EMBASE, Cochrane Library, Scopus, AMED, CNKI, and WANGFANG will be performed from inception to the present without language restriction. In addition, other sources will also be searched to avoid losing more potential studies. We will only consider randomized controlled trials that examined the efficacy of sertraline for depression in patients with AD. Two team members will independently undertake literature selection, data collection, and risk of bias assessment. We will use Cochrane Risk of Bias Tool to assess the risk of bias for each eligible trial, and will utilize RevMan 5.3 software to carry out data analysis.

RESULTS: This study will recapitulate high-quality evidence to assess the efficacy of sertraline for the treatment of depression following AD.

CONCLUSION: The findings of this study will help to determine whether or not sertraline is effective for the treatment of depression after AD. OSF REGISTRATION:: osf.io/f29v6.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

RJR Picks from Around the Web (updated 11 MAY 2018 )