Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

Brain, Journal Year: 2019, Volume and Issue: 142(6), P. 1503 - 1527

Published: March 22, 2019

We describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by stereotypical proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC common proteinopathy, associated an amnestic dementia syndrome that mimicked Alzheimer's-type retrospective autopsy studies. distinguished from frontotemporal lobar degeneration pathology based on its epidemiology (LATE generally affects subjects), and relatively restricted neuroanatomical distribution of proteinopathy. In community-based cohorts, ∼25% brains had sufficient burden to be discernible cognitive impairment. Many subjects have comorbid brain pathologies, often including amyloid-β plaques tauopathy. Given the 'oldest-old' are at greatest risk for LATE-NC, advanced age constitute rapidly growing demographic group many countries, has expanding but under-recognized impact public health. For these reasons, working was convened develop diagnostic criteria LATE, aiming both stimulate research promote awareness this pathway dementia. report consensus-based recommendations guidelines diagnosis staging LATE-NC. routine workup anatomically-based preliminary scheme proposed immunohistochemistry tissue three areas, reflecting hierarchical pattern involvement: amygdala, hippocampus, middle frontal gyrus. appears affect medial temporal lobe structures preferentially, other areas also impacted. Neuroimaging studies demonstrated atrophy lobes, cortex, regions. Genetic thus far indicated five genes alleles LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, APOE. The discovery genetic variants indicate shares pathogenetic mechanisms Alzheimer's disease, suggests disease-specific underlying mechanisms. Large gaps remain our understanding LATE. advances prevention, diagnosis, treatment, there urgent need focused vitro animal models. An obstacle clinical progress lack tools, such as biofluid neuroimaging biomarkers, ante-mortem detection Development biomarker would augment observational seeking further define factors, natural history, features well eventual subject recruitment targeted therapies trials.

Language: Английский

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The Amyloid-β Pathway in Alzheimer’s Disease

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 26(10), P. 5481 - 5503

Published: Aug. 30, 2021

Abstract Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at center of Alzheimer’s disease (AD) pathophysiology. While detailed mechanisms and spatial-temporal dynamics leading to synaptic failure, neurodegeneration, clinical onset are still under intense investigation, established biochemical alterations Aβ cycle remain core biological hallmark AD promising targets for development disease-modifying therapies. Here, we systematically review update vast state-of-the-art literature science with evidence from basic research studies human genetic multi-modal biomarker investigations, which supports a crucial role dyshomeostasis pathophysiological dynamics. We discuss highlighting differentiated interaction distinct species other AD-related mechanisms, such as tau-mediated, neuroimmune inflammatory changes, well neurochemical imbalance. Through lens latest multimodal vivo biomarkers AD, this cross-disciplinary examines compelling hypothesis- data-driven rationale Aβ-targeting therapeutic strategies early treatment AD.

Language: Английский

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Education and Cognitive Functioning Across the Life Span

Psychological Science in the Public Interest, Journal Year: 2020, Volume and Issue: 21(1), P. 6 - 41

Published: Aug. 1, 2020

Cognitive abilities are important predictors of educational and occupational performance, socioeconomic attainment, health, longevity. Declines in cognitive linked to impairments older adults' everyday functions, but people differ from one another their rates decline over the course adulthood old age. Hence, identifying factors that protect against compromised late-life cognition is great societal interest. The number years formal education completed by individuals positively correlated with function throughout predicts lower risk dementia late life. These observations have led propositions prolonging might (a) affect ability (b) attenuate aging-associated declines cognition. We evaluate these reviewing literature on attainment aging, including recent analyses data harmonized across multiple longitudinal cohort studies related meta-analyses. In line first proposition, evidence indicates has positive effects function. also find associated selection into longer durations there common (e.g., parental resources) both development. There likely reciprocal interplay among factors, abilities, during Education-cognitive associations apparent entire adult life span full range levels, (to some degree) tertiary education. However, contrary second we between negligible a threshold model can account for association risk. conclude exerts its influences primarily contributing individual differences skills emerge early persist note widespread absence puts constraints theoretical notions such as concepts reserve brain maintenance. Improving conditions shape development decades carries potential improving reducing public-health burdens aging dementia.

Language: Английский

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The Role of NMDA Receptors in Alzheimer’s Disease

Frontiers in Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: Feb. 8, 2019

In Alzheimer's disease (AD), early synaptic dysfunction is associated with the increased oligomeric amyloid-beta peptide, which causes NMDAR-dependent depression and spine elimination. Memantine, low-affinity NMDAR channel blocker, has been used in treatment of moderate to severe AD. However, clear evidence still deficient demonstrating underlying mechanisms a relationship between NMDARs This review focuses on not only changes expression different subunits, but also some unconventional modes action.

Language: Английский

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Amyloid-PET and 18F-FDG-PET in the diagnostic investigation of Alzheimer's disease and other dementias

The Lancet Neurology, Journal Year: 2020, Volume and Issue: 19(11), P. 951 - 962

Published: Oct. 21, 2020

Language: Английский

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Alzheimer’s disease and its treatment by different approaches: A review

European Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 216, P. 113320 - 113320

Published: Feb. 23, 2021

Language: Английский

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Hypothesis: Tau pathology is an initiating factor in sporadic Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2020, Volume and Issue: 17(1), P. 115 - 124

Published: Oct. 19, 2020

Abstract The etiology of the common, sporadic form Alzheimer's disease (sAD) is unknown. We hypothesize that tau pathology within select projection neurons with susceptible microenvironments can initiate sAD. This postulate rests on extensive data demonstrating in human brains appears about a decade before formation Aβ plaques (Aβps), especially targeting glutamate association cortex. Data from aging rhesus monkeys show abnormal phosphorylation vulnerable neurons, associated calcium dysregulation. Abnormally phosphorylated (pTau) microtubules traps APP‐containing endosomes, which increase production. As oligomers tau, this would drive vicious cycles leading to sAD over long lifespan, genetic and environmental factors may accelerate pathological events. hypothesis could be testable aged monkey cortex naturally expresses characteristics capable promoting sustaining

Language: Английский

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Fiery Cell Death: Pyroptosis in the Central Nervous System

Trends in Neurosciences, Journal Year: 2019, Volume and Issue: 43(1), P. 55 - 73

Published: Dec. 13, 2019

Language: Английский

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Reasons for Failed Trials of Disease-Modifying Treatments for Alzheimer Disease and Their Contribution in Recent Research

Biomedicines, Journal Year: 2019, Volume and Issue: 7(4), P. 97 - 97

Published: Dec. 9, 2019

Despite all scientific efforts and many protracted expensive clinical trials, no new drug has been approved by FDA for treatment of Alzheimer disease (AD) since 2003. Indeed, more than 200 investigational programs have failed or abandoned in the last decade. The most probable explanations failures disease-modifying treatments (DMTs) AD may include late initiation during course development, inappropriate dosages, erroneous selection targets, mainly an inadequate understanding complex pathophysiology AD, which necessitate combination rather monotherapy. Clinical trials’ methodological issues also criticized. Drug-development research is aimed to overcome these drawbacks. Preclinical prodromal populations, as well traditionally investigated populations representing stages are included recent trials. Systematic use biomarkers staging preclinical a single primary outcome trials regularly integrated. application amyloid, tau, neurodegeneration biomarkers, including biomarkers—such Tau positron emission tomography, neurofilament light chain (blood Cerebrospinal fluid (CSF) biomarker axonal degeneration) neurogranin (CSF synaptic functioning)—to allows precise AD. Additionally, Bayesian statistics, modifiable trial designs, simulators enrich methodology. Besides, therapy regimens assessed above-mentioned diagnostic statistical advances, recently integrated relevant studies treatments. Their experiential theoretical origins better equip potentially successful drug-development strategies.

Language: Английский

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Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update

Frontiers in Pharmacology, Journal Year: 2019, Volume and Issue: 10

Published: Aug. 23, 2019

Alzheimer disease (AD) is a progressive and deleterious neurodegenerative disorder that affects mostly the elderly population. At moment, no effective treatments are available in market, making whole situation compelling challenge for societies worldwide. Recently, novel mechanisms have been proposed to explain etiology of this leading new concept AD multifactor pathology. Among others, function mitochondria has considered as one intracellular processes severely compromised since early stages likely represents common feature many diseases. Many mitochondrial parameters decline already during aging, reaching an extensive functional failure concomitant with onset conditions, although exact timeline these events still unclear. Thereby, it not surprising therapeutic targets diseases including AD. Together overview role dysfunction, review examines pros cons tested approaches targeting context Since therapies shown different degrees progress, imperative perform detailed analysis significance deterioration pharmacological treatment at level. This step would be very important field, drug missing concepts urgently needed.

Language: Английский

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