Alzheimer's disease

Handbook of clinical neurology, Journal Year: 2019, Volume and Issue: unknown, P. 231 - 255

Published: Jan. 1, 2019

Language: Английский

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Plasma p-tau231: a new biomarker for incipient Alzheimer’s disease pathology

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(5), P. 709 - 724

Published: Feb. 14, 2021

Abstract The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise detecting Alzheimer’s disease (AD) pathophysiology. Tau at threonine 231 (p-tau231) is one such biomarker CSF but its usefulness as a blood currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the plasma p-tau231 which was validated four independent cohorts ( n = 588) different settings, including full AD continuum and non-AD neurodegenerative disorders. Plasma able to identify patients with differentiate them from amyloid-β negative cognitively unimpaired (CU) older adults high accuracy (AUC 0.92–0.94). also distinguished disorders 0.93), well MCI 0.89). In neuropathology cohort, samples taken on avergae 4.2 years prior post-mortem very accurately identified comparison 0.99), this despite all being given dementia diagnosis during life. highly correlated p-tau231, pathology assessed by [ 18 F]MK-6240 positron emission tomography (PET), brain amyloidosis F]AZD469 PET. Remarkably, inflection point increasing function continuous PET standardized uptake value ratio, be earlier than standard thresholds positivity increase p-tau181. Furthermore, significantly increased quartiles 2–4, whereas p-tau217 p-tau181 only 3–4 4, respectively. Finally, differentiated individuals across entire Braak stage spectrum, staging 0 through I–II, not observed To conclude, novel assay identifies clinical stages equally p-tau181, increases earlier, already subtle deposition, threshold been attained, response early deposition. Thus, promising emerging potential facilitate trials vulnerable populations below apparent entorhinal

Language: Английский

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Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects

Frontiers in Aging Neuroscience, Journal Year: 2019, Volume and Issue: 11

Published: Aug. 7, 2019

Microtubules (MTs) play a fundamental role in many vital processes such as cell division and neuronal activity. They are key structural functional elements axons, supporting neurite differentiation growth, well transport along the axons by motor proteins, which use MTs support tracks. Tau is stabilizing MT associated protein, whose functions mainly regulated phosphorylation. A disruption of network, might be caused loss function, observed group related diseases called tauopathies, includes Alzheimer's disease (AD). found hyperphosphorylated AD, account for its capacity. Since destabilization after dissociation could contribute to toxicity neurodegenerative diseases, molecular understanding this interaction regulation, essential.

Language: Английский

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An update on genetic frontotemporal dementia

Journal of Neurology, Journal Year: 2019, Volume and Issue: 266(8), P. 2075 - 2086

Published: May 22, 2019

Frontotemporal dementia (FTD) is a highly heritable group of neurodegenerative disorders, with around 30% patients having strong family history. The majority that heritability accounted for by autosomal dominant mutations in the chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) genes, more rarely seen number other genes. This review will discuss recent updates field genetic FTD. Age at symptom onset FTD variable recently identified modifiers including TMEM106B (in GRN carriers particularly) polymorphism locus containing two overlapping genes LOC101929163 C6orf10 C9orf72 carriers). Behavioural variant (bvFTD) most common diagnosis each groups, although amyotrophic lateral sclerosis either alone, or bvFTD, also common. An atypical neuropsychiatric presentation members are greater risk psychiatric disorders schizophrenia autistic spectrum disorders. Large natural history studies presymptomatic now underway both Europe/Canada (GENFI—the Genetic Initiative) US (ARTFL/LEFFTDS study), collaborating together under banner Prevention Initiative (FPI). These taking forward validation cognitive, imaging fluid biomarkers aim to robustly measure disease onset, staging progression Grey matter changes on MRI hypometabolism FDG-PET least 10 years before white abnormalities earlier, but pattern exact timing differ between different groups. In contrast, PET has yet show promise Three key have been so far likely be helpful clinical trials—CSF blood neurofilament light chain levels all groups), CSF carriers) poly(GP) dipeptide repeat Increased knowledge about led testing this not mirrored development an accepted FTD-specific protocol provision appropriate psychological support mechanisms those living through at-risk phase. become even relevant as disease-modifying therapy trials start groups over next few years.

Language: Английский

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Distribution patterns of tau pathology in progressive supranuclear palsy

Acta Neuropathologica, Journal Year: 2020, Volume and Issue: 140(2), P. 99 - 119

Published: May 7, 2020

Progressive supranuclear palsy (PSP) is a 4R-tauopathy predominated by subcortical pathology in neurons, astrocytes, and oligodendroglia associated with various clinical phenotypes. In the present international study, we addressed question of whether or not sequential distribution patterns can be recognized for PSP pathology. We evaluated heat maps neuronal, astroglial, oligodendroglial tau pathologies their combinations different subtypes postmortem brains. used conditional probability logistic regression to model across brain regions. Tau uniformly predominates neurons pallido-nigro-luysian axis subtypes. However, are distinguished only total load but rather cell-type (neuronal versus glial) specific vulnerability regions suggesting distinct dynamics circuit-specific segregation propagation pathologies. For Richardson syndrome (n = 81) recognize six steps involvement combination cellular This translated stages practical neuropathological diagnosis evaluation subthalamic nucleus, globus pallidus, striatum, cerebellum dentate frontal occipital cortices. system applied further emphasizing they show caudal (cerebellum/dentate nucleus) rostral (cortical) predominant, both types pattern. Defining cell-specific helps identify preclinical early-stage cases better understanding early pathogenic events, has implications subtype-specific disease-propagation, informs tau-neuroimaging on patterns.

Language: Английский

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BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Medicinal Research Reviews, Journal Year: 2019, Volume and Issue: 40(1), P. 339 - 384

Published: July 26, 2019

Abstract Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches AD inhibition β‐site APP cleaving enzyme‐1 (BACE1), which involved in rate‐limiting step cleavage process amyloid precursor protein (APP) leading to generation neurotoxic β (Aβ) after γ‐secretase completes its function. The produced insoluble Aβ aggregates lead plaques deposition and neurodegeneration. BACE1 is, therefore, one attractive targets for treatment AD. This approach led development potent inhibitors, many were advanced late stages clinical trials. Nonetheless, high failure rate drug candidates targeting brought forefront need finding new uncover mystery behind In this review, we aim discuss most promising classes inhibitors a description analysis their pharmacodynamic pharmacokinetic parameters, more focus on that reached trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, CNP520. addition, manuscript discusses safety concerns insignificant physiological effects, highlighted successful inhibitors. Furthermore, review demonstrates increasing evidence despite tremendous efforts results conceived latest studies suggest use treating should be reconsidered. Finally, sheds light alternative options

Language: Английский

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Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies

Science, Journal Year: 2021, Volume and Issue: 371(6532)

Published: Feb. 25, 2021

The many faces of tau protein is implicated in several brain disorders, including Alzheimer's disease, suggesting that it could be a target therapeutics. However, because unclear how the pleiotropic roles lead to neural pathology different diseases, drug development remains challenging. Chang et al. review possible mechanisms diseases and paths forward improving research development. Science , this issue p. eabb8255

Language: Английский

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Molecular pathology of neurodegenerative diseases: principles and practice

Journal of Clinical Pathology, Journal Year: 2019, Volume and Issue: 72(11), P. 725 - 735

Published: Aug. 8, 2019

Neurodegenerative diseases are characterised by selective dysfunction and progressive loss of synapses neurons associated with pathologically altered proteins that deposit primarily in the human brain spinal cord. Recent discoveries have identified a spectrum distinct immunohistochemically biochemically detectable proteins, which serve as basis for protein-based disease classification. Diagnostic criteria been updated staging procedures proposed. These based on novel concepts recognise (1) most these follow sequential distribution pattern suggesting seeding mechanism cell-to-cell propagation; (2) some neurodegeneration-associated can be detected peripheral organs; (3) concomitant presence is more rule than exception. concepts, together fact clinical symptoms do not unequivocally reflect molecular pathological background, place neuropathological examination at centre requirements an accurate diagnosis. The need quality control biomarker development, neuroimaging studies, evaluation therapy trials, well increasing demand general public to better understand disorders, underlines importance renaissance postmortem studies this time. This review summarises recent advances diagnosis reports aspects relevance practice.

Language: Английский

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Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(21), P. 12841 - 12841

Published: Oct. 25, 2022

Alzheimer’s disease (AD) is the leading cause of dementia in elderly people. Amyloid beta (Aβ) deposits and neurofibrillary tangles are major pathological features an brain. These proteins highly expressed nerve cells found most tissues. Tau primarily provides stabilization to microtubules part axons dendrites. However, tau a state becomes hyperphosphorylated, causing dysfunction synaptic impairment degeneration neurons. This article presents summary role tau, phosphorylated (p-tau) AD, other tauopathies. Tauopathies, including Pick’s disease, frontotemporal dementia, corticobasal degeneration, argyrophilic grain progressive supranuclear palsy, Huntington’s result misprocessing accumulation within neuronal glial cells. also focuses on current research post-translational modifications genetics pathology, tauopathies development new drugs targeting p-tau, therapeutics for treating possibly preventing

Language: Английский

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Role of tau protein in Alzheimer's disease: The prime pathological player

International Journal of Biological Macromolecules, Journal Year: 2020, Volume and Issue: 163, P. 1599 - 1617

Published: Aug. 9, 2020

Language: Английский

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