Hallmarks of neurodegenerative diseases

Cell, Год журнала: 2023, Номер 186(4), С. 693 - 714

Опубликована: Фев. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Язык: Английский

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Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's Association Workgroup

Alzheimer s & Dementia, Год журнала: 2024, Номер 20(8), С. 5143 - 5169

Опубликована: Июнь 27, 2024

Abstract The National Institute on Aging and the Alzheimer's Association convened three separate work groups in 2011 single 2012 2018 to create recommendations for diagnosis characterization of disease (AD). present document updates research framework response several recent developments. Defining diseases biologically, rather than based syndromic presentation, has long been standard many areas medicine (e.g., oncology), is becoming a unifying concept common all neurodegenerative diseases, not just AD. consistent with this principle. Our intent objective criteria staging AD, incorporating advances biomarkers, serve as bridge between clinical care. These are intended provide step‐by‐step practice guidelines workflow or specific treatment protocols, but general principles inform AD that reflect current science. Highlights We define (AD) be biological process begins appearance neuropathologic change (ADNPC) while people asymptomatic. Progression burden leads later progression symptoms. Early‐changing Core 1 biomarkers (amyloid positron emission tomography [PET], approved cerebrospinal fluid accurate plasma [especially phosphorylated tau 217]) map onto either amyloid beta tauopathy pathway; however, these presence ADNPC more generally (i.e., both neuritic plaques tangles). An abnormal biomarker result sufficient establish decision making throughout continuum. Later‐changing 2 (biofluid PET) can prognostic information, when abnormal, will increase confidence contributing integrated scheme described accommodates fact copathologies, cognitive reserve, resistance may modify relationships stages.

Язык: Английский

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The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease

Alzheimer s & Dementia, Год журнала: 2022, Номер 18(12), С. 2669 - 2686

Опубликована: Июль 31, 2022

Abstract Blood‐based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well improve design interventional trials. Here we discuss in detail further research needed be performed before widespread use BBMs. We already now recommend BBMs (pre‐)screeners identify individuals likely AD pathological changes for inclusion trials evaluating disease‐modifying therapies, provided status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. also encourage studying longitudinal BBM ongoing future However, should not yet used primary endpoints pivotal Further, cautiously start using specialized memory clinics part patients cognitive symptoms results whenever possible CSF PET. Additional data are stand‐alone markers, considering care.

Язык: Английский

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Head-to-head comparison of 10 plasma phospho-tau assays in prodromal Alzheimer’s disease

Brain, Год журнала: 2022, Номер 146(4), С. 1592 - 1601

Опубликована: Сен. 10, 2022

Plasma phospho-tau (p-tau) species have emerged as the most promising blood-based biomarkers of Alzheimer's disease. Here, we performed a head-to-head comparison p-tau181, p-tau217 and p-tau231 measured using 10 assays to detect abnormal brain amyloid-β (Aβ) status predict future progression dementia. The study included 135 patients with baseline diagnosis mild cognitive impairment (mean age 72.4 years; 60.7% women) who were followed for an average 4.9 years. Seventy-one participants had Aβ-status (i.e. CSF Aβ42/40) at baseline; 45 these Aβ-positive progressed dementia during follow-up. P-tau concentrations determined in plasma CSF. P-tau217 p-tau181 both immunoassays developed by Lilly Research Laboratories (Lilly) mass spectrometry Washington University (WashU). was also analysed Simoa immunoassay Janssen Development (Janss). P-tau181 from ADxNeurosciences (ADx), Lumipulse Fujirebio (Fuji) Splex Mesoscale Discovery (Splex). Both quantified Gothenburg (UGOT). We found that spectrometry-based (p-tau217WashU) exhibited significantly better performance than all other p-tau when detecting Aβ [area under curve (AUC) = 0.947; Pdiff < 0.015] or (AUC 0.932; 0.027). Among immunoassays, p-tau217Lilly highest AUCs (0.886-0.889), which not different p-tau217Janss, p-tau181ADx p-tau181WashU (AUCrange 0.835-0.872; > 0.09), but higher compared AUC p-tau231UGOT, p-tau181Lilly, p-tau181UGOT, p-tau181Fuji p-tau181Splex 0.642-0.813; ≤ 0.029). Correlations between values strongest p-tau217WashU (R 0.891) 0.755; 0.003 versus p-tau217WashU) weak moderate rest (Rrange 0.320-0.669). In conclusion, our findings suggest among tested assays, measures perform best identifying those will subsequently progress Several (p-tau217Lilly, p-tau181WashU) showed relatively high consistent accuracy across outcomes. results further indicate performing metrics rival gold standards Aβ-PET If validated, significant impacts diagnosis, screening treatment future.

Язык: Английский

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Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring

Nature Medicine, Год журнала: 2022, Номер 28(12), С. 2555 - 2562

Опубликована: Дек. 1, 2022

Abstract Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages the disease. Distinctive may be optimal for identification AD or monitoring progression. that correlate with changes cognition atrophy during course could used clinical trials to identify successful interventions thereby accelerate development efficient therapies. When disease-modifying treatments become approved use, blood-based might also inform on treatment implementation management practice. In BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 amyloid-β42/40 ratio were more changed at lower thresholds amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent over 4–6 years disease, no such observed p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein neurofilament light. Only longitudinal increases associated deterioration brain AD. The selective increase its associations cognitive decline was confirmed an independent cohort (Wisconsin Registry Prevention). These findings support differential association strongly highlight as a surrogate marker progression prodromal AD, impact new treatments.

Язык: Английский

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Blood‐based biomarkers for Alzheimer's disease

EMBO Molecular Medicine, Год журнала: 2021, Номер 14(1)

Опубликована: Дек. 3, 2021

Язык: Английский

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Blood biomarkers for Alzheimer’s disease in clinical practice and trials

Nature Aging, Год журнала: 2023, Номер 3(5), С. 506 - 519

Опубликована: Май 18, 2023

Язык: Английский

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Blood phospho-tau in Alzheimer disease: analysis, interpretation, and clinical utility

Nature Reviews Neurology, Год журнала: 2022, Номер 18(7), С. 400 - 418

Опубликована: Май 18, 2022

Язык: Английский

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Solving neurodegeneration: common mechanisms and strategies for new treatments

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Март 21, 2022

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology site disease pathology. To address these and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus the Melza M. Frank Theodore Barr Foundation collaborated to bring together key opinion leaders experts field for a virtual meeting titled "Solving Neurodegeneration". This "think-tank" style focused uncovering mechanistic roots promising new catalyzed by goal finding treatments glaucoma, world's leading cause irreversible blindness interest three hosting foundations. Glaucoma, which causes vision loss through degeneration optic nerve, likely shares early cellular molecular events with other diseases central nervous system. Here we major areas overlap between system: neuroinflammation, bioenergetics metabolism, genetic contributions, neurovascular interactions. We summarize important discussion points emphasis research that are most innovative treatment neurodegeneration yet require further development. The is highlighted provides unique opportunities collaboration will lead efforts preventing ultimately loss.

Язык: Английский

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Mental health care for older adults: recent advances and new directions in clinical practice and research

World Psychiatry, Год журнала: 2022, Номер 21(3), С. 336 - 363

Опубликована: Сен. 8, 2022

The world's population is aging, bringing about an ever-greater burden of mental disorders in older adults. Given multimorbidities, the health care these people and their family caregivers labor-intensive. At same time, ageism a big problem for people, with without disorders. Positive elements such as resilience, wisdom prosocial behaviors, need to be highlighted promoted, both combat stigma help protect improve positive psychiatry aging not oxymoron, but scientific construct strongly informed by research evidence. We champion broader concept geriatric - one that encompasses well illness. In present paper, we address issues context four are greatest source years lived disability: neurocognitive disorders, major depression, schizophrenia, substance use emphasize implementation multidisciplinary team care, comprehensive assessment, clinical management, intensive outreach, coordination mental, physical social services. also underscore further into moderators mediators treatment response variability. Because optimal adults patient-focused family-centered, call enhancing well-being caregivers. To optimize safety efficacy pharmacotherapy, attention metabolic, cardiovascular neurological tolerability much needed, together development testing medications reduce risk suicide. normal cognitive antidote catalyst change way think per se late-life more specifically. It this provide directions future research.

Язык: Английский

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