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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Cognitive effects of Lewy body pathology in clinically unimpaired individuals

Nature Medicine, Год журнала: 2023, Номер 29(8), С. 1971 - 1978

Опубликована: Июль 18, 2023

Abstract α-Synuclein aggregates constitute the pathology of Lewy body (LB) disease. Little is known about effects LB in preclinical (presymptomatic) individuals, either as isolated or coexisting with Alzheimer’s disease (AD) (β-amyloid (Aβ) and tau). We examined using a cerebrospinal fluid α-synuclein-seed amplification assay 1,182 cognitively neurologically unimpaired participants from BioFINDER study: 8% were positive, 26% Aβ positive (13% those positive) 16% tau positive. positivity occurred more often presence but not positivity. had independently negative on cross-sectional longitudinal global cognition memory attention/executive function. Tau cognitive similar magnitude, these less pronounced for Aβ. Participants both AD (Aβ tau) exhibited faster decline than only pathology. LB, AD, was associated reduced sense smell. Only LB-positive progressed to clinical over 10 years. These results are important individualized prognosis, recruitment choice outcome measures trials, also design early trials because >10% individuals have

Язык: Английский

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Clinical effects of Lewy body pathology in cognitively impaired individuals

Nature Medicine, Год журнала: 2023, Номер 29(8), С. 1964 - 1970

Опубликована: Июль 18, 2023

There is poor knowledge about the clinical effects of Lewy body (LB) pathology in patients with cognitive impairment, especially when coexisting Alzheimer's disease (AD) (amyloid-β and tau). Using a seed amplification assay, we analyzed cerebrospinal fluid for misfolded LB-associated α-synuclein 883 memory clinic mild impairment or dementia from BioFINDER study. Twenty-three percent had LB pathology, which only 21% fulfilled criteria Parkinson's bodies at baseline. Among these LB-positive patients, 48% AD pathology. Fifty-four whole sample (17% 24% were also LB-positive). When examining independent cross-sectional effects, but not amyloid-β tau, was associated hallucinations worse attention/executive, visuospatial motor function. faster longitudinal decline all examined functions, amyloid-β, stage baseline diagnosis bodies/Parkinson's disease. status provides better precision-medicine approach to predict trajectories biomarkers diagnosis, could have implications management design drug trials.

Язык: Английский

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α‐Synuclein Seed Amplification Assays in the Diagnosis of Synucleinopathies Using Cerebrospinal Fluid—A Systematic Review and Meta‐Analysis

Movement Disorders Clinical Practice, Год журнала: 2023, Номер 10(5), С. 737 - 747

Опубликована: Март 3, 2023

Real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) have been developed to detect minute amounts of amyloidogenic proteins via techniques used misfolded α-synuclein (αSyn) aggregates in the cerebrospinal fluid (CSF) other source materials patients with Parkinson's Disease synucleinopathies.The aim this systematic review meta-analysis was evaluate diagnostic accuracy αSyn seed assays (αSyn-SAAs), including RT-QuIC PMCA, using CSF as material differentiate synucleinopathies from controls.The electronic MEDLINE database PubMed searched for relevant articles published until June 30, 2022. Study quality assessment performed QUADAS-2 toolbox. A random effects bivariate model exploited data synthesis.Our identified 27 eligible studies according predefined inclusion criteria, which 22 were included final analysis. Overall, 1855 1378 non-synucleinopathies control subjects meta-analysis. The pooled sensitivity specificity controls αSyn-SAA 0.88 (95% CI, 0.82-0.93) 0.95 0.92-0.97), respectively. Evaluating performance a subgroup analysis detection multiple system atrophy decreased 0.30 0.11-0.59).While our study clearly demonstrated high PMCA differentiating Lewy bodies controls, results diagnosis less robust.

Язык: Английский

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Performance of a seed amplification assay for misfolded alpha-synuclein in cerebrospinal fluid and brain tissue in relation to Lewy body disease stage and pathology burden

Acta Neuropathologica, Год журнала: 2024, Номер 147(1)

Опубликована: Янв. 19, 2024

Abstract The development of in vitro seed amplification assays (SAA) detecting misfolded alpha-synuclein (αSyn) cerebrospinal fluid (CSF) and other tissues has provided a pathology-specific biomarker for Lewy body disease (LBD). However, αSyn SAA diagnostic performance early pathological stages or low (LB) pathology load only been assessed small cohorts. Moreover, the relationship between kinetic parameters, number brain seeds LB burden by immunohistochemistry never systematically investigated. We tested 269 antemortem CSF samples 138 serially diluted homogenates from patients with without neuropathological evidence LBD different Real-Time Quaking-Induced Conversion (RT-QuIC) SAA. we looked consecutive series 604 Creutzfeldt–Jakob (CJD)-affected brains. RT-QuIC showed 100% sensitivity limbic neocortical stages. assay was significantly lower (37.5% Braak 1 2, 73.3% 3) focal (50% amygdala-predominant). average positive replicates correlated stage. Brain homogenate higher than detection αSyn. In latter, parameter lag phase (time to reach threshold) strongly concentration serial dilution experiments. Finally, incidental prevalence 8% CJD cohort. present results indicate that (a) high specificity sufficient detect all at > 3 most those stage 3; (b) deposition precedes formation neurites; (c) provides “quantitative” information regarding burden, being promising variables be used clinical setting.

Язык: Английский

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CSF α-synuclein seed amplification kinetic profiles are associated with cognitive decline in Parkinson’s disease

npj Parkinson s Disease, Год журнала: 2024, Номер 10(1)

Опубликована: Янв. 20, 2024

Abstract Seed amplification assays have been implemented in Parkinson’s disease to reveal disease-specific misfolded alpha-synuclein aggregates biospecimens. While the assays’ qualitative dichotomous seeding response is valuable stratify and enrich cohorts for pathology general, more quantitative parameters that are associated with clinical dynamics of progression might potentially serve as exploratory outcome measures trials targeting would add important information. To evaluate whether kinetic time required reach threshold (LAG phase), peak fluorescence (Imax), area under curve (AUC) trajectories, we analyzed LAG, Imax, AUC relation development cognitive decline a longitudinal cohort 199 people positive CSF status. Patients were stratified into tertiles based on their individual properties. The effect impairment defined by MoCA ≤25 was Cox-Regression. higher number replicates tertile groups shorter showed prevalence duration until longitudinally (3, 6, 3 years earlier p ≤ 0.001, respectively). Results remained similar separate subgroup analyses patients without GBA mutation. We conclude prominent profile translates rapid decline.

Язык: Английский

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Detecting Misfolded α‐Synuclein in Blood Years before the Diagnosis of Parkinson's Disease

Movement Disorders, Год журнала: 2024, Номер 39(8), С. 1289 - 1299

Опубликована: Апрель 23, 2024

Identifying individuals with Parkinson's disease (PD) already in the prodromal phase of has become a priority objective for opening window early disease-modifying therapies.

Язык: Английский

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Alpha-synuclein: a pathological factor with Aβ and tau and biomarker in Alzheimer’s disease

Alzheimer s Research & Therapy, Год журнала: 2022, Номер 14(1)

Опубликована: Дек. 31, 2022

Abstract Background Alpha-synuclein (α-syn) is considered the main pathophysiological protein component of Lewy bodies in synucleinopathies. α-Syn an intrinsically disordered (IDP), and several types structural conformations have been reported, depending on environmental factors. Since IDPs may distinctive functions their structures, α-syn can play different roles interact with proteins, including amyloid-beta (Aβ) tau, Alzheimer’s disease (AD) other neurodegenerative disorders. Main body In previous studies, aggregates AD brains suggested a close relationship between α-syn. addition, directly interacts Aβ promoting mutual aggregation exacerbating cognitive decline. The interaction tau presented consequences forms proteins. AD, levels CSF were both elevated revealed high positive correlation. Especially, concentration was significantly early stages AD. Therefore, it could be diagnostic marker help distinguish from disorders by incorporating biomarkers. Conclusion overall physiological functions, genetics are reviewed summarized. numerous associations significance α-syn, as partner Understanding involvements pathology address unresolved issues particular, current status recommends additional biomarker panel for diagnosis.

Язык: Английский

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CSF Synaptic Biomarkers in AT(N)-Based Subgroups of Lewy Body Disease

Neurology, Год журнала: 2023, Номер 101(1)

Опубликована: Май 15, 2023

Patients with Lewy body disease (LBD) often show a co-occurring Alzheimer (AD) pathology. CSF biomarkers allow the detection in vivo of AD-related pathologic hallmarks included amyloid-tau-neurodegeneration (AT(N)) classification system. Here, we aimed to investigate whether synaptic and neuroaxonal damage are correlated presence AD copathology LBD can be useful differentiate patients different AT(N) profiles.

Язык: Английский

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Clinical trials in dementia with Lewy bodies: the evolving concept of co-pathologies, patient selection and biomarkers

Current Opinion in Neurology, Год журнала: 2023, Номер unknown

Опубликована: Июнь 28, 2023

Purpose of review Currently, no disease modifying therapies (DMTs) have been approved for use in dementia with Lewy bodies (DLB). Clinical trials face difficulties due to the clinical and neuropathological heterogeneity condition a diverse array neuropathogenic mechanisms contributing phenotype. The purpose this is describe how recent advances development biofluid biomarkers may be used tackle some these challenges. Recent findings Biomarkers are essential both support accurate diagnosis DLB delineate influence coexisting pathologies. α-synuclein seeding amplification assays (SAA) allow identification from prodromal stages DLB. Additionally, validation plasma phosphorylated tau ongoing offers an accessible biomarker indicate existence AD co-pathology. Use group stratification growing likely increasing importance future. Summary In vivo can enhance patient selection allowing greater diagnostic accuracy, more homogeneous trial population, by co-pathology create subgroups most derive therapeutic benefit DMTs.

Язык: Английский

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