Highly accurate blood test for Alzheimer’s disease is similar or superior to clinical cerebrospinal fluid tests

Nature Medicine, Journal Year: 2024, Volume and Issue: 30(4), P. 1085 - 1095

Published: Feb. 21, 2024

With the emergence of Alzheimer's disease (AD) disease-modifying therapies, identifying patients who could benefit from these treatments becomes critical. In this study, we evaluated whether a precise blood test perform as well established cerebrospinal fluid (CSF) tests in detecting amyloid-β (Aβ) plaques and tau tangles. Plasma %p-tau217 (ratio phosporylated-tau217 to non-phosphorylated tau) was analyzed by mass spectrometry Swedish BioFINDER-2 cohort (n = 1,422) US Charles F. Joanne Knight Alzheimer Disease Research Center (Knight ADRC) 337). Matched CSF samples were with clinically used FDA-approved automated immunoassays for Aβ42/40 p-tau181/Aβ42. The primary secondary outcomes detection brain Aβ or pathology, respectively, using positron emission tomography (PET) imaging reference standard. Main analyses focused on individuals cognitive impairment (mild mild dementia), which is target population available treatments. equivalent classifying PET status, an area under curve (AUC) both between 0.95 0.97. generally superior classification tau-PET AUCs 0.95-0.98. cognitively impaired subcohorts (BioFINDER-2: n 720; ADRC: 50), plasma had accuracy, positive predictive value negative 89-90% 87-88% tests, further improving 95% two-cutoffs approach. Blood demonstrated performance that AD pathology. Use high-performance clinical practice can improve access accurate diagnosis AD-specific

Language: Английский

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

World Psychiatry, Journal Year: 2022, Volume and Issue: 21(3), P. 336 - 363

Published: Sept. 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.

Language: Английский

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Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography

JAMA Neurology, Journal Year: 2022, Volume and Issue: 80(2), P. 188 - 188

Published: Dec. 12, 2022

Importance The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies Alzheimer disease (AD): amyloid-β plaques and neurofibrillary tangles. Objective To determine whether cerebrospinal fluid (CSF) plasma p-tau preferentially reflect cerebral β-amyloidosis or tangle aggregation measured positron emission tomography (PET). Design, Setting, Participants This was a cross-sectional study 2 observational cohorts: Translational Biomarkers in Aging Dementia (TRIAD) study, data collected between October 2017 August 2021, Alzheimer’s Disease Neuroimaging Initiative (ADNI), September 2015 November 2019. TRIAD single-center ADNI multicenter study. Two independent subsamples were derived from TRIAD. first subsample comprised individuals assessed CSF (p-tau 181 , 217 231 235 ), [ 18 F]AZD4694 amyloid PET, F]MK6240 PET. second included An cohort F]florbetapir F]flortaucipir based on availability PET biomarker assessments within 9 months each other. Exclusion criteria history head trauma magnetic resonance imaging/PET safety contraindications. No participants who met eligibility excluded. Exposures Amyloid single molecule array (Simoa) assay enzyme-linked immunosorbent assay. Main Outcomes Measures Associations Results A total 609 (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) For all 4 phosphorylation sites CSF, significantly more closely associated amyloid-PET values than tau-PET difference, 13%; 95% CI, 3%-22%; P = .006; 11%; 3%-20%; .003; 15%; 5%-22%; < .001; 9%; 1%-19%; .02) . These results replicated (difference, 1%-22%; .02), 3%-24%; .009), 1%-21%; cohorts. Conclusions Relevance this cohorts suggest that abnormality as an early event AD pathogenesis accumulation highlights need for careful interpretation context amyloid/tau/neurodegeneration, A/T/(N), framework.

Language: Английский

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Association of Donanemab Treatment With Exploratory Plasma Biomarkers in Early Symptomatic Alzheimer Disease

JAMA Neurology, Journal Year: 2022, Volume and Issue: 79(12), P. 1250 - 1250

Published: Oct. 17, 2022

Importance Plasma biomarkers of Alzheimer disease may be useful as minimally invasive pharmacodynamic measures treatment outcomes. Objective To analyze the association donanemab with plasma associated disease. Design, Setting, and Participants TRAILBLAZER-ALZ was a randomized, double-blind, placebo-controlled clinical trial conducted from December 18, 2017, to 4, 2020, across 56 sites in US Canada. Exploratory were prespecified post hoc addition glial fibrillary acidic protein amyloid-β. Men women aged 60 85 years gradual progressive change memory function for at least 6 months included. A total 1955 participants assessed eligibility. Key eligibility criteria include Mini-Mental State Examination scores 20 28 elevated amyloid intermediate tau levels. Interventions Randomized received or placebo every 4 weeks up 72 weeks. The first 3 doses given 700 mg then increased 1400 blinded dose reductions specified based on reduction. Main Outcomes Measures Change biomarker levels after treatment. Results In TRAILBLAZER-ALZ, 272 (mean [SD] age, 75.2 [5.5] years; 145 [53.3%] female) randomized. phosphorylated 217 (pTau ) significantly lower compared early 12 start (least square mean difference vs placebo, –0.04 [95% CI, –0.07 –0.02]; P = .002 –0.01]; .01, respectively). No significant differences amyloid-β 42/40 neurofilament light chain observed between arms end Changes pTau correlated Centiloid percent (Spearman rank correlation coefficient [ R ] 0.484 0.359-0.592]; < .001 0.453 0.306-0.579]; .001, respectively) following Additionally, baseline ( 0.399 0.278-0.508], 0.393 0.254-0.517]; Conclusions Relevance Significant patients symptomatic These easily accessible might provide additional evidence pathology through anti-amyloid therapy. Usefulness assessing response will require further evaluation. Trial Registration ClinicalTrials.gov Identifier: NCT03367403

Language: Английский

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Two Phase 3 Trials of Gantenerumab in Early Alzheimer’s Disease

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 389(20), P. 1862 - 1876

Published: Nov. 15, 2023

Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody highest affinity for aggregated Aβ has been tested treatment of Download PDF Research Summary. We conducted two phase 3 trials (GRADUATE I II) involving participants 50 90 years age mild impairment or dementia due disease evidence amyloid plaques on positron-emission tomography (PET) cerebrospinal fluid (CSF) testing. Participants were randomly assigned receive gantenerumab placebo every 2 weeks. The primary outcome was change from baseline score Clinical Dementia Rating scale–Sum Boxes (CDR-SB; range, 0 18, higher scores indicating greater impairment) at week 116. A total 985 980 enrolled GRADUATE II trials, respectively. CDR-SB 3.7 trial 3.6 trial. 116 3.35 3.65 (difference, –0.31; 95% confidence interval [CI], –0.66 0.05; P=0.10) 2.82 3.01 –0.19; CI, –0.55 0.17; P=0.30). At 116, difference level PET between group –66.44 –56.46 centiloids respectively, amyloid-negative status attained 28.0% 26.8% receiving trials. Across both had lower CSF levels phosphorylated tau 181 Aβ42 than those placebo; accumulation similar groups. Amyloid-related imaging abnormalities edema (ARIA-E) occurred 24.9% gantenerumab, symptomatic ARIA-E 5.0%. Among disease, use led plaque burden weeks but not associated slower clinical decline. (Funded by F. Hoffmann–La Roche; ClinicalTrials.gov numbers, NCT03444870 NCT03443973, respectively.) QUICK TAKE VIDEO SUMMARYGantenerumab Early Disease 02:01

Language: Английский

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Accelerated Brain Volume Loss Caused by Anti–β-Amyloid Drugs

Neurology, Journal Year: 2023, Volume and Issue: 100(20)

Published: March 27, 2023

To evaluate brain volume changes caused by different subclasses of anti-β-amyloid (Aβ) drugs trailed in patients with Alzheimer disease.

Language: Английский

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Alzheimer's disease: From immunotherapy to immunoprevention

Cell, Journal Year: 2023, Volume and Issue: 186(20), P. 4260 - 4270

Published: Sept. 1, 2023

Language: Английский

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Anti-amyloid antibody therapies in Alzheimer’s disease

Brain, Journal Year: 2023, Volume and Issue: 146(3), P. 842 - 849

Published: Jan. 19, 2023

After years of failed attempts to develop a disease-modifying therapy for Alzheimer's disease, consistent evidence in support clinical efficacy was finally presented monoclonal antibody targeting the amyloid-β protofibrils. In addition meeting primary outcome slowing disease progression over 18 months, secondary outcomes and lowering on PET also underpin positive results trial. this opinion piece, we highlight key characteristics previous unsuccessful trials analyse potential reasons why those treatment early failed. We compare safety profiles different antibodies cautionary measures their routine use. Last, discuss role blood-based biomarkers transforming care pathway facilitate uptake treatments, proposing an integrated case-finding model crossing healthcare sectors. Taken together, real breakthrough may have been achieved by proving that reduction benefits, rather than just biomarker changes. At same time, use new generation drugs will show if statistical translates into clinically meaningful change. This be beginning era drug development.

Language: Английский

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Anti-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer’s Disease

BioDrugs, Journal Year: 2023, Volume and Issue: 38(1), P. 5 - 22

Published: Nov. 13, 2023

Two monoclonal antibodies (mAbs), aducanumab and lecanemab, have received accelerated approval from the US FDA for initiation of treatment in early Alzheimer's disease patients who proven β-amyloid pathology (Aβ). One these, has subsequently full other are poised positive review approval. Anti-amyloid mAbs share feature producing a marked reduction total brain Aβ revealed by amyloid positron emission tomography. Trials associated with slowing cognitive decline achieved measurable plaque range 15–25 centiloids; trials agents that did not reach this threshold were benefit. differences terms titration schedules, MRI monitoring schedules amyloid-related imaging abnormalities (ARIA), continuing versus interrupted therapy. The approximate 30% observed is clinically meaningful extended integrity delay onset more severe dementia phases disease. Approval these initiates new era therapeutics disease-modifying properties. Further advances needed, i.e. greater efficacy, improved safety, enhanced convenience, better understanding ill-understood observations such as volume loss.

Language: Английский

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Blood-based biomarkers for Alzheimer’s disease: Current state and future use in a transformed global healthcare landscape

Neuron, Journal Year: 2023, Volume and Issue: 111(18), P. 2781 - 2799

Published: June 8, 2023

Language: Английский

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