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

---

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

---

Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology

JAMA Neurology, Год журнала: 2024, Номер 81(3), С. 255 - 255

Опубликована: Янв. 22, 2024

Importance Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of tests research and clinical use has been limited. Expanding access this highly accurate AD crucial wider evaluation implementation tests. Objective To determine utility novel commercially available immunoassay plasma detect pathology evaluate reference ranges abnormal amyloid β (Aβ) longitudinal change across 3 selected cohorts. Design, Setting, Participants This cohort study examined data from single-center observational cohorts: cross-sectional Translational Biomarkers in Aging Dementia (TRIAD) (visits October 2017–August 2021) Wisconsin Registry Alzheimer’s Prevention (WRAP) February 2007–November 2020) Sant Pau Initiative on Neurodegeneration (SPIN) (baseline visits March 2009–November 2021). included individuals without cognitive impairment grouped by (AT) status using PET or CSF biomarkers. Data were analyzed June 2023. Exposures Magnetic resonance imaging, Aβ positron emission tomography (PET), PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 p-tau immunoassays), (ALZpath pTau217 assay). Main Outcomes Measures Accuracy detecting according baseline status. Results The 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] 282 males [35.9%]). High accuracy was observed identifying elevated (area under curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) (AUC, 0.93-0.97; 0.84-0.99) all These accuracies comparable determining signal. detection 3-range yielded reproducible results reduced confirmatory testing approximately 80%. Longitudinally, values showed an annual increase only Aβ-positive individuals, highest those positivity. Conclusions Relevance found that accurately identified biological AD, biomarkers, cut-offs It detected changes, including at preclinical stage.

Язык: Английский

---

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

---

Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration

Brain, Год журнала: 2022, Номер 146(3), С. 1152 - 1165

Опубликована: Дек. 27, 2022

Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies agreements with their corresponding CSF neuroimaging in the amyloid/tau/neurodegeneration [A/T/(N)] framework Alzheimer's disease. However, blood-based neurodegeneration marker neurofilament light is not specific to disease while total-tau shows lack of correlation total-tau. Recent studies suggest that blood originates principally from peripheral, non-brain sources. We sought address this challenge by generating an anti-tau antibody selectively binds brain-derived avoids peripherally expressed 'big tau' isoform. applied develop ultrasensitive assay tau, validated it five independent cohorts (n = 609) including a blood-to-autopsy cohort, biomarker-classified memory clinic cohorts. In paired samples, serum were significantly correlated (rho 0.85, P < 0.0001), 0.23, 0.3364). showed equivalent performance as separate biomarker-positive participants biomarker-negative controls. Furthermore, plasma accurately distinguished autopsy-confirmed other neurodegenerative diseases (area under curve 86.4%) did 54.3%). These performances presence concomitant pathologies. Plasma 0.52-0.67, 0.003), but -0.14-0.17, 0.501), was associated global regional plaque neurofibrillary tangle counts. results further verified two where differentiated range disorders, frontotemporal lobar degeneration atypical parkinsonian disorders up 99.6%). Notably, plasma/serum only diseases. Across cohorts, AT(N) cognitive function. Brain-derived new biomarker outperforms and, unlike light, specificity disease-type neurodegeneration. Thus, demonstrates potential complete scheme blood, will be useful evaluate disease-dependent processes clinical research purposes.

Язык: Английский

---

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

Neuron, Год журнала: 2023, Номер 111(18), С. 2781 - 2799

Опубликована: Июнь 8, 2023

Язык: Английский

---

A two-step workflow based on plasma p-tau217 to screen for amyloid β positivity with further confirmatory testing only in uncertain cases

Nature Aging, Год журнала: 2023, Номер 3(9), С. 1079 - 1090

Опубликована: Авг. 31, 2023

Cost-effective strategies for identifying amyloid-β (Aβ) positivity in patients with cognitive impairment are urgently needed recent approvals of anti-Aβ immunotherapies Alzheimer's disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow reduce the number confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests while classifying patients. We evaluated two-step determining Aβ-PET status mild (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4 was developed BioFINDER-1 (area under curve (AUC) 89.3%) validated BioFINDER-2 (AUC 94.3%). In step 1, used to stratify low, intermediate high risk positivity. 2, we assumed referral only intermediate-risk CSF Aβ42/Aβ40 testing, whereas 1 alone determined Aβ-status low- high-risk groups. Depending on lenient, moderate stringent thresholds were overall accuracy detecting 88.2%, 90.5% 92.0%, respectively, reducing necessary by 85.9%, 72.7% 61.2%, respectively. secondary analyses, an adapted version led successful validation different p-tau217 immunoassay TRIAD cohort 84). conclusion, using p-tau217-based stratification MCI substantially need testing patients, offering cost-effective strategy clinic settings.

Язык: Английский

---

Plasma phospho-tau in Alzheimer’s disease: towards diagnostic and therapeutic trial applications

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Март 16, 2023

As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, healthcare systems. Although AD can be identified diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence clinical symptoms, challenges regarding practicality accessibility hinder widespread availability implementation. Consequently, many people suspected cognitive impairment due to do not receive biomarker-supported diagnosis. Blood have capacity help expand access diagnostics worldwide. One such promising biomarker plasma phosphorylated tau (p-tau), which has demonstrated specificity versus non-AD neurodegenerative diseases, will extremely important inform diagnosis eligibility for therapies recently been approved. This review provides an update diagnostic prognostic performances p-tau181, p-tau217 p-tau231, associations in vivo autopsy-verified pathological hallmarks. Additionally, we discuss potential applications unanswered questions p-tau therapeutic trials, given recent addition toolbox participant screening, recruitment during-trial monitoring. Outstanding include assay standardization, threshold generation verification diverse cohorts reflective wider community attending memory clinics included trials.

Язык: Английский

---

Plasma proteomic profiles predict future dementia in healthy adults

Nature Aging, Год журнала: 2024, Номер 4(2), С. 247 - 260

Опубликована: Фев. 12, 2024

Язык: Английский

---

The performance of plasma amyloid beta measurements in identifying amyloid plaques in Alzheimer’s disease: a literature review

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

Опубликована: Дек. 27, 2022

Abstract The extracellular buildup of amyloid beta (Aβ) plaques in the brain is a hallmark Alzheimer’s disease (AD). Detection Aβ pathology essential for AD diagnosis and identifying recruiting research participants clinical trials evaluating disease-modifying therapies. Currently, diagnoses are usually made by assessments, although detection with positron emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis can be used specialty clinics. These measures aggregation, e.g. plaques, protofibrils, oligomers, medically invasive often only available at specialized medical centers not covered insurance, PET costly. Therefore, major goal recent years has been to identify blood-based biomarkers that accurately detect cost-effective, minimally procedures. To assess performance plasma assays predicting burden central nervous system (CNS), this review compares twenty-one different manuscripts measurements 42 40 amino acid-long (Aβ42 Aβ40) predict CNS status. Methodologies quantitate Aβ42 peptides blood via immunoassay immunoprecipitation-mass spectrometry (IP-MS) were considered, their ability distinguish amyloidosis compared CSF as reference standards was evaluated. Recent studies indicate some IP-MS perform well precisely measuring detecting aggregates.

Язык: Английский

---