Comparison of CSF phosphorylated tau 181 and 217 for cognitive decline

ObjectiveTo examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles.MethodsPooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1–42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination. We compared the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years).ResultsUsing different model formulations and cut points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A−T−N−). Replicating prior findings using the 2011 National Institute on Aging–Alzheimer's Association/suspected non–Alzheimer disease pathophysiology schema, only individuals with abnormal levels of both amyloid and phosphorylated tau 181 or total tau (stage 2) showed greater cognitive decline than those with normal biomarker levels (stage 0).ConclusionThe results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline.

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Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer’s disease pathology and clinical disease progression

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00805-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Christopher Clark ◽

Piotr Lewczuk ◽

Johannes Kornhuber ◽

Jonas Richiardi ◽

Bénédicte Maréchal ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Cognitive Impairment ◽

Cognitive Decline ◽

Disease Progression ◽

Reference Model ◽

Csf Biomarkers ◽

Phosphorylated Tau ◽

Memory Clinic ◽

Neurofilament Light ◽

Phosphorylated Tau 181

Abstract Background To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer’s disease (AD) pathology and predict clinical progression in a memory clinic setting. Methods Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36 months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression. Results Plasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/Aβ1–42 > 0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, Aβ1–42, and Aβ1–42/Aβ1–40 in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants. Conclusion Plasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment.

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Plasma Neurofilament Light and Phosphorylated Tau 181 as Biomarkers of Alzheimer’s Disease Pathology and Clinical Disease Progression

10.21203/rs.3.rs-135649/v1 ◽

2020 ◽

Author(s):

Christopher Clark ◽

Piotr Lewczuk ◽

Johannes Kornhuber ◽

Jonas Richiardi ◽

Bénédicte Maréchal ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Decline ◽

Disease Progression ◽

Reference Model ◽

P Value ◽

Csf Biomarkers ◽

Phosphorylated Tau ◽

Memory Clinic ◽

Neurofilament Light ◽

Phosphorylated Tau 181

Abstract Background: To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer’s disease (AD) pathology and predict clinical progression in a memory clinic setting. Methods: Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology (CSF β-amyloid 1-42 (Aβ1-42), Aβ1-42 /Aβ1-40, total-tau (tau), and p-tau181) were measured in participants with normal cognition (CN, n=91) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI, n=127). Clinical and neuropsychological evaluations were performed at inclusion and follow-up visits at 18 and 36 months, to measure decline in global cognition and progression of disease severity. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with the presence of cerebral AD pathology (a priori defined by a CSF p-tau181/Aβ1-42 > 0.0779), single CSF biomarkers, and clinical measures of disease progression. Results: Plasma NfL levels were higher in CN participants with an AD CSF profile, and in CI participants when compared to CN non-AD participants, while p-tau181 plasma levels were higher in CI patients with AD when compared to the other participants. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF biomarkers in CI participants. Compared to a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients (AUC 0.861, p-value = 0.048) while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants (AUC 0.838, p-value = 0.032). Using a plasma p-tau181 cutoff of 9.68 pg/ml the models reached a sensitivity of 0.80 and specificity of 0.79 for AD prediction, and of 0.88 and 0.69 for the prediction of cognitive decline.Conclusion: Plasma NfL may be useful as a marker of neuronal injury, although it is not specific for AD. P-tau181 can serve, in a memory clinic setting, as a blood-based biomarker of both cerebral AD pathology and cognitive decline. The predictive performance of both markers depends on the presence of cognitive impairment.

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Assessment of cerebral microbleeds by susceptibility-weighted imaging in Alzheimer’s disease patients: A neuroimaging biomarker of the disease

The Neuroradiology Journal ◽

10.1177/1971400916689483 ◽

2017 ◽

Vol 30 (4) ◽

pp. 330-335 ◽

Cited By ~ 12

Author(s):

Gianvincenzo Sparacia ◽

Francesco Agnello ◽

Giuseppe La Tona ◽

Alberto Iaia ◽

Federico Midiri ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Decline ◽

Amyloid Beta ◽

Cerebral Microbleeds ◽

Susceptibility Weighted Imaging ◽

Phosphorylated Tau ◽

Protein Levels ◽

Phosphorylated Tau 181

Purpose The objective of this study was to correlate the presence and distribution of cerebral microbleeds in Alzheimer’s disease patients with cerebrospinal fluid biomarkers (amyloid-beta and phosphorylated tau 181 protein levels) and cognitive decline by using susceptibility-weighted imaging magnetic resonance sequences at 1.5 T. Material and methods Fifty-four consecutive Alzheimer’s disease patients underwent brain magnetic resonance imaging at 1.5 T to assess the presence and distribution of cerebral microbleeds on susceptibility-weighted imaging images. The images were analyzed in consensus by two neuroradiologists, each with at least 10 years’ experience. Dementia severity was assessed with the Mini-Mental State Examination score. A multiple regression analysis was performed to assess the associations between the number and location of cerebral microbleed lesions with the age, sex, duration of the disease, cerebrospinal fluid amyloid-beta and phosphorylated tau 181 protein levels, and cognitive functions. Results A total of 296 microbleeds were observed in 54 patients; 38 patients (70.4%) had lobar distribution, 13 patients (24.1%) had non-lobar distribution, and the remaining three patients (5.6%) had mixed distribution, demonstrating that Alzheimer’s disease patients present mainly a lobar distribution of cerebral microbleeds. The age and the duration of the disease were correlated with the number of lobar cerebral microbleeds ( P < 0.001). Cerebrospinal fluid amyloid-beta, phosphorylated tau 181 protein levels, and cognitive decline were correlated with the number of lobar cerebral microbleeds in Alzheimer’s disease patients ( P < 0.001). Conclusion Lobar distribution of cerebral microbleeds is associated with Alzheimer’s disease and the number of lobar cerebral microbleeds directly correlates with cerebrospinal fluid amyloid-beta and phosphorylated tau 181 protein levels and with the cognitive decline of Alzheimer’s disease patients.

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