Plasma p‐tau 181 shows stronger network association to Alzheimer's disease dementia than neurofilament light and total tau

2021 ◽  
Author(s):  
Brandon Frank ◽  
Madeline Ally ◽  
Bailee Brekke ◽  
Henrik Zetterberg ◽  
Kaj Blennow ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofilament Light ◽  
Total Tau ◽  
Alzheimer’S Disease Dementia

scholarly journals Plasma tau, neurofilament light chain and amyloid-β levels and risk of dementia; a population-based cohort study

Brain ◽  
2020 ◽  
Vol 143 (4) ◽  
pp. 1220-1232 ◽  
Author(s):  
Frank de Wolf ◽  
Mohsen Ghanbari ◽  
Silvan Licher ◽  
Kevin McRae-McKee ◽  
Luuk Gras ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plasma Levels ◽  
Amyloid Β ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Total Tau ◽  
Quartile Group ◽  
Alzheimer’S Disease Dementia

Abstract CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-β, are increasingly being used to define and stage Alzheimer’s disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer’s disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-β40 and amyloid-β42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer’s disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ε4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer’s disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer’s disease dementia. A log2 higher baseline amyloid-β42 plasma level was associated with a lower risk of developing all-cause or Alzheimer’s disease dementia, adjusted hazard ratio (HR) 0.61 [95% confidence interval (CI), 0.47–0.78; P < 0.0001] and 0.59 (95% CI, 0.43–0.79; P = 0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia [adjusted HR 1.59 (95% CI, 1.38–1.83); P < 0.0001] or Alzheimer’s disease [adjusted HR 1.50 (95% CI, 1.26–1.78); P < 0.0001]. Combining the lowest quartile group of amyloid-β42 with the highest of NfL resulted in a stronger association with all-cause dementia [adjusted HR 9.5 (95% CI, 2.3–40.4); P < 0.002] and with Alzheimer’s disease [adjusted HR 15.7 (95% CI, 2.1–117.4); P < 0.0001], compared to the highest quartile group of amyloid-β42 and lowest of NfL. Total-tau and amyloid-β40 levels were not associated with all-cause or Alzheimer’s disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer’s disease compared to those who remained dementia-free (P < 0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer’s disease diagnosis. Amyloid-β42 levels began to decrease in Alzheimer’s disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-β42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer’s disease dementia. These data indicate that plasma NfL and amyloid-β42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer’s disease dementia.

scholarly journals A longitudinal examination of plasma neurofilament light and total tau for the clinical detection and monitoring of Alzheimer's disease

2020 ◽  
Vol 94 ◽  
pp. 60-70
Author(s):  
Michael A. Sugarman ◽  
Henrik Zetterberg ◽  
Kaj Blennow ◽  
Yorghos Tripodis ◽  
Ann C. McKee ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofilament Light ◽  
Total Tau ◽  
Clinical Detection ◽  
Longitudinal Examination

scholarly journals Utility of plasma neurofilament light and total tau for clinical trials in Alzheimer's disease

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Lars Lau Raket ◽  
Line Kühnel ◽  
Ellen Schmidt ◽  
Kaj Blennow ◽  
Henrik Zetterberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Neurofilament Light ◽  
Total Tau

scholarly journals Performance of Plasma Amyloid β, Total Tau and Neurofilament Light Chain Levels for Alzheimer’s Disease Identification

2020 ◽  
Author(s):  
Bin Jiao ◽  
Hui Liu ◽  
Lina Guo ◽  
Xinxin Liao ◽  
Yafang Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Light Chain ◽  
Amyloid Β ◽  
Amyloid Pet ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Plasma Biomarkers ◽  
Total Tau ◽  
T Tau

Abstract BackgroundRobust studies have focused on blood-based biomarkers for diagnosis of Alzheimer’s disease (AD), while the results were still controversary and failed verified in different cohorts. The aim of this study was to detect the levels of plasma amyloid β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) in patients with AD and cognitive normal (CN) subjects, and clarify their associations with Aβ, t-tau, and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) as well as brain amyloid PET, and calculate the diagnostic efficiency of these characteristics regarding AD.Methods Plasma Aβ42, Aβ40, t-tau and NfL levels were detected by single-molecule array (Simoa) in 379 AD patients and 153 CN subjects. Additionally, lumbar puncture was conducted in 125 AD patients to detect Aβ42, Aβ40, t-tau, and p-tau levels. Brain amyloid PET was performed in 52 AD patients to identify brain amyloid deposition levels. Correlation analysis were performed between plasma biomarkers and typical biomarkers of AD, including CSF core biomarkers and amyloid PET burden. Finally, the diagnostic value of plasma biomarkers was further assessed by receiver operating characteristic (ROC) curve.ResultsCompared with the CN group, plasma Aβ42 and Aβ42/Aβ40 levels were significantly lower in AD patients, while Aβ40, t-tau and NfL levels were higher in AD patients. Among the AD patients, plasma Aβ42 was positively correlated with CSF Aβ42 (r = 0.195, p = 0.03) and Aβ42/Aβ40 (r = 0.208, p = 0.04). Moreover, plasma NfL was positively correlated with age, disease course and severity. The diagnostic model with combined plasma Aβ42, t-tau, and NfL levels controlled for age and APOE genotype showed the best performance to identify AD (area under the curve (AUC) = 0.88, sensitivity = 82.84%, specificity = 81.69%, cutoff value = 0.64).ConclusionsTrends revealed by core biomarkers were generally consistent in AD patients’ plasma and CSF. Combining plasma biomarkers can provide comparatively high AD diagnostic performance.

scholarly journals Effects of simufilam on cerebrospinal fluid biomarkers in Alzheimer’s disease: A randomized clinical trial

2021 ◽  
Author(s):  
Hoau-Yan Wang ◽  
Zhe Pei ◽  
Kuo-Chieh Lee ◽  
Yaneicy Gonzalez Rojas ◽  
Tamara Doehner ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Working Memory ◽  
Csf Biomarkers ◽  
Filamin A ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Total Tau ◽  
Primary Endpoints ◽  
Csf Levels

Abstract BACKGROUND Simufilam is a first-in-class drug candidate targeting altered filamin A, a proteopathy in Alzheimer’s disease. The primary objective of this Phase 2 clinical trial was to evaluate the effects of simufilam on cerebrospinal fluid (CSF) biomarkers in Alzheimer’s disease patients. A secondary objective was to assess cognitive enhancement. METHODS In a randomized, placebo-controlled trial conducted across 9 clinical sites in the US, 64 mild-to-moderate Alzheimer’s disease patients were randomized to simufilam 50 or 100 mg b.i.d. or placebo for 28 days. Clinical diagnosis was confirmed by CSF total tau/amyloid-beta1 − 42 (Aβ42) > 0.28. Co-primary endpoints were changes in CSF Aβ42, total tau, phospho-tau (P-tau181), neurogranin, neurofilament light chain, and YKL-40. Secondary endpoints included additional CSF biomarkers assessing neuroinflammation and blood brain barrier integrity, and tests of episodic and spatial working memory. RESULTS Adjusting for multiplicity of the six co-primary endpoints (p < 0.008 versus placebo required for significance), simufilam 50 and 100 mg significantly reduced CSF levels of total tau, hyperphosphorylated tau (P-tau181), neurogranin, neurofilament light chain and YKL-40. Simufilam 50 mg significantly increased CSF levels of Aβ42. On secondary CSF biomarker endpoints, both doses of simufilam significantly reduced IL-6, soluble TREM2 (triggering receptor expressed on myeloid cells-2), HMGB1 (high mobility group box-1), albumin and immunoglobulin G. All but one patient improved from baseline across biomarkers. Simufilam 50 and 100 mg showed effect sizes versus placebo (0.23–0.46) in change from baseline in episodic memory and spatial working memory. Episodic memory improvements correlated most strongly with decreases in P-tau181 (R2 = 0.48). Simufilam was safe and well tolerated. Target engagement was demonstrated by filamin A linkages to nicotinic acetylcholine receptor subtype α7 (α7nAChR) and toll-like receptor 4 (TLR4) in lymphocytes. CONCLUSIONS Simufilam was safe and well tolerated and significantly improved eleven CSF biomarkers in patients with Alzheimer’s disease, implying biological evidence of disease modification. Simufilam will be further evaluated in large, definitive clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04079803.

scholarly journals Stage-specific links between plasma neurofilament light and imaging biomarkers of Alzheimer’s disease

Brain ◽  
2020 ◽  
Author(s):  
Andréa L Benedet ◽  
Antoine Leuzy ◽  
Tharick A Pascoal ◽  
Nicholas J Ashton ◽  
Sulantha Mathotaarachchi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
White Matter ◽  
Imaging Biomarkers ◽  
Cognitively Impaired ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Tau Pet ◽  
Alzheimer’S Disease Dementia

Abstract Neurofilament light (NfL) is a marker of neuroaxonal injury, a prominent feature of Alzheimer’s disease. It remains uncertain, however, how it relates to amyloid and tau pathology or neurodegeneration across the Alzheimer’s disease continuum. The aim of this study was to investigate how plasma NfL relates to amyloid and tau PET and MRI measures of brain atrophy in participants with and without cognitive impairment. We retrospectively examined the association between plasma NfL and MRI measures of grey/white matter volumes in the Alzheimer’s Disease Neuroimaging Initiative [ADNI: n = 1149; 382 cognitively unimpaired control subjects and 767 cognitively impaired participants (mild cognitive impairment n = 420, Alzheimer’s disease dementia n = 347)]. Longitudinal plasma NfL was measured using single molecule array (Simoa) technology. Cross-sectional associations between plasma NfL and PET amyloid and tau measures were independently assessed in two cohorts: ADNI [n = 198; 110 cognitively unimpaired, 88 cognitively impaired (MCI n = 67, Alzheimer’s disease dementia n = 21), data accessed October 2018]; and Translational Biomarkers in Aging and Dementia [TRIAD, n = 116; 74 cognitively unimpaired, 42 cognitively impaired (MCI n = 16, Alzheimer’s disease dementia n = 26), data obtained November 2017 to January 2019]. Associations between plasma NfL and imaging-derived measures were examined voxel-wise using linear regression (cross-sectional) and linear mixed effect models (longitudinal). Cross-sectional analyses in both cohorts showed that plasma NfL was associated with PET findings in brain regions typically affected by Alzheimer’s disease; associations were specific to amyloid PET in cognitively unimpaired and tau PET in cognitively impaired (P &lt; 0.05). Longitudinal analyses showed that NfL levels were associated with grey/white matter volume loss; grey matter atrophy in cognitively unimpaired was specific to APOE ε4 carriers (P &lt; 0.05). These findings suggest that plasma NfL increases in response to amyloid-related neuronal injury in preclinical stages of Alzheimer’s disease, but is related to tau-mediated neurodegeneration in symptomatic patients. As such, plasma NfL may a useful measure to monitor effects in disease-modifying drug trials.

scholarly journals Validation of the Alzheimer Disease Dementia Conversion-Related Pattern as an ATN Biomarker of Neurodegeneration

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000011521
Author(s):  
Ganna Blazhenets ◽  
Lars Frings ◽  
Yilong Ma ◽  
Arnd Sörensen ◽  
David Eidelberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Fdg Pet ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Total Tau ◽  
The Subject ◽  
Related Pattern

Objective:To determine whether the Alzheimer’s disease dementia conversion-related pattern (ADCRP) on [18F]FDG PET can serve as a valid predictor for the development of Alzheimer’s disease dementia, the individual expression of the ADCRP (subject score) and its prognostic value were examined in subjects with mild cognitive impairment and biologically defined Alzheimer’s disease.Methods:269 subjects with available [18F]FDG PET, [18F]AV-45 PET, phosphorylated and total tau in CSF, and neurofilament light chain in plasma were included. Following the AT(N) classification scheme, where Alzheimer’s disease is defined biologically by in vivo biomarkers of Aβ deposition (“A”) and pathological tau (“T”), subjects were categorized to the A-T-, A+T-, A+T+ (Alzheimer’s disease), and A-T+ groups.Results:The mean subject score of the ADCRP was significantly higher in the A+T+ group compared to each of the other group (all p < 0.05) but was similar among the latter (all p > 0.1). Within the A+T+ group, the subject score of ADCRP was a significant predictor of conversion to dementia (HR = 2.02 per z-score increase, p < 0.001), with higher predictive value than of alternative biomarkers of neurodegeneration (total tau and neurofilament light chain). Stratification of A+T+ subjects by the subject score of ADCRP yielded well-separated groups of high, medium, and low conversion risks.Conclusions:The ADCRP is a valuable biomarker of neurodegeneration in subjects with mild cognitive impairment and biologically defined Alzheimer’s disease. It shows great potential for stratifying the risk and estimating the time to conversion to dementia in subjects with mild cognitive impairment and underlying Alzheimer’s disease (A+T+).Classification of Evidence:This study provides Class I evidence that [18F]FDG PET predicts the development of AD dementia in individuals with MCI and underlying AD as defined by the AT(N) framework.

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