scholarly journals Plasma tau and neurofilament light in frontotemporal lobar degeneration and Alzheimer's disease

Neurology ◽  
2020 ◽  
pp. 10.1212/WNL.0000000000011226
Author(s):  
Ignacio Illán-Gala ◽  
Alberto Lleo ◽  
Anna Karydas ◽  
Adam M. Staffaroni ◽  
Henrik Zetterberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Severity ◽  
Cortical Thickness ◽  
Frontotemporal Lobar Degeneration ◽  
Amyloid Pet ◽  
Class Iii ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
T Tau

ObjectiveTo test the hypothesis that plasma total tau (t-tau) and neurofilament light chain (NfL) concentrations may have a differential role in the study of frontotemporal lobar degeneration syndromes (FTLD-S) and clinically-diagnosed Alzheimer's disease (AD-S), we determined their diagnostic and prognostic value in FTLD-S and AD-S and their sensitivity to pathologic diagnoses.MethodsWe measured plasma t-tau and NfL with the Simoa platform in 265 participants: 167 FTLD-S, 43 AD-S, and 55 healthy controls (HC), including 82 pathology-proven cases (50 FTLD-Tau, 18 FTLD-TDP, 2 FTLD-FUS, and 12 AD) and 98 participants with amyloid PET. We compared cross-sectional and longitudinal biomarker concentrations between groups, their correlation with clinical measures of disease severity, progression and survival and cortical thickness.ResultsPlasma NfL, but not plasma t-tau discriminated FTLD-S from HC and AD-S from HC. Both plasma NfL and t-tau were poor discriminators between FLTD-S and AD-S. In pathology confirmed cases, plasma NfL was higher in FTLD than AD and in FTLD-TDP compared to FTLD-Tau, after accounting for age and disease severity. Plasma NfL, but not plasma t-tau, predicted clinical decline and survival and correlated with regional cortical thickness in both FTLD-S and AD-S. The combination of plasma NfL with plasma t-tau did not outperform plasma NfL alone.ConclusionsPlasma NfL is superior to plasma t-tau for the diagnosis and prediction of clinical progression of FTLD-S and AD-S.Classification of evidenceThis study provides Class III evidence that plasma NfL has superior diagnostic and prognostic performance than plasma t-tau in FTLD and AD.

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 Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012513
Author(s):  
Michel J. Grothe ◽  
Alexis Moscoso ◽  
Nicholas J. Ashton ◽  
Thomas K. Karikari ◽  
Juan Lantero-Rodriguez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Csf Biomarkers ◽  
Amyloid Pet ◽  
Braak Stage ◽  
Neuritic Plaques ◽  
Neurofilament Light ◽  
T Tau

Objective:To study cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) analyzed by fully automated Elecsys immunoassays in comparison to neuropathologic gold standards, and compare their accuracy to plasma phosphorylated tau (p-tau181) measured using a novel Simoa method.Methods:We studied ante-mortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized post-mortem assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analysed ante-mortem levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET-negative healthy controls (HC).Results:All CSF biomarkers clearly distinguished pathology-confirmed AD dementia (N=27) from HC (AUCs=0.86-1.00). CSF total-tau (t-tau), p-tau181, and their ratios with Aβ1-42, also accurately distinguished pathology-confirmed AD from non-AD dementia (N=8; AUCs=0.94-0.97). In pathology-specific analyses, intermediate-to-high Thal amyloid phases were best detected by CSF Aβ1-42 (AUC[95% CI]=0.91[0.81-1]), while intermediate-to-high CERAD neuritic plaques and Braak tau stages were best detected by CSF p-tau181 (AUC=0.89[0.79-0.99] and 0.88[0.77-0.99], respectively). Optimal Elecsys biomarker cut-offs were derived at 1097/229/19 pg/ml for Aβ1-42, t-tau, and p-tau181. In the plasma subsample, both plasma p-tau181 (AUC=0.91[0.86-0.96]) and NfL (AUC=0.93[0.87-0.99]) accurately distinguished pathology-confirmed AD (N=14) from HC. However, only p-tau181 distinguished AD from non-AD dementia cases (N=4; AUC=0.96[0.88-1.00]), and showed a similar, though weaker, pathologic specificity for neuritic plaques (AUC=0.75[0.52-0.98]) and Braak stage (AUC=0.71[0.44-0.98]) as CSF p-tau181.Conclusions:Elecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in-vivo. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology.Classification of Evidence:This study provides Class II evidence that fully-automated CSF t-tau and p-tau181measurements discriminate between autopsy-confirmed Alzheimer's disease and other dementias.

scholarly journals CSF biomarker profiles in CNS infection associated with HSV and VZV mimic pattern in Alzheimer’s disease.

2020 ◽  
Author(s):  
Makiko Shinomoto ◽  
TAKASHI KASAI ◽  
Harutsugu Tatebe ◽  
Fukiko Kitani-Morii ◽  
Takuma Ohmichi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Severity ◽  
Amyloid Β ◽  
Cns Infection ◽  
Control Group ◽  
Neurofilament Light Chain ◽  
Cns Infections ◽  
Csf Biomarker ◽  
T Tau

Abstract Background: Central nervous system (CNS) infections have been reported to have a certain etiological relevance to Alzheimer’s disease (AD). In particular, herpes simplex virus (HSV) and varicella zoster virus (VZV) infections has been reported as risk factors for AD. The aim of this study was to determine whether or not AD-related biomarkers were changed in patients with HSV or VZV CNS infections.Methods: Nine patients with HSV infection of the CNS, eight patients with VZV complicated by CNS involvement, and eighteen age-matched controls were enrolled. Amyloid β (Aβ)1-42, Aβ1-40, total-tau (t-tau), tau phosphorylated at threonine 181 (p-tau), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (p-NfH), glial fibrillary acidic protein (GFAP), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in were measured in cerebrospinal fluid (CSF), and NfL in serum.Results: Compared with the control group, CSF Aβ1-42, Aβ1-40, and the Aβ1-42/ Aβ1-40 ratio were significantly decreased, and CSF t-tau, p-tau, sTREM2, and GFAP were significantly increased in the HSV and VZV combined group, in which biomarker changes were similar to those reported in AD. CSF NfL levels measured on admission were significantly correlated with the disease severity and a poor outcome after age adjustment. Serum NfL on admission was also associated with disease severity after age adjustment.Conclusions: The fact that the biomarker profile in patients with CNS HSV and VZV infections mimicked that in AD patients should be paid attention to as a potential confounding factor in CSF biomarker-based diagnosis of AD, and it suggests an etiological similarity between herpetic virus infection and AD. The CSF NfL concentration on admission may be useful as a predictive marker of severity and prognosis in patients with CNS HSV and VZV infections.

scholarly journals Optimal Combinations of AT(N) Biomarkers to Determine Longitudinal Cognition in the Alzheimer's Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Rong-Rong Lin ◽  
Yan-Yan Xue ◽  
Xiao-Yan Li ◽  
Yi-He Chen ◽  
Qing-Qing Tao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Thickness ◽  
Clinical Manifestations ◽  
Cognitive Status ◽  
Youden Index ◽  
Amyloid Pet ◽  
Cognitive Changes ◽  
Neurofilament Light ◽  
Tau Pet

Background: National Institute on Aging—Alzheimer's Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer's disease (AD) as a biological construct. However, the associations between different AT(N) combinations and cognitive progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Methods: A total of 341 participants were classified into cognitively unimpaired (CU; n = 200) and cognitively impaired (CI; n = 141) groups according to the clinical manifestations and neuropsychological tests. Cerebrospinal fluid (CSF) Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), hippocampal volume, temporal cortical thickness, [18F]fluorodeoxyglucose (FDG) PET, and plasma neurofilament light (NfL) were used as biomarkers for (N). Binary biomarkers were obtained from the Youden index and publicly available cutoffs. Prevalence of AT(N) categories was compared between different biomarkers within the group using related independent sample non-parametric test. The relationship between AT(N) combinations and 12-year longitudinal cognition was assessed using linear mixed-effects modeling.Results: Among the CU participants, A–T–(N)– was most common. More T+ were detected using p-tau than tau PET (p < 0.05), and more (N)+ were observed using fluid biomarkers (p < 0.001). A+T+(N)+ was more common in the CI group. Tau PET combined with cortical thickness best predicted cognitive changes in the CI group and MRI predicted changes in the CU group.Conclusions: These findings suggest that optimal AT(N) combinations to determine longitudinal cognition differ by cognitive status. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for future studies.

scholarly journals Optimal Combinations of Biomarkers to Determine AT(N) in the Alzheimer’s Disease 

2020 ◽  
Author(s):  
Rong-Rong Lin ◽  
Yan-Yan Xue ◽  
Xiao-Yan Li ◽  
Yi-He Chen ◽  
Qing-Qing Tao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Thickness ◽  
Clinical Stage ◽  
Youden Index ◽  
Amyloid Pet ◽  
Clinical Dementia Rating ◽  
Cognitive Changes ◽  
Neurofilament Light ◽  
Tau Pet

Abstract Background: National Institute on Aging—Alzheimer’s Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer’s disease (AD) as a biological construct. However, the associations between different AT(N) combinations and clinical stage and progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Methods: A total of 341 participants from ADNI cohort were classified into AT(N) groups, including 200 cognitively unimpaired (CU) participants and 141 cognitively impaired (CI) participants (101 mild cognitive impairment [MCI] and 40 Alzheimer’s disease [AD]). CSF Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), FDG-PET, hippocampal volume, temporal cortical thickness and plasma neurofilament light (NfL) were used as biomarkers for (N). Binarization of biomarkers was acquired from Youden index and public cutoffs. The relationship between different AT(N) biomarkers combinations and cognitive changes (longitudinal Mini-Mental State Examination scores and Clinical Dementia Rating Sum of Boxes) was examined using linear mixed modeling and coefficient of variation.Results: Among CU participants, A−T−(N)− variants were most common. More T+ cases were shown using p-tau than tau PET, and more N+ cases were shown using fluid biomarkers than neuroimaging. Among CI participants, A+T+(N)+ was more common. Tau PET combined with cortical thickness best predicted longitudinal cognitive decline in CI and MRI measurements in CU participants. Conclusion: These findings suggest that optimal combinations of biomarkers to determine AT(N) are differed by clinical stage. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for the future studies.

scholarly journals Diagnostic Fluid Biomarkers in Alzheimer’s Disease: Blood and Cerebrospinal Fluid

2021 ◽  
Author(s):  
Jung Eun Park ◽  
Tamil Iniyan Gunasekaran ◽  
Yeong Hee Cho ◽  
Seong-Min Choi ◽  
Min-Kyung Song ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Diagnosis ◽  
Disease Progression ◽  
Early Stage ◽  
Amyloid Β ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Preclinical Ad ◽  
T Tau

Abstract Background: Potential biomarkers for Alzheimer’s disease (AD) include amyloid β 1-42 (Aβ 1-42 ), t-Tau, p-Tau 181 , neurofilament light chain (NFL), and neuroimaging, but the feasibility of using these for the diagnosis and monitoring of AD has not been reported. Therefore, further development of these biomarkers is essential. Methods: We measured NFL and Aβ 1-42 concentrations in CSF and plasma samples from 136 participants and performed correlation analysis to evaluate the utility of these biomarkers for early diagnosis and monitoring of disease progression in AD spectrum. Results: With disease progression, concentrations of NFL increased, and those of Aβ 1-42 were decreases. The plasma and CSF values of NFL/Aβ 1-42 were strongly correlated ( r = 0.558). In addition, the plasma value of NFL/Aβ 1-42 was strong correlated with hippocampal volume/ICV ( r = 0.409). In the early stage of AD, the plasma_NFL/Aβ 1-42 was associated with higher diagnostic accuracy than were the individual biomarkers. Moreover, in preclinical AD, plasma_NFL/Aβ 1-42 changed more rapidly than did either the t-Tau or the p-Tau 181 values measured in the CSF. Conclusions: Taken together, our findings highlight the utility of plasma_NFL/Aβ 1-42 as a biomarker for early diagnosis and monitoring of disease progression in AD spectrum.

scholarly journals Performance of Plasma Amyloid β, Total Tau, and Neurofilament Light Chain in the Identification of Probable Alzheimer's Disease in South China

2021 ◽  
Vol 13 ◽  
Author(s):  
Bin Jiao ◽  
Hui Liu ◽  
Lina Guo ◽  
Xinxin Liao ◽  
Yafang Zhou ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Correlation Analysis ◽  
Light Chain ◽  
Amyloid Β ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Plasma Biomarkers ◽  
Total Tau ◽  
T Tau

Background: Alzheimer's disease (AD) is the most common type of dementia and has no effective treatment to date. It is essential to develop a minimally invasive blood-based biomarker as a tool for screening the general population, but the efficacy remains controversial. This cross-sectional study aimed to evaluate the ability of plasma biomarkers, including amyloid β (Aβ), total tau (t-tau), and neurofilament light chain (NfL), to detect probable AD in the South Chinese population.Methods: A total of 277 patients with a clinical diagnosis of probable AD and 153 healthy controls with normal cognitive function (CN) were enrolled in this study. The levels of plasma Aβ42, Aβ40, t-tau, and NfL were detected using ultra-sensitive immune-based assays (SIMOA). Lumbar puncture was conducted in 89 patients with AD to detect Aβ42, Aβ40, t-tau, and phosphorylated (p)-tau levels in the cerebrospinal fluid (CSF) and to evaluate the consistency between plasma and CSF biomarkers through correlation analysis. Finally, the diagnostic value of plasma biomarkers was further assessed by constructing a receiver operating characteristic (ROC) curve.Results: After adjusting for age, sex, and the apolipoprotein E (APOE) alleles, compared to the CN group, the plasma t-tau, and NfL were significantly increased in the AD group (p < 0.01, Bonferroni correction). Correlation analysis showed that only the plasma t-tau level was positively correlated with the CSF t-tau levels (r = 0.319, p = 0.003). The diagnostic model combining plasma t-tau and NfL levels, and age, sex, and APOE alleles, showed the best performance for the identification of probable AD [area under the curve (AUC) = 0.89, sensitivity = 82.31%, specificity = 83.66%].Conclusion: Blood biomarkers can effectively distinguish patients with probable AD from controls and may be a non-invasive and efficient method for AD pre-screening.

scholarly journals Diagnostic Fluid Biomarkers in Alzheimer’s Disease: Blood and Cerebrospinal Fluid

2021 ◽  
Author(s):  
Jung Eun Park ◽  
Tamil Iniyan Gunasekaran ◽  
Yeong Hee Cho ◽  
Seong-Min Choi ◽  
Min-Kyung Song ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Diagnosis ◽  
Disease Progression ◽  
Early Stage ◽  
Amyloid Β ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Preclinical Ad ◽  
T Tau

Abstract Background: Potential biomarkers for Alzheimer’s disease (AD) include amyloid β1-42 (Aβ1-42), t-Tau, p-Tau 181 , neurofilament light chain (NFL), and neuroimaging, but the feasibility of using these for the diagnosis and monitoring of AD has not been reported. Therefore, further development of these biomarkers is essential.Methods: We measured NFL and Aβ1-42 concentrations in CSF and plasma samples from 136 participants and performed correlation analysis to evaluate the utility of these biomarkers for early diagnosis and monitoring of disease progression in AD spectrum.Results: With disease progression, concentrations of NFL increased, and those of Aβ1-42 were decreases. The plasma and CSF values of NFL/Aβ1-42 were strongly correlated (r = 0.558). In addition, the plasma value of NFL/Aβ1-42 was strong correlated with hippocampal volume/ICV ( r = 0.409). In the early stage of AD, the plasma_NFL/Aβ1-42 was associated with higher diagnostic accuracy than were the individual biomarkers. Moreover, in preclinical AD, plasma_NFL/Aβ1-42 changed more rapidly than did either the t-Tau or the p-Tau181 values measured in the CSF.Conclusions: Taken together, our findings highlight the utility of plasma_NFL/Aβ1-42 as a biomarker for early diagnosis and monitoring of disease progression in AD spectrum.

scholarly journals Plasma Neurofilament Light and Future Declines in Cognition and Function in Alzheimer’s Disease in the FIT-AD Trial

2021 ◽  
pp. 1-11
Author(s):  
Danni Li ◽  
Lin Zhang ◽  
Nathaniel W. Nelson ◽  
Michelle M. Mielke ◽  
Fang Yu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Daily Living ◽  
Short Term ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Linear Mixed Effects ◽  
Future Studies ◽  
Rate Of Decline ◽  
And Function

Background: Utilities of blood-based biomarkers in Alzheimer’s disease (AD) clinical trials remain unknown. Objective: To evaluate the ability of plasma neurofilament light chain (NfL) to predict future declines in cognition and activities of daily living (ADL) outcomes in 26 older adults with mild-to-moderate AD dementia from the FIT-AD Trial. Methods: Plasma NfL was measured at baseline and 3 and 6 months. Cognition and ADL were assessed using the AD Assessment Scale-Cognition (ADAS-Cog) and AD Uniform Dataset Instruments and Disability Assessment for Dementia (DAD), respectively, at baseline, 3, 6, 9, and 12 months. Linear mixed effects models were used to examine the associations between baseline or change in plasma NfL and changes in outcomes. Results: Higher baseline plasma NfL was associated with greater rate of decline in ADAS-Cog from baseline to 6 months (standardized estimate of 0.00462, p = 0.02853) and in ADL from baseline to 12 months (standardized estimate of –0.00284, p = 0.03338). Greater increase in plasma NfL in short term from baseline to 3 months was associated with greater rate of decline in memory and ADL from 3 to 6 months (standardized estimate of –0.04638 [0.003], p = 0.01635; standardized estimate of –0.03818, p = 0.0435) and greater rate of decline in ADL from 3 to 12 month (standardized estimate of –0.01492, p = 0.01082). Conclusion: This study demonstrated that plasma NfL might have the potential to predict cognitive and function decline up to 12 months. However, future studies with bigger sample sizes need to confirm the findings.

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