Comparison of plasma neurofilament light and total tau as neurodegeneration markers: associations with cognitive and neuroimaging outcomes

Abstract Background Total tau protein (T-Tau) and neurofilament light chain (NfL) have emerged as candidate plasma biomarkers of neurodegeneration, but studies have not compared how these biomarkers cross-sectionally or longitudinally associate with cognitive and neuroimaging measures. We therefore compared plasma T-Tau and NfL as cross-sectional and longitudinal markers of (1) global and domain-specific cognitive decline and (2) neuroimaging markers of cortical thickness, hippocampal volume, white matter integrity, and white matter hyperintensity volume. Methods We included 995 participants without dementia who were enrolled in the Mayo Clinic Study of Aging cohort. All had concurrent plasma NfL and T-tau, cognitive status, and neuroimaging data. Follow-up was repeated approximately every 15 months for a median of 6.2 years. Plasma NfL and T-tau were measured on the Simoa-HD1 Platform. Linear mixed effects models adjusted for age, sex, and education examined associations between baseline z-scored plasma NfL or T-tau and cognitive or neuroimaging outcomes. Analyses were replicated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) among 387 participants without dementia followed for a median of 3.0 years. Results At baseline, plasma NfL was more strongly associated with all cognitive and neuroimaging outcomes. The combination of having both elevated NfL and T-tau at baseline, compared to elevated levels of either alone, was more strongly associated at cross-section with worse global cognition and memory, and with neuroimaging measures including temporal cortex thickness and increased number of infarcts. In longitudinal analyses, baseline plasma T-tau did not add to the prognostic value of baseline plasma NfL. Results using ADNI data were similar. Conclusions Our results indicate plasma NfL had better utility as a prognostic marker of cognitive decline and neuroimaging changes. Plasma T-tau added cross-sectional value to NfL in specific contexts. Trial registration Not applicable

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Plasma neurofilament light chain is associated with cognitive decline in non-dementia older adults

Scientific Reports ◽

10.1038/s41598-021-91038-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lingxiao He ◽

John E. Morley ◽

Geetika Aggarwal ◽

Andrew D. Nguyen ◽

Bruno Vellas ◽

...

Keyword(s):

Older Adults ◽

Cognitive Decline ◽

Light Chain ◽

Cognitive Functions ◽

Linear Models ◽

Cognitive Status ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

State Examination

AbstractNeurofilament light chain (NfL) has been associated with cognitive status in multiple neurodegenerative conditions. Studies about plasma NfL and cognitive decline in older adults are still limited. 504 older adults (median age 75 years) who expressed memory complaints were selected from the Multidomain Alzheimer’s Preventive Trial (MAPT) and were classified as normal cognition (NC) or mild cognitive impairment (MCI). Cognitive functions were measured as mini mental state examination (MMSE) and composite cognitive score (CCS) over a 4-year period. Plasma NfL was measured at the first or the second year of the MAPT. Mixed-effects linear models were performed to evaluate cross-sectional and longitudinal associations. In the whole population, higher plasma NfL was cross-sectionally associated with lower cognitive functions (MMSE: β = − 0.007, 95% CI [− 0.013, − 0.001]; CCS: β = − 0.003, 95% CI [− 0.006, − 0.001]). In adults with MCI, but not NC, higher plasma NfL was associated with lower CCS at the cross-sectional level (β = − 0.003, 95% CI [− 0.005, − 0.0002]). The upper quartile NfL group further demonstrated more over time decline in CCS (β = − 0.07, 95% CI [− 0.12, − 0.01]) under the MCI status. Plasma NfL can be a promising biomarker of progressive cognition decline in older adults with MCI.

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Neurofilament light chain in the vitreous humor of the eye

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00677-4 ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Manju L. Subramanian ◽

Viha Vig ◽

Jaeyoon Chung ◽

Marissa G. Fiorello ◽

Weiming Xia ◽

...

Keyword(s):

Sex Education ◽

Inflammatory Cytokines ◽

Amyloid Beta ◽

Light Chain ◽

Systemic Disease ◽

Vitreous Humor ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

T Tau

Abstract Background Neurofilament light chain (NfL) is a promising biomarker of neurodegeneration in the cerebrospinal fluid and blood. This study investigated the presence of NfL in the vitreous humor and its associations with amyloid beta, tau, inflammatory cytokines and vascular proteins, apolipoprotein E (APOE) genotypes, Mini-Mental State Examination (MMSE) scores, systemic disease, and ophthalmic diseases. Methods This is a single-site, prospective, cross-sectional cohort study. Undiluted vitreous fluid (0.5–1.0 mL) was aspirated during vitrectomy, and whole blood was drawn for APOE genotyping. NfL, amyloid beta (Aβ), total Tau (t-Tau), phosphorylated Tau (p-Tau181), inflammatory cytokines, chemokines, and vascular proteins in the vitreous were quantitatively measured by immunoassay. The main outcome measures were the detection of NfL levels in the vitreous humor and its associations with the aforementioned proteins. Linear regression was used to test the associations of NfL with other proteins, APOE genotypes, MMSE scores, and ophthalmic and systemic diseases after adjustment for age, sex, education level, and other eye diseases. Results NfL was detected in all 77 vitreous samples. NfL was not found to be associated with ophthalmic conditions, APOE genotypes, MMSE scores, or systemic disease (p > 0.05). NfL levels were positively associated with increased vitreous levels of Aβ40 (p = 7.7 × 10−5), Aβ42 (p = 2.8 × 10−4), and t-tau (p = 5.5 × 10−7), but not with p-tau181 (p = 0.53). NfL also had significant associations with inflammatory cytokines such as interleukin-15 (IL-15, p = 5.3 × 10−4), IL-16 (p = 2.2 × 10−4), monocyte chemoattractant protein-1 (MCP1, p = 4.1 × 10−4), and vascular proteins such as vascular endothelial growth factor receptor-1 (VEGFR1, p = 2.9 × 10−6), Vegf-C (p = 8.6 × 10−6), vascular cell adhesion molecule-1 (VCAM-1, p = 5.0 × 10−4), Tie-2 (p = 6.3 × 10−4), and intracellular adhesion molecular-1 (ICAM-1, p = 1.6 × 10−4). Conclusion NfL is detectable in the vitreous humor of the eye and significantly associated with amyloid beta, t-tau, and select inflammatory and vascular proteins in the vitreous. Additionally, NfL was not associated with patients’ clinical eye condition. Our results serve as a foundation for further investigation of NfL in the ocular fluids to inform us about the potential utility of its presence in the eye.

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CSF neurofilament light concentration is increased in presymptomatic CHMP2B mutation carriers

Neurology ◽

10.1212/wnl.0000000000004799 ◽

2017 ◽

Vol 90 (2) ◽

pp. e157-e163 ◽

Cited By ~ 6

Author(s):

Nina Rostgaard ◽

Peter Roos ◽

Erik Portelius ◽

Kaj Blennow ◽

Henrik Zetterberg ◽

...

Keyword(s):

Continuous Process ◽

Csf Biomarkers ◽

Neurofilament Light Chain ◽

Cross Sectional ◽

Neurofilament Light ◽

Preclinical Phase ◽

Mutation Carriers ◽

Amyloid Aβ ◽

Multiplexed Immunoassay ◽

T Tau

ObjectiveA rare cause of familial frontotemporal dementia (FTD) is a mutation in the CHMP2B gene on chromosome 3 (FTD-3), described in a Danish family. Here we examine whether CSF biomarkers change in the preclinical phase of the disease.MethodsIn this cross-sectional explorative study, we analyzed CSF samples from 16 mutation carriers and 14 noncarriers from the Danish FTD-3 family. CSF biomarkers included total tau (t-tau) and neurofilament light chain (NfL) as a marker for neurodegeneration, phosphorylated tau (p-tau) as a marker for tau pathology, β-amyloid (Aβ) 38, 40, and 42 (Aβ38, Aβ40, and Aβ42) to monitor Aβ metabolism, and YKL-40 as a marker of neuroinflammation. Aβ isoform concentrations were measured using a multiplexed immunoassay; t-tau, p-tau, NfL, and YKL-40 concentrations were measured using sandwich ELISAs.ResultsCSF NfL concentration was significantly increased in mutation carriers vs noncarriers. Further, CSF NfL concentration was significantly higher in symptomatic mutation carriers compared to presymptomatic carriers, and also significantly higher in presymptomatic carriers compared to noncarriers. No differences in t-tau and p-tau and YKL-40 concentrations between controls and mutation carriers were observed. CSF concentrations of the Aβ peptides Aβ38 and Aβ40 but not Aβ42 were significantly lower in mutation carriers compared to noncarriers.ConclusionsIncreased NfL levels in presymptomatic individuals and in symptomatic patients with FTD-3 indicate a continuous process of neurodegeneration from the presymptomatic to symptomatic state. Although not specific for FTD-3 pathology, our data suggest that CSF NfL could serve as a valuable biomarker to detect onset of neurodegeneration in FTD-3 mutation carriers.

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

10.21203/rs.3.rs-88939/v1 ◽

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.

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Human anterolateral entorhinal cortex volumes are associated with preclinical cognitive decline

10.1101/080374 ◽

2016 ◽

Cited By ~ 1

Author(s):

RK Olsen ◽

L-K Yeung ◽

A Noly-Gandon ◽

MC D’Angelo ◽

A Kacollja ◽

...

Keyword(s):

Older Adults ◽

White Matter ◽

Cognitive Decline ◽

Entorhinal Cortex ◽

Medial Temporal Lobe ◽

Cognitive Status ◽

Community Dwelling ◽

White Matter Hyperintensity ◽

Whole Brain ◽

Community Dwelling Older Adults

AbstractWe investigated whether older adults without subjective memory complaints, but who present with cognitive decline in the laboratory, demonstrate atrophy in medial temporal lobe (MTL) subregions associated with Alzheimer's disease. Forty community-dwelling older adults were categorized based on Montreal Cognitive Assessment (MoCA) performance. Total grey/white matter, cerebrospinal fluid, and white matter hyperintensity load were quantified from whole-brain T1-weighted and FLAIR magnetic resonance imaging scans, while hippocampal subfields and MTL cortical subregion volumes (CA1, dentate gyrus/CA2/3, subiculum, anterolateral and posteromedial entorhinal, perirhinal, and parahippocampal cortices) were quantified using high-resolution T2-weighted scans. Cognitive status was evaluated using standard neuropsychological assessments. No significant differences were found in the whole-brain measures. However, MTL volumetry revealed that anterolateral entorhinal cortex (alERC) volume -- the same region in which Alzheimer's pathology originates -- was strongly associated with MoCA performance. This is the first study to demonstrate that alERC volume is related to cognitive decline in preclinical, community-dwelling older adults.

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Plasma Aβ42 and Total Tau Predict Cognitive Decline in Amnestic Mild Cognitive Impairment

Scientific Reports ◽

10.1038/s41598-019-50315-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Ting-Bin Chen ◽

Yi-Jung Lee ◽

Szu-Ying Lin ◽

Jun-Peng Chen ◽

Chaur-Jong Hu ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Decline ◽

Predictive Value ◽

Cognitive Status ◽

Amnestic Mild Cognitive Impairment ◽

Total Tau ◽

Amnestic Mci ◽

T Tau

Abstract Levels of amyloid-β (Aβ) and tau peptides in brain have been associated with Alzheimer disease (AD). The current study investigated the abilities of plasma Aβ42 and total-tau (t-tau) levels in predicting cognitive decline in subjects with amnestic mild cognitive impairment (MCI). Plasma Aβ42 and t-tau levels were quantified in 22 participants with amnestic MCI through immunomagnetic reduction (IMR) assay at baseline. The cognitive performance of participants was measured through neuropsychological tests at baseline and annual follow-up (average follow-up period of 1.5 years). The predictive value of plasma Aβ42 and t-tau for cognitive status was evaluated. We found that higher levels of Aβ42 and t-tau are associated with lower episodic verbal memory performance at baseline and cognitive decline over the course of follow-up. While Aβ42 or t-tau alone had moderate-to-high discriminatory value in the identification of future cognitive decline, the product of Aβ42 and t-tau offered greater differential value. These preliminary results might suggest that high levels of plasma Aβ42 and t-tau in amnestic MCI are associated with later cognitive decline. A further replication with a larger sample over a longer time period to validate and determine their long-term predictive value is warranted.

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eGFR and deep white matter hyperintensity as predictors of cognitive decline long after carotid endarterectomy

Scientific Reports ◽

10.1038/s41598-019-54459-6 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Akira Nakamizo ◽

Toshiyuki Amano ◽

Takahiro Kuwashiro ◽

Masahiro Yasaka ◽

Yasushi Okada

Keyword(s):

Cognitive Impairment ◽

Cognitive Function ◽

White Matter ◽

Cognitive Decline ◽

Carotid Endarterectomy ◽

Area Under The Curve ◽

Cognitive Status ◽

White Matter Hyperintensity ◽

Characteristic Analysis ◽

Severe Cognitive Impairment

AbstractChronic kidney disease and white matter hyperintensity (WMH) are associated with cognitive decline. The aim of this study was to assess the correlations between estimated glomerular filtration rate (eGFR) or WMH and cognitive function in patients who have undergone carotid endarterectomy (CEA). Cognitive functions were investigated using the Neurobehavioral Cognitive Status Examination (Cognistat) in 83 patients who had undergone CEA. The eGFR at 5 years prior to examination was significantly associated with severe cognitive impairment (odds ratio, 0.89 per 1-mL/min/1.73 m2 increase, 95% confidence interval 0.82–0.97, p = 0.0004). Receiver operating characteristic analysis revealed that a cutoff eGFR of 46.8 mL/min/1.73 m2 at 5 years prior to examination offered the most reliable predictor of severe cognitive impairment (sensitivity 88.9%, specificity 76.5%, area under the curve 0.848). The eGFR at 5 years prior to examination showed a significant linear association with total Cognistat score (r2 = 0.11035, p = 0.0032) compared to eGFR at 3 years prior to examination (r2 = 0.06455, p = 0.0230) or at examination (r2 = 0.0210, p = 0.0210). Spearman’s correlation coefficient revealed that orientation, comprehension, repetition, construction, memory, and similarity correlated with eGFR at 5 years prior to examination. Conversely, Fazekas grade for deep WMH at examination was associated with total Cognistat score (p = 0.0016), unlike that at 3 years (p = 0.0100) or 5 years prior to examination (p = 0.0172). While eGFR correlates with future cognitive function, deep WMH associates with present cognitive function in patients who have undergone CEA.

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Magnetic Resonance Imaging-Visible Perivascular Spaces in the Basal Ganglia Are Associated With the Diabetic Retinopathy Stage and Cognitive Decline in Patients With Type 2 Diabetes

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.666495 ◽

2021 ◽

Vol 13 ◽

Author(s):

Eun Young Choi ◽

Yae Won Park ◽

Minyoung Lee ◽

Min Kim ◽

Christopher Seungkyu Lee ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Basal Ganglia ◽

Cognitive Decline ◽

Small Vessel Disease ◽

Cognitive Status ◽

White Matter Hyperintensity ◽

Imaging Biomarkers ◽

Diabetic Patients ◽

Perivascular Spaces ◽

Cross Sectional

Purpose: The aim of this study was to evaluate whether perivascular space (PVS) severity and retinal ganglion cell layer (GCL) thickness differed based on the stage of diabetic retinopathy (DR) and the cognitive status in patients with DR.Methods: A total of 81 patients with DR (51 in the non-proliferative group and 30 in the proliferative group) were included in this retrospective, cross-sectional study. PVS severity was assessed in the basal ganglia (BG) and centrum semiovale using MRI. The total cerebral small vessel disease (SVD) score was determined based on the numbers of lacunes and microbleeds and the severity of white matter hyperintensity. Optical coherence tomography was used to measure foveal and perifoveal GCL thicknesses. Cerebral SVD markers and cognitive function were compared between the groups, and correlations between the BG-PVS severity and the Mini-Mental Status Examination (MMSE) scores and GCL parameters were evaluated.Results: Patients with proliferative DR had higher BG-PVS severity (P = 0.012), higher total cerebral SVD scores (P = 0.035), reduced GCL thicknesses in the inferior (P = 0.027), superior (P = 0.046), and temporal (P = 0.038) subfields compared to patients with non-proliferative DR. In addition, the BG-PVS severity was negatively correlated with the MMSE score (P = 0.007), and the GCL thickness was negatively correlated with the BG-PVS severity (P-values < 0.05 for inferior, superior, and temporal subfields).Conclusion: BG-PVS severity and retinal GCL thickness may represent novel imaging biomarkers reflecting the stage of DR and cognitive decline in diabetic patients. Furthermore, these results suggest a possible link between cerebral and retinal neurodegeneration at the clinical level.

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Cognitively Normal APOE ε4 Carriers Have Specific Elevation of CSF SNAP-25

10.21203/rs.3.rs-122858/v1 ◽

2020 ◽

Author(s):

Omar Hameed Butt ◽

Justin M Long ◽

Rachel L. Henson ◽

Elizabeth Herries ◽

Courtney L. Sutphen ◽

...

Keyword(s):

Alzheimer Disease ◽

Genetic Risk ◽

Carrier Status ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Cognitively Normal ◽

Disease Research ◽

Total Tau ◽

T Tau ◽

Phosphorylated Tau 181

Abstract Background: Cerebrospinal fluid (CSF) synaptosomal-associated protein 25 (SNAP-25) and neurogranin are recently described biomarkers for synaptic integrity that are known to be elevated in the CSF of symptomatic Alzheimer disease (AD). Their relationship with Apolipoprotein E (APOE) ε4 carrier status, the major genetic risk factor for AD, remains unclear.Methods: In this study, CSF SNAP-25 and neurogranin were compared in cognitively normal APOE ε4 carriers and non-carriers (n=274, mean age 65.0 ± 9.0 years, 39% APOE ε4 carriers, 58% female) enrolled at the Knight Alzheimer Disease Research Center, and in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.Results: SNAP-25, a biomarker of pre-synaptic integrity, was specifically elevated in APOE ε4 carriers versus non-carriers (5.95 ± 1.72 pg/ml, 4.44 ± 1.40 pg/ml, p <0.0001), even after adjusting for age, sex, years of education, and amyloid status (p <0.0001). In contrast, CSF neurogranin, a biomarker of post-synaptic integrity, did not vary by APOE ε4 status. Further, CSF total tau (t-tau), phosphorylated-tau-181 (ptau181), and neurofilament light chain (NfL) also did not vary by APOE ε4 status. Similar results were observed in the ADNI cohort. Conclusion: Our findings suggest APOE ε4 carriers have both amyloid-related and amyloid-independent presynaptic disruption as reflected by elevated CSF SNAP-25 levels. In contrast, post-synaptic disruption as reflected by elevations in CSF neurogranin is related to amyloid status.

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

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.749649 ◽

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.

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