scholarly journals Plasma neurofilament light is associated with white matter damage in Alzheimer's disease

2020 ◽  
Author(s):  
Fardin Nabizadeh ◽  
Mohammad Balabandian ◽  
Mohammad Reza Rostami ◽  
Samuel Berchi Kankam ◽  
Fetemeh Ranjbaran ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Diffusion Tensor ◽  
Amyloid Β ◽  
Brain Regions ◽  
Csf Biomarkers ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Microstructural Changes

Abstract The most replicated blood biomarker for monitoring Alzheimer’s disease is neurofilament light (NFL). Recent evidence revealed that the plasma level of the NFL has a strong predictive value in cognitive decline and is elevated in AD patients. The Diffusion Tensor Imaging (DTI) is understood to reflect white matter disruption, neurodegeneration, and synaptic damage in AD. However, few investigations have been carried out on the association between plasma NFL and white matter microstructure integrity. We have investigated the cross-sectional associations of plasma NFL, CSF total tau, phosphorylated tau, and Amyloid β with white matter microstructural changes as measured by DTI in 92 mild cognitive impairment (MCI) participants. We investigated potential correlations of the DTI values of each region of the MNI atlas, with plasma NFL, separately using a partial correlation model controlled for the effect of age, sex, and APOE ε4 genotype. Our findings revealed a significant correlation between plasma and CSF biomarkers with altered white matter microstructural changes in widespread brain regions. Plasma NFL negatively correlates with FA and the positive correlation with RD, DA, and MD values in different regions. Our findings showed that plasma NFL is associated with white matter changes and AD-related features, including atrophy and hypometabolism. Plasma NFL promises to be an early biomarker of microstructural changes in MCI and MCI progression to AD.

scholarly journals Plasma neurofilament light and cerebrospinal fluid biomarkers are associated with white matter damage in Alzheimer's disease

2020 ◽  
Author(s):  
Fardin Nabizadeh ◽  
Mohammad Balabandian ◽  
Mohammad Reza Rostami ◽  
Samuel Berchi Kankam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Diffusion Tensor ◽  
Brain Regions ◽  
Csf Biomarkers ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Microstructural Changes ◽  
Cerebrospinal Fluid Biomarkers

Abstract The most replicated blood biomarker for monitoring Alzheimer’s disease is neurofilament light (NFL). Recent evidence revealed that the plasma level of the NFL has a strong predictive value in cognitive decline and is elevated in AD patients. The Diffusion Tensor Imaging (DTI) is understood to reflect white matter disruption, neurodegeneration largely, and synaptic damage in AD. However, there is no investigation of the association between plasma NFL and white matter microstructure integrity. we have investigated the cross-sectional associations of plasma NFL, CSF tau, p tau, and Aβ with white matter microstructural changes as measured by DTI in 92 mild cognitive impairment (MCI) participants. We investigated potential correlations of the DTI values of each region of the MNI atlas, with plasma NFL, CSF total tau, CSF p tau, and as well as CSF Aβ, separately using a partial correlation model controlled for the effect of age, sex and APOE ε4 genotype. Our findings revealed a significant correlation between plasma and CSF biomarkers with altered white matter microstructural changes in widespread brain regions. Plasma NFL has a negative correlation with FA and positive correlation with RD, AD, and MD values in different regions. Plasma NFL promises to be an early biomarker of microstructural changes in MCI and for MCI progression to AD.

scholarly journals 18F-florbetapir PET as a marker of myelin integrity across the Alzheimer’s disease spectrum

2021 ◽  
Author(s):  
Alexis Moscoso ◽  
Jesus Silva-Rodriguez ◽  
Jose Manuel Aldrey ◽  
Julia Cortes ◽  
Juan Manuel Pias-Peleteiro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Diffusion Tensor ◽  
Amyloid Β ◽  
Cerebral White Matter ◽  
Csf Biomarkers ◽  
Cognitively Impaired ◽  
Disease Course ◽  
Clinical Progression

Abstract Purpose: Recent evidence suggest that PET imaging with amyloid-β (Aβ) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer’s disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aβ PET, contributes to AD progression remains unexplored.Methods: Participants with concurrent 18F-florbetapir (FBP), MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aβ-positive cognitively impaired, and 207 Aβ-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n=195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and CSF biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline. Results: In AD-continuum individuals, FBP retention in NAWM was 1) higher compared to WMH regions, 2) associated with DTI-based measures of WM integrity, and 3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aβ, and WMH burden. Most of these associations were also observed in Aβ-negative cognitively impaired individuals.Conclusion: These results support the hypothesis that FBP retention in the WM is myelin-dependent. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.

scholarly journals 18F-florbetapir PET as a marker of myelin integrity across the Alzheimer’s disease spectrum

2021 ◽  
Author(s):  
Alexis Moscoso ◽  
Jesús Silva-Rodríguez ◽  
Jose Manuel Aldrey ◽  
Julia Cortés ◽  
Juan Manuel Pías-Peleteiro ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Diffusion Tensor ◽  
Amyloid Β ◽  
Cerebral White Matter ◽  
Csf Biomarkers ◽  
Cognitively Impaired ◽  
Disease Course ◽  
Clinical Progression

Abstract Purpose Recent evidence suggests that PET imaging with amyloid-β (Aβ) tracers can be used to assess myelin integrity in cerebral white matter (WM). Alzheimer’s disease (AD) is characterized by myelin changes that are believed to occur early in the disease course. Nevertheless, the extent to which demyelination, as measured with Aβ PET, contributes to AD progression remains unexplored. Methods Participants with concurrent 18F-florbetapir (FBP) PET, MRI, and cerebrospinal fluid (CSF) examinations were included (241 cognitively normal, 347 Aβ-positive cognitively impaired, and 207 Aβ-negative cognitively impaired subjects). A subset of these participants had also available diffusion tensor imaging (DTI) images (n = 195). We investigated cross-sectional associations of FBP retention in the white matter (WM) with MRI-based markers of WM degeneration, AD clinical progression, and fluid biomarkers. In longitudinal analyses, we used linear mixed models to assess whether FBP retention in normal-appearing WM (NAWM) predicted progression of WM hyperintensity (WMH) burden and clinical decline. Results In AD-continuum individuals, FBP retention in NAWM was (1) higher compared with WMH regions, (2) associated with DTI-based measures of WM integrity, and (3) associated with longitudinal progression of WMH burden. FBP uptake in WM decreased across the AD continuum and with increasingly abnormal CSF biomarkers of AD. Furthermore, FBP retention in the WM was associated with large-calibre axon degeneration as reflected by abnormal plasma neurofilament light chain levels. Low FBP uptake in NAWM predicted clinical decline in preclinical and prodromal AD, independent of demographics, global cortical Aβ, and WMH burden. Most of these associations were also observed in Aβ-negative cognitively impaired individuals. Conclusion These results support the hypothesis that FBP retention in the WM is myelin-related. Demyelination levels progressed across the AD continuum and were associated with clinical progression at early stages, suggesting that this pathologic process might be a relevant degenerative feature in the disease course.

scholarly journals Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives

2021 ◽  
Vol 11 (2) ◽  
pp. 215
Author(s):  
Donovan A. McGrowder ◽  
Fabian Miller ◽  
Kurt Vaz ◽  
Chukwuemeka Nwokocha ◽  
Cameil Wilson-Clarke ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Late Onset ◽  
Amyloid Β ◽  
Current Evidence ◽  
Csf Biomarkers ◽  
Diagnostic Efficacy ◽  
Neurofilament Light ◽  
New Biomarkers

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ42), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented.

scholarly journals Untangling the association of amyloid-β and tau with synaptic and axonal loss in Alzheimer’s disease

Brain ◽  
2020 ◽  
Author(s):  
Joana B Pereira ◽  
Shorena Janelidze ◽  
Rik Ossenkoppele ◽  
Hlin Kvartsberg ◽  
Ann Brinkmalm ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Light Chain ◽  
Diffusion Tensor ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Dependent Manner ◽  
Tau Pathology ◽  
Neurofilament Light Chain ◽  
Neurofilament Light

Abstract It is currently unclear how amyloid-β and tau deposition are linked to changes in synaptic function and axonal structure over the course of Alzheimer’s disease. Here, we assessed these relationships by measuring presynaptic (synaptosomal-associated protein 25, SNAP25; growth-associated protein 43, GAP43), postsynaptic (neurogranin, NRGN) and axonal (neurofilament light chain) markers in the CSF of individuals with varying levels of amyloid-β and tau pathology based on 18F-flutemetamol PET and 18F-flortaucipir PET. In addition, we explored the relationships between synaptic and axonal markers with cognition as well as functional and anatomical brain connectivity markers derived from resting-state functional MRI and diffusion tensor imaging. We found that the presynaptic and postsynaptic markers SNAP25, GAP43 and NRGN are elevated in early Alzheimer’s disease i.e. in amyloid-β-positive individuals without evidence of tau pathology. These markers were associated with greater amyloid-β pathology, worse memory and functional changes in the default mode network. In contrast, neurofilament light chain was abnormal in later disease stages, i.e. in individuals with both amyloid-β and tau pathology, and correlated with more tau and worse global cognition. Altogether, these findings support the hypothesis that amyloid-β and tau might have differential downstream effects on synaptic and axonal function in a stage-dependent manner, with amyloid-related synaptic changes occurring first, followed by tau-related axonal degeneration.

scholarly journals Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer’s Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study

2021 ◽  
Vol 10 (9) ◽  
pp. 1907
Author(s):  
James A. Hendrix ◽  
David C. Airey ◽  
Angela Britton ◽  
Anna D. Burke ◽  
George T. Capone ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Β ◽  
Neurofilament Light Chain ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Plasma Biomarkers ◽  
Show Evidence ◽  
Biomarker Data

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer’s disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.

scholarly journals Plasma P-tau181 levels reflects white matter microstructural changes across Alzheimer’s disease progression

2021 ◽  
Author(s):  
Fardin Nabizadeh ◽  
Seyed Behnamedin Jameie ◽  
Saghar Khani ◽  
Aida Rezaei ◽  
Fatemeh Ranjbaran ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Behavioral Problems ◽  
Structural Changes ◽  
Diffusion Tensor ◽  
Cognitive Impairments ◽  
Mean Diffusivity ◽  
Diagnostic Procedures ◽  
Microstructural Changes

Abstract Alzheimer’s Disease (AD) is characterized by cognitive impairments and memory difficulties that hinder daily activities and lead to personal and behavioral problems. Plasma hyperphosphorylated tau protein at threonine 181 (p-tau181), a blood-based biomarker, has recently emerged as a new tool with sufficient sensitivity for distinguishing AD patients from healthy people. We herein investigated the association of plasma P-tau181 and white matter (WM) microstructural changes in AD. We examined data from a large prospective cohort of elderly individuals participating in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) which covers a wide clinical spectrum from normal cognition to AD dementia with measurements of plasma P-tau181 and imaging findings at baseline. A subset of 41 patients with AD, 119 patients with mild cognitive impairments (MCI), and 43 healthy controls (HC) were included in the study, all of whom had baseline blood P-tau181 levels and had also undergone Diffusion Tensor Imaging (DTI). The analysis revealed that the plasma level of P-tau181 have positive correlation with changes in Mean Diffusivity (MD), Radial Diffusivity (RD), and Axial Diffusivity (AxD), but a negative with Fractional Anisotropy (FA) parameters in WM regions of all participants. There is also a significant association between WM microstructural changes in different regions and P-tau181 plasma measurements within each MCI, HC and AD group. In conclusion, our findings clarified that plasma P-tau181 levels are associated with changes in WM integrity in AD. P-tau181 could improve the accuracy of diagnostic procedures and support the application of blood-based biomarkers to diagnose WM neurodegeneration. Longitudinal clinical studies are also needed to demonstrate the efficacy of the P-tau181 biomarker and predict its role in structural changes.

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 < 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 < 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.

Comparison of Serum Triiodothyronine with Biomarkers for Alzheimer’s Disease Continuum in Euthyroid Subjects

2021 ◽  
pp. 1-10
Author(s):  
Feifei Ge ◽  
Lin Dong ◽  
Donglin Zhu ◽  
Xingjian Lin ◽  
Jingping Shi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Characteristic Curve ◽  
Amyloid Β ◽  
Diagnostic Value ◽  
Thyroid Stimulating Hormone ◽  
Csf Biomarkers ◽  
Free Triiodothyronine ◽  
Diagnostic Significance ◽  
Cross Sectional

Background: Accumulating studies have implicated thyroid dysfunction in the pathogenesis of Alzheimer’s disease (AD). Objective: This study aimed to explore the association between thyroid hormone (TH) levels and cerebrospinal fluid (CSF) biomarkers for AD continuum among euthyroid subjects. Methods: In all, 93 clinically euthyroid subjects with a cognitive decline were included in this prospective cross-sectional study and were divided into groups with abnormal AD biomarkers (belonging to the “Alzheimer’s continuum”; A+ patients) and those with “normal AD biomarkers” or “non-AD pathological changes” (A–patients), according to the ATN research framework classification for AD. A partial correlation analysis of serum thyroid-stimulating hormone (TSH) or TH levels with CSF biomarkers was conducted. The predictor for A+ patients was analyzed via binary logistic regressions. Finally, the diagnostic significance of individual biochemical predictors for A+ patients was estimated via receiver operating characteristic curve analysis. Results: Serum total triiodothyronine (TT3) and free triiodothyronine (FT3) levels were found to affect the levels of CSF amyloid-β (Aβ)42 and the ratios of Aβ 42/40. Further, FT3 was found to be a significant predictor for A+ via binary logistic regression modeling. Moreover, FT3 showed a high diagnostic value for A+ in euthyroid subjects. Conclusion: Even in a clinical euthyroid state, low serum FT3 and TT3 levels appear to be differentially associated with AD-specific CSF changes. These data indicate that serum FT3 is a strong candidate for differential diagnosis between AD continuum and non-AD dementia, which benefits the early diagnosis and effective management of preclinical and clinical AD patients.

scholarly journals White Matter Hyperintensities Are No Major Confounder for Alzheimer’s Disease Cerebrospinal Fluid Biomarkers

2021 ◽  
Vol 79 (1) ◽  
pp. 163-175
Author(s):  
Linda J.C. van Waalwijk van Doorn ◽  
Mohsen Ghafoorian ◽  
Esther M.C. van Leijsen ◽  
Jurgen A.H.R. Claassen ◽  
Andrea Arighi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
White Matter ◽  
White Matter Hyperintensities ◽  
Linear Regression Analysis ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Csf Biomarker ◽  
T Tau

Background: The cerebrospinal fluid (CSF) biomarkers amyloid-β 1–42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) are increasingly used to assist in the clinical diagnosis of Alzheimer’s disease (AD). However, CSF biomarker levels can be affected by confounding factors. Objective: To investigate the association of white matter hyperintensities (WMHs) present in the brain with AD CSF biomarker levels. Methods: We included CSF biomarker and magnetic resonance imaging (MRI) data of 172 subjects (52 controls, 72 mild cognitive impairment (MCI), and 48 AD patients) from 9 European Memory Clinics. A computer aided detection system for standardized automated segmentation of WMHs was used on MRI scans to determine WMH volumes. Association of WMH volume with AD CSF biomarkers was determined using linear regression analysis. Results: A small, negative association of CSF Aβ42, but not p-tau and t-tau, levels with WMH volume was observed in the AD (r2 = 0.084, p = 0.046), but not the MCI and control groups, which was slightly increased when including the distance of WMHs to the ventricles in the analysis (r2 = 0.105, p = 0.025). Three global patterns of WMH distribution, either with 1) a low, 2) a peak close to the ventricles, or 3) a high, broadly-distributed WMH volume could be observed in brains of subjects in each diagnostic group. Conclusion: Despite an association of WMH volume with CSF Aβ42 levels in AD patients, the occurrence of WMHs is not accompanied by excess release of cellular proteins in the CSF, suggesting that WMHs are no major confounder for AD CSF biomarker assessment.

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