Association between cerebrospinal fluid and plasma neurodegeneration biomarkers with brain atrophy in Alzheimer's disease.

The aggregation and deposition of amyloid-β (Aβ) peptides into plaques is an early event in Alzheimer's disease (AD), which is followed by different aspects of neurodegeneration that can be measured in the cerebrospinal fluid (CSF) or plasma using neurofilament light (NFL), neurogranin (Ng), total Tau (T-Tau), and phosphorylated tau (P-Tau) levels. The relationship between these biomarkers and regional brain atrophy across the different stages of AD remains largely unexplored. In this study, we assessed whether NFL, Ng, T-Tau, and P-Tau levels in CSF and NFL in plasma are associated with cortical thinning and subcortical volume loss in cognitively normal, mild cognitive impairment, and AD subjects with and without Aβ pathology. Our main findings showed that CSF NFL levels were associated with brain atrophy in all groups, but plasma NFL only correlated with atrophy in symptomatic cases. In contrast, Ng was associated with regional brain atrophy only in individuals with Aβ pathology. Altogether, our main findings suggest that Ng is strongly associated with Aβ pathology, whereas NFL is more unspecific.

Pereira JB ，Westman E ，Hansson O ，Alzheimer's Disease Neuroimaging Initiative ... -  《-》

Association Between Longitudinal Plasma Neurofilament Light and Neurodegeneration in Patients With Alzheimer Disease.

Mattsson N ，Cullen NC ，Andreasson U ，Zetterberg H ，Blennow K ... -  《-》

Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum.

We investigated relations between amyloid-β (Aβ) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau). We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ- vs. Aβ+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition. Ng and T-tau distinguished between Aβ+ from Aβ- individuals in each clinical group, whereas NFL and YKL-40 were associated with Aβ+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aβ+ individuals. NFL was the best predictor of cognitive decline in Aβ+ individuals across the cognitive spectrum. Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.

Bos I ，Vos S ，Verhey F ，Scheltens P ，Teunissen C ，Engelborghs S ，Sleegers K ，Frisoni G ，Blin O ，Richardson JC ，Bordet R ，Tsolaki M ，Popp J ，Peyratout G ，Martinez-Lage P ，Tainta M ，Lleó A ，Johannsen P ，Freund-Levi Y ，Frölich L ，Vandenberghe R ，Westwood S ，Dobricic V ，Barkhof F ，Legido-Quigley C ，Bertram L ，Lovestone S ，Streffer J ，Andreasson U ，Blennow K ，Zetterberg H ，Visser PJ ... -  《-》

Cerebrospinal fluid tau, neurogranin, and neurofilament light in Alzheimer's disease.

Cerebrospinal fluid (CSF) tau (total tau, T-tau), neurofilament light (NFL), and neurogranin (Ng) are potential biomarkers for neurodegeneration in Alzheimer's disease (AD). It is unknown whether these biomarkers provide similar or complementary information in AD. We examined 93 patients with AD, 187 patients with mild cognitive impairment, and 109 controls. T-tau, Ng, and NFL were all predictors of AD diagnosis. Combinations improved the diagnostic accuracy (AUC 85.5% for T-tau, Ng, and NFL) compared to individual biomarkers (T-tau 80.8%; Ng 71.4%; NFL 77.7%). T-tau and Ng were highly correlated (ρ = 0.79, P < 0.001) and strongly associated with β-amyloid (Aβ) pathology, and with longitudinal deterioration in cognition and brain structure, primarily in people with Aβ pathology. NFL on the other hand was not associated with Aβ pathology and was associated with cognitive decline and brain atrophy independent of Aβ. T-tau, Ng, and NFL provide partly independent information about neuronal injury and may be combined to improve the diagnostic accuracy for AD. T-tau and Ng reflect Aβ-dependent neurodegeneration, while NFL reflects neurodegeneration independently of Aβ pathology.

Mattsson N ，Insel PS ，Palmqvist S ，Portelius E ，Zetterberg H ，Weiner M ，Blennow K ，Hansson O ，Alzheimer's Disease Neuroimaging Initiative ... -  《-》

Comparison of CSF neurofilament light chain, neurogranin, and tau to MRI markers.

We determined whether cerebrospinal fluid (CSF) neurofilament light (NfL), neurogranin (Ng), and total-tau (t-tau) differentially mapped to magnetic resonance imaging (MRI) measures of cortical thickness, microstructural integrity (corpus callosum and cingulum fractional anisotropy [FA]), and white matter hyperintensities (WMH). Analyses included 536 non-demented Mayo Clinic Study of Aging participants with CSF NfL, Ng, t-tau, amyloid beta (Aβ)42 and longitudinal MRI scans. Linear mixed models assessed longitudinal associations between CSF markers and MRI changes. Higher CSF NfL was associated with decreasing microstructural integrity and WMH. Higher t-tau was associated with decreasing temporal lobe and Alzheimer's disease (AD) meta region of interest (ROI) cortical thickness. There was no association between Ng and any MRI measure. CSF Aβ42 interacted with Ng for declines in temporal lobe and AD meta ROI cortical thickness and cingulum FA. CSF NfL predicts changes in white matter integrity, t-tau reflects non-specific changes in cortical thickness, and Ng reflects AD-specific synaptic and neuronal degeneration.

Mielke MM ，Przybelski SA ，Lesnick TG ，Kern S ，Zetterberg H ，Blennow K ，Knopman DS ，Graff-Radford J ，Petersen RC ，Jack CR Jr ，Vemuri P ... -  《-》