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 ... -  《-》

Contribution of CSF biomarkers to early-onset Alzheimer's disease and frontotemporal dementia neuroimaging signatures.

Prior studies have described distinct patterns of brain gray matter and white matter alterations in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), as well as differences in their cerebrospinal fluid (CSF) biomarkers profiles. We aim to investigate the relationship between early-onset AD (EOAD) and FTLD structural alterations and CSF biomarker levels. We included 138 subjects (64 EOAD, 26 FTLD, and 48 controls), all of them with a 3T MRI brain scan and CSF biomarkers available (the 42 amino acid-long form of the amyloid-beta protein [Aβ42], total-tau protein [T-tau], neurofilament light chain [NfL], neurogranin [Ng], and 14-3-3 levels). We used FreeSurfer and FSL to obtain cortical thickness (CTh) and fraction anisotropy (FA) maps. We studied group differences in CTh and FA and described the "AD signature" and "FTLD signature." We tested multiple regression models to find which CSF-biomarkers better explained each disease neuroimaging signature. CTh and FA maps corresponding to the AD and FTLD signatures were in accordance with previous literature. Multiple regression analyses showed that the biomarkers that better explained CTh values within the AD signature were Aβ and 14-3-3; whereas NfL and 14-3-3 levels explained CTh values within the FTLD signature. Similarly, NfL levels explained FA values in the FTLD signature. Ng levels were not predictive in any of the models. Biochemical markers contribute differently to structural (CTh and FA) changes typical of AD and FTLD.

Falgàs N ，Ruiz-Peris M ，Pérez-Millan A ，Sala-Llonch R ，Antonell A ，Balasa M ，Borrego-Écija S ，Ramos-Campoy O ，Augé JM ，Castellví M ，Tort-Merino A ，Olives J ，Fernández-Villullas G ，Blennow K ，Zetterberg H ，Bargalló N ，Lladó A ，Sánchez-Valle R ... -  《-》

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 ... -  《-》

Associations of Neurodegeneration Biomarkers in Cerebrospinal Fluid with Markers of Alzheimer's Disease and Vascular Pathology.

Shir D ，Mielke MM ，Hofrenning EI ，Lesnick TG ，Knopman DS ，Petersen RC ，Jack CR ，Algeciras-Schimnich A ，Vemuri P ，Graff-Radford J ... -  《-》

Cerebrospinal fluid biomarkers of neurofibrillary tangles and synaptic dysfunction are associated with longitudinal decline in white matter connectivity: A multi-resolution graph analysis.

In addition to the development of beta amyloid plaques and neurofibrillary tangles, Alzheimer's disease (AD) involves the loss of connecting structures including degeneration of myelinated axons and synaptic connections. However, the extent to which white matter tracts change longitudinally, particularly in the asymptomatic, preclinical stage of AD, remains poorly characterized. In this study we used a novel graph wavelet algorithm to determine the extent to which microstructural brain changes evolve in concert with the development of AD neuropathology as observed using CSF biomarkers. A total of 118 participants with at least two diffusion tensor imaging (DTI) scans and one lumbar puncture for CSF were selected from two observational and longitudinally followed cohorts. CSF was assayed for pathology specific to AD (Aβ42 and phosphorylated-tau), neurodegeneration (total-tau), axonal degeneration (neurofilament light chain protein; NFL), and synaptic degeneration (neurogranin). Tractography was performed on DTI scans to obtain structural connectivity networks with 160 nodes where the nodes correspond to specific brain regions of interest (ROIs) and their connections were defined by DTI metrics (i.e., fractional anisotropy (FA) and mean diffusivity (MD)). For the analysis, we adopted a multi-resolution graph wavelet technique called Wavelet Connectivity Signature (WaCS) which derives higher order representations from DTI metrics at each brain connection. Our statistical analysis showed interactions between the CSF measures and the MRI time interval, such that elevated CSF biomarkers and longer time were associated with greater longitudinal changes in white matter microstructure (decreasing FA and increasing MD). Specifically, we detected a total of 17 fiber tracts whose WaCS representations showed an association between longitudinal decline in white matter microstructure and both CSF p-tau and neurogranin. While development of neurofibrillary tangles and synaptic degeneration are cortical phenomena, the results show that they are also associated with degeneration of underlying white matter tracts, a process which may eventually play a role in the development of cognitive decline and dementia.

Kim WH ，Racine AM ，Adluru N ，Hwang SJ ，Blennow K ，Zetterberg H ，Carlsson CM ，Asthana S ，Koscik RL ，Johnson SC ，Bendlin BB ，Singh V ... -  《NeuroImage-Clinical》