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》

The association between biomarkers in cerebrospinal fluid and structural changes in the brain in patients with Alzheimer's disease.

Biochemical changes in the cerebrospinal fluid (CSF) could reflect pathophysiological processes in Alzheimer's disease (AD). However, it is still not clear how these processes correlate with grey matter (GM) volume and microstructural changes in the brain. To assess the relationship between CSF biomarkers and structural brain changes in AD. Cross-sectional study in a memory clinic-based sample. A total of 78 subjects were included in the study: 22 with subjective cognitive impairment (SCI), 35 with mild cognitive impairment (MCI) and 21 with AD. Voxel-wise correlations between CSF biomarkers, including β-amyloid42 (Aβ42), tau phosphorylated at position threonine 181 and total tau protein, and GM volume, self-diffusion fractional anisotropy (FA) and mean diffusivity (MD) maps using voxel-based morphometry and tract-based spatial statistical analyses. FA and MD maps were obtained using diffusion tensor imaging. In the whole sample (patients with SCI, MCI and AD), there was positive correlation between GM volume and Aβ42 concentration, and negative correlation with total tau protein. Higher FA was only related to higher concentration of Aβ42. MD showed significant negative correlation with Aβ42 and positive correlation with T-tau levels. The majority of brain regions with significant correlation with CSF biomarkers overlapped with the default mode network and extended to the adjacent white matter. Early AD pathological changes can be detected with voxel-based morphometric analysis and diffusion tensor imaging measurements. Furthermore, there was an association between CSF AD biomarkers and structural brain changes in areas related to the default mode network.

Li X ，Li TQ ，Andreasen N ，Wiberg MK ，Westman E ，Wahlund LO ... -  《-》

Association of longitudinal white matter degeneration and cerebrospinal fluid biomarkers of neurodegeneration, inflammation and Alzheimer's disease in late-middle-aged adults.

Racine AM ，Merluzzi AP ，Adluru N ，Norton D ，Koscik RL ，Clark LR ，Berman SE ，Nicholas CR ，Asthana S ，Alexander AL ，Blennow K ，Zetterberg H ，Kim WH ，Singh V ，Carlsson CM ，Bendlin BB ，Johnson SC ... -  《-》

Cerebrospinal Fluid Markers of Alzheimer's Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer's Disease.

Melah KE ，Lu SY ，Hoscheidt SM ，Alexander AL ，Adluru N ，Destiche DJ ，Carlsson CM ，Zetterberg H ，Blennow K ，Okonkwo OC ，Gleason CE ，Dowling NM ，Bratzke LC ，Rowley HA ，Sager MA ，Asthana S ，Johnson SC ，Bendlin BB ... -  《-》

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 ... -  《-》