Biology subjects

Wolk, D.

Publications and source records attributed to Wolk, D..

7 recordsLinked to original sources

bioRxiv2026

Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.

neuroscience↗

bioRxiv2025

The precision of hippocampal representations predicts incremental value-learning across the adult lifespan

Correctly assigning value to different options and leveraging this information to guide choice is a cornerstone of adaptive decision-making. Reinforcement learning (RL) has provided a computational framework to study this process, and neural signals linked to RL have been identified in the striatum and medial prefrontal cortex. More recently, hippocampal contributions to this kind of value-learning have been proposed, at least under some conditions. Here, we test whether the hippocampus provides a signal of the options identity that aids in credit assignment when learning about several perceptually similar items, and evaluate how this process differs across the lifespan. A sample of 251 younger and older adults, including a subset (n = 76) with simultaneous fMRI, completed an RL task in which they learned the value of four houses through trial-and-error. Older adults showed decreased choice accuracy, accompanied by reduced neural signaling of value at choice but not feedback. Using representational similarity analysis, we found that the precision with which choice options were represented in the posterior hippocampus during choice predicted accurate decisions across age groups. Interestingly, despite previous evidence for neural de-differentiation in older adults, we found no support for a "blurring" of these stimulus representations in older adults. Rather, we observed reduced connectivity between the posterior hippocampus and the medial PFC in older adults, and this connectivity correlated with choice consistency. Taken together, these findings identify a hippocampal contribution to incremental value learning, and that reductions in incremental value learning in older adults are associated with the reduced transfer of information between the hippocampus and mPFC, rather than the precision of the information in the hippocampus itself.

neuroscience↗

bioRxiv2024

Cytoarchitectonic gradients of laminar degeneration in behavioral variant frontotemporal dementia

Behavioral variant frontotemporal dementia (bvFTD) is a clinical syndrome primarily caused by either tau (bvFTD-tau) or TDP-43 (bvFTD-TDP) proteinopathies. We previously found lower cortical layers and dorsolateral regions accumulate greater tau than TDP-43 pathology; however, patterns of laminar neurodegeneration across diverse cytoarchitecture in bvFTD is understudied. We hypothesized that bvFTD-tau and bvFTD-TDP have distinct laminar distributions of pyramidal neurodegeneration along cortical gradients, a topologic order of cytoarchitectonic subregions based on increasing pyramidal density and laminar differentiation. Here, we tested this hypothesis in a frontal cortical gradient consisting of five cytoarchitectonic types (i.e., periallocortex, agranular mesocortex, dysgranular mesocortex, eulaminate-I isocortex, eulaminate-II isocortex) spanning anterior cingulate, paracingulate, orbitofrontal, and mid-frontal gyri in bvFTD-tau (n=27), bvFTD-TDP (n=47), and healthy controls (HC; n=32). We immunostained all tissue for total neurons (NeuN; neuronal-nuclear protein) and pyramidal neurons (SMI32; non-phosphorylated neurofilament) and digitally quantified NeuN-immunoreactivity (ir) and SMI32-ir in supragranular II-III, infragranular V-VI, and all I-VI layers in each cytoarchitectonic type. We used linear mixed-effects models adjusted for demographic and biologic variables to compare SMI32-ir between groups and examine relationships with the cortical gradient, long-range pathways, and clinical symptoms. We found regional and laminar distributions of SMI32-ir expected for HC, validating our measures within the cortical gradient framework. While SMI32-ir loss was not related to the cortical gradient in bvFTD-TDP, SMI32-ir progressively decreased along the cortical gradient of bvFTD-tau and included greater SMI32-ir loss in supragranular eulaminate-II isocortex in bvFTD-tau vs bvFTD-TDP (p=0.039). In a structural model for long-range laminar connectivity between infragranular mesocortex and supragranular isocortex, we found a larger laminar ratio of mesocortex-to-isocortex SMI32-ir in bvFTD-tau vs bvFTD-TDP (p=0.019), suggesting select long-projecting pathways may contribute to isocortical-predominant degeneration in bvFTD-tau. In cytoarchitectonic types with the highest NeuN-ir, we found lower SMI32-ir in bvFTD-tau vs bvFTD-TDP (p=0.047), suggesting pyramidal neurodegeneration may occur earlier in bvFTD-tau. Lastly, we found that reduced SMI32-ir related to behavioral severity and frontal-mediated letter fluency, not temporal-mediated confrontation naming, demonstrating the clinical relevance and specificity of frontal pyramidal neurodegeneration to bvFTD-related symptoms. Our data suggest loss of neurofilament-rich pyramidal neurons is a clinically relevant feature of bvFTD that selectively worsens along a frontal cortical gradient in bvFTD-tau, not bvFTD-TDP. Therefore, tau-mediated degeneration may preferentially involve pyramidal-rich layers that connect more distant cytoarchitectonic types. Moreover, the hierarchical arrangement of cytoarchitecture along cortical gradients may be an important neuroanatomical framework for identifying which types of cells and pathways are differentially involved between proteinopathies.

neuroscience↗

bioRxiv2023

Expansion of a frontostriatal salience network in individuals with depression

Hundreds of neuroimaging studies spanning two decades have revealed differences in brain structure and functional connectivity in depression, but with modest effect sizes, complicating efforts to derive mechanistic pathophysiologic insights or develop biomarkers.1 Furthermore, although depression is a fundamentally episodic condition, few neuroimaging studies have taken a longitudinal approach, which is critical for understanding cause and effect and delineating mechanisms that drive mood state transitions over time. The emerging field of precision functional mapping using densely-sampled longitudinal neuroimaging data has revealed unexpected, functionally meaningful individual differences in brain network topology in healthy individuals,2-5 but these approaches have never been applied to individuals with depression. Here, using precision functional mapping techniques and 11 datasets comprising n=187 repeatedly sampled individuals and >21,000 minutes of fMRI data, we show that the frontostriatal salience network is expanded two-fold in most individuals with depression. This effect was replicable in multiple samples, including large-scale, group-average data (N=1,231 subjects), and caused primarily by network border shifts affecting specific functional systems, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was unexpectedly stable over time, unaffected by changes in mood state, and detectable in children before the subsequent onset of depressive symptoms in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in specific frontostriatal circuits that tracked fluctuations in specific symptom domains and predicted future anhedonia symptoms before they emerged. Together, these findings identify a stable trait-like brain network topology that may confer risk for depression and mood-state dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time.

neuroscience↗

bioRxiv2022

Genetic, clinical underpinnings of subtle early brain change along Alzheimer's dimensions

Alzheimers disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised clustering technique known as Surreal-GAN, through which we identified two dominant dimensions of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE {varepsilon}4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE {varepsilon}4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction - driven by genes different from APOE - which may collectively contribute to the early pathogenesis of AD.

bioengineering↗

bioRxiv2021

TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy

The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well-understood. Here, we investigated the influence of genotypes at TMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions in C9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)- allele homozygotes at the TMEM106B locus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions. C9orf72 expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting for C9orf72 expansion status did not affect the relationship between TMEM106B genotype and TDP-43 pathology. In order to elucidate the direction of causality for this association, we directly manipulated TMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown of TMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.

neuroscience↗

bioRxiv2019

Disconnectome Associated with Progressive Ischemic Periventricular White Matter Lesions

Periventricular white matter (PVWM) hyperintensities on T2-weighted MRI are ubiquitous in older adults and associated with dementia. Efforts to determine how PVWM lesions impact structural connectivity to impinge on brain function remain challenging in part because white matter tractography algorithms for diffusion tensor imaging (DTI) may lose fidelity in the presence of lesions. We used a "virtual lesion" approach to characterize the "disconnectome" associated with periventricular white matter (PVWM) lesions. We simulated progressive ischemic PVWM lesions using sub-threshold cerebral blood flow (CBF) masks derived from a previously published group-averaged map acquired from N=436 middle aged subjects in which the lowest CBF values were seen in PVWM and morphologically recapitulated the spatial pattern of PVWM hyperintensities seen in typical aging. We mimicked the age-dependent evolution of PVWM lesion burden by varying the threshold applied to the CBF map. We found that the optic radiations, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, corpus callosum, temporopontine tract and fornix were affected in early simulated PVWM lesion burdens, and that the connectivity of subcortical, cerebellar, and visual regions were significantly disrupted with increasing simulated PVWM lesion burdens. We also validated the use of virtual lesions to simulate the disconnectome due to WM hyperintensities in a cognitively normal elderly cohort (N=46) by evaluating correlations between structural and functional connectomes. The virtual lesion approach provides new insights into the spatial-temporal changes of the brain structural connectome under progressive PVWM burdens during normal aging. Significance StatementWe determined the disconnectomes caused by periventricular white matter (PVWM) lesions using the "virtual lesion" approach. We validated the approach using lesions, DTI and resting-state fMRI data from elderly subjects. We simulated disconnectome of progressive PVWM lesions using cerebral blood flow (CBF) masks in PVWM region with normative DTI data, which provides specificity for an ischemic mechanism and begins to address the possibility that connectivity may be affected by reduced CBF prior to the development of overt lesions on T2-weighted FLAIR MRI. The current study presented new insights into the spatial-temporal evolutions of the brain structural connectome under progressive PVWM burdens under normal aging.

neuroscience↗