Biology subjects

Kramer, J. H.

Publications and source records attributed to Kramer, J. H..

6 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↗

bioRxiv2024

Interrogating the plasma proteome of repetitive head impact exposure and chronic traumatic encephalopathy

BackgroundExposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration are not well understood. We interrogated the plasma proteome in aging adults with prior RHI compared to healthy controls (CTL) and individuals with Alzheimers disease (AD), including a subset characterized neuropathologically at autopsy. MethodsProximity extension assay (Olink Explore(R)) quantified 2,779 plasma proteins in 22 RHI patients (all AD-biomarker negative), 39 biomarker-confirmed AD, and 44 CTL. A subset of participants went to autopsy (N=16) allowing for comparisons of the antemortem plasma proteome between autopsy-confirmed CTE+ (N=7) and CTE-(N=9). Differential abundance and co-expression network analyses identified plasma proteomic signatures of RHI, which were functionally annotated using gene ontology and cell type enrichment analysis. Nonparametric correlations examined plasma proteomic associations with orthogonally-measured plasma biomarkers, global cognitive function, and semi-quantitative ratings of neuropathology burden at autopsy. ResultsDifferential abundance analysis revealed 434 increased (vs. 6 decreased) proteins in RHI vs. CTL and 193 increased (vs. 14 decreased) in RHI vs. AD. Network analysis identified 9 protein co-expression modules (M1-M9), of which 7 were elevated in RHI compared to AD or CTL. Modules with increased abundance in RHI were enriched for mitochondrial/metabolic, cell division, and immunovascular (e.g., cell adhesion, TNF-signaling) processes. RHI-related modules exhibited strong and selective correlations with immunoassay-based plasma IL-6 in RHI cases, including the M2 TNF-signaling/cell adhesion module which harbored proteins that strongly tracked with cognitive function. RHI-related plasma protein signatures were similar in the subset of participants with autopsy-confirmed CTE, including immune and metabolic modules that positively correlated with medial temporal lobe tau and TDP-43 burden. ConclusionsMolecular pathways in plasma most consistently implicated in RHI were tied to immune response, mitochondrial function, and cell metabolism. RHI-related proteomic signatures tracked with antemortem cognitive severity and postmortem neuropathological burden, providing converging evidence for their role in disease progression. Differentially abundant proteins and co-expression modules in RHI may inform mechanisms linking RHI to increased dementia risk, thus guiding diagnostic biomarker and therapeutic development for at-risk populations.

molecular biology↗

bioRxiv2023

Atrophy-driven functional network collapse in neurodegenerative disease

Cognitive and behavioral deficits in Alzheimers disease (AD) and frontotemporal dementia (FTD) result from brain atrophy and altered functional connectivity. However, it is unclear how atrophy relates to functional connectivity disruptions across dementia subtypes and stages. We addressed this question using structural and functional MRI from 221 patients with AD (n=82), behavioral variant FTD (n=41), corticobasal syndrome (n=27), nonfluent (n=34) and semantic (n=37) variant primary progressive aphasia, and 100 cognitively normal individuals. Using partial least squares regression, we identified three principal structure-function components. The first component showed overall atrophy correlating with primary cortical hypo-connectivity and subcortical/association cortical hyper-connectivity. Components two and three linked focal syndrome-specific atrophy to peri-lesional hypo-connectivity and distal hyper-connectivity. Structural and functional component scores predicted global and domain-specific cognitive deficits. Anatomically, functional connectivity changes reflected alterations in specific brain activity gradients. Eigenmode analysis identified temporal phase and amplitude collapse as an explanation for atrophy-driven functional connectivity changes.

neuroscience↗

bioRxiv2021

Dynamic autonomic nervous system patterns differentiate human emotions and manifest in resting physiology

Whether activity in the autonomic nervous system differs during distinct emotions remains controversial. We obtained continuous multichannel recordings of autonomic nervous system activity in healthy adults during a video-based emotional reactivity task. Dimensionality reduction revealed five principal components in the autonomic time series data, and these modes of covariation differentiated periods of baseline from those of video-viewing. Unsupervised clustering of the principal component time series data uncovered separable autonomic states that distinguished among the five emotion-inducing trials. These autonomic states were also detected in baseline physiology but were intermittent and of smaller magnitude. Our results suggest the autonomic nervous system assembles dynamic activity patterns during emotions that are similar across people and are present even during undirected moments of rest. One Sentence SummaryDynamic autonomic patterns distinguish among emotions and are evident in resting physiology.

neuroscience↗

bioRxiv2019

COMT Val158Met polymorphism associated with greater susceptibility to framing effects in healthy older adults

Age-related neural changes may compromise older adults decision-making, increasing their risk of fraud and financial abuse. One manifestation of nonrational influences on decision-making is susceptibility to \"framing effects,\" in which decisions are biased by irrelevant contextual features of how choice information is presented. We investigated whether polymorphisms in genes related to dopamine neurotransmission (COMT) and neurodegeneration (ApoE) influence the susceptibility of older adults to framing effects. We administered an online test of susceptibility to framing effects to a cohort of 113 healthy older adults who had undergone genetic testing for COMT and ApoE genotype. The task required the participant to choose a risky or safe option in pairs of situations that were monetarily equivalent but differed in whether the choice was framed in terms of gains or losses. A general linear model was used to test for associations between inconsistency in choice across the set of choice pairs and these genotypes, controlling for age, education, gender and traditional measures of executive function. While no association to framing effects was found for ApoE, the Valine allele of COMT Val158Met was significantly associated with greater susceptibility to framing, although the association was no longer significant after adjustment for demographic covariates. Our results suggest that greater frontal dopamine concentrations associated with the COMT Met allele are protective against less consistent decision making in older adults. When compared to previous findings in young adults, our findings provide additional support for an inverted-U shaped model of prefrontal dopamine function.

neuroscience↗

bioRxiv2019

Endothelial-derived exosomes demonstrate a link between endothelial innate inflammation and brain dysfunction and injury in aging

We test the hypothesis that endothelial cells take on an inflammatory phenotype in functionally intact human subjects with radiographic evidence of white matter injury. Markers within all three complement effector pathways and regulatory proteins were quantified from endothelial-derived exosomes (EDE) of subjects (age 70-82) with (n=11) and without (n=16) evidence of white matter hyperintensity on MRI. Group differences and associations with systemic markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling.\n\nEDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of several factors demonstrated significant associations with cognitive slowing and systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Systemic inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several factors.\n\nThese findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter injury, cognition, and brain degeneration in functionally normal older individuals, and form the basis for future biomarker development in early or preclinical stages of vascular cognitive impairment and dementia.

neuroscience↗