Biology subjects

Higginbotham, L.

Publications and source records attributed to Higginbotham, L..

4 recordsLinked to original sources

bioRxiv2025

Multiplex Proteomics of Lewy Body Dementia Reveals Cerebrospinal Fluid Biomarkers of Disease Pathology and Progression

Lewy body dementia (LBD), which encompasses Parkinsons disease dementia (PDD) and Dementia with Lewy bodies (DLB), lacks established biofluid markers of its complex clinical and neuropathological heterogeneity. Multiplex proteomic tools, such as the recently developed NUcleic acid Linked ImmunoSandwich Assay (NULISATM), can assess a diverse array of neurodegenerative targets and address these biomarker gaps. We used this platform to analyze 852 baseline and longitudinal cerebrospinal fluid (CSF) samples from control, PD, and DLB subjects from the Parkinsons Disease Biomarker Program (PDBP). We then examined LBD protein signatures across different clinical diagnoses, patterns of cognitive progression, and underlying neuropathologies. Of the 124 markers analyzed, 54 were significantly altered in PD with cognitive impairment and/or DLB compared to controls, many serving as informative clinical classifiers in machine learning models. We also identified 15 proteins with significant baseline and/or longitudinal changes linked to cognitive progression. To identify neuropathological signatures, we stratified 209 cases by the presence of underlying synuclein and amyloid-beta (A{beta}) pathology using CSF alpha-synuclein seed amplification assay (Syn-SAA) results and NULISA pTau-217 levels, respectively. Select synaptic markers were decreased relative to synucleinopathy but increased relative to A{beta} accumulation, complicating their interpretation in cases with co-pathology. These neuropathological analyses were replicated in an independent cohort of 917 cases from the Alzheimers Disease Neuroimaging Initiative (ADNI). Overall, these results highlight the utility of multiplex proteomic analysis in the identification of candidate CSF biomarkers of disease heterogeneity in LBD. One Sentence SummaryThis multiplex proteomic analysis using the recently released NULISA platform revealed unique targets of Lewy body dementia progression and neuropathology.

systems biology↗

bioRxiv2024

Network Proteomics of the Lewy Body Dementia Brain Reveals Presynaptic Signatures Distinct from Alzheimer's Disease

Lewy body dementia (LBD), a class of disorders comprising Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimers disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinsons disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or "modules" of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.

systems biology↗

bioRxiv2023

CD28-Selective Inhibition Prolongs Non-Human Primate Kidney Transplant Survival

Costimulation blockade using belatacept results in improved renal function after kidney transplant as well as decreased likelihood of death/graft loss and reduced cardiovascular risk; however, higher rates and grades of acute rejection have prevented its widespread clinical adoption. Treatment with belatacept blocks both positive (CD28) and negative (CTLA-4) T cell signaling. CD28-selective therapies may offer improved potency by blocking CD28-mediated costimulation while leaving CTLA-4 mediated coinhibitory signals intact. Here we test a novel domain antibody directed at CD28 (anti-CD28 dAb (BMS-931699)) in a non-human primate kidney transplant model. Sixteen macaques underwent native nephrectomy and received life-sustaining renal allotransplantation from an MHC-mismatched donor. Animals were treated with belatacept alone, anti-CD28 dAb alone, or anti-CD28 dAb plus clinically relevant maintenance (MMF, Steroids) and induction therapy with either anti-IL-2R or T cell depletion. Treatment with anti-CD28 dAb extended survival compared to belatacept monotherapy (MST 187 vs. 29 days, p=0.07). The combination of anti-CD28 dAb and conventional immunosuppression further prolonged survival to MST [~]270 days. Animals maintained protective immunity with no significant infectious issues. These data demonstrate CD28-directed therapy is a safe and effective next-generation costimulatory blockade strategy with a demonstrated survival benefit and presumed advantage over belatacept by maintaining intact CTLA-4 coinhibitory signaling.

immunology↗

bioRxiv2019

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease

Alzheimers disease (AD) features a complex web of pathological processes beyond amyloid accumulation and tau-mediated neuronal death. To meaningfully advance AD therapeutics, there is an urgent need for novel biomarkers that comprehensively reflect these disease mechanisms. Here we applied an integrative proteomics approach to identify cerebrospinal fluid (CSF) biomarkers linked to a diverse set of pathophysiological processes in the diseased brain. Using multiplex proteomics, we identified >3,500 proteins across 40 CSF samples from control and AD patients and >12,000 proteins across 48 postmortem brain tissues from control, asymptomatic AD (AsymAD), AD, and other neurodegenerative cases. Co-expression network analysis of the brain tissues resolved 44 protein modules, nearly half of which significantly correlated with AD neuropathology. Fifteen modules robustly overlapped with proteins quantified in the CSF, including 271 CSF markers highly altered in AD. These 15 overlapping modules were collapsed into five panels of brain-linked fluid markers representing a variety of cortical functions. Neuron-enriched synaptic and metabolic panels demonstrated decreased levels in the AD brain but increased levels in diseased CSF. Conversely, glial-enriched myelination and immunity panels were highly increased in both the brain and CSF. Using high-throughput proteomic analysis, proteins from these panels were validated in an independent CSF cohort of control, AsymAD, and AD samples. Remarkably, several validated markers were significantly altered in AsymAD CSF and appeared to stratify subpopulations within this cohort. Overall, these brain-linked CSF biomarker panels represent a promising step toward a physiologically comprehensive tool that could meaningfully enhance the prognostic and therapeutic management of AD.

systems biology↗