Biology subjects

Moghekar, A.

Publications and source records attributed to Moghekar, A..

4 recordsLinked to original sources

bioRxiv2024

Molecular Signatures of Normal Pressure Hydrocephalus: A Large-scale Proteomic Analysis of Cerebrospinal Fluid

Given the persistent challenge of differentiating idiopathic Normal Pressure Hydrocephalus (iNPH) from similar clinical entities, we conducted an in-depth proteomic study of cerebrospinal fluid (CSF) in 28 shunt-responsive iNPH patients, 38 Mild Cognitive Impairment (MCI) due to Alzheimers disease, and 49 healthy controls. Utilizing the Olink Explore 3072 panel, we identified distinct proteomic profiles in iNPH that highlight significant downregulation of synaptic markers and cell-cell adhesion proteins. Alongside vimentin and inflammatory markers upregulation, these results suggest ependymal layer and transependymal flow dysfunction. Moreover, downregulation of multiple proteins associated with congenital hydrocephalus (e.g., L1CAM, PCDH9, ISLR2, ADAMTSL2, and B4GAT1) points to a possible shared molecular foundation between congenital hydrocephalus and iNPH. Through orthogonal partial least squares discriminant analysis (OPLS-DA), a panel comprising 13 proteins has been identified as potential diagnostic biomarkers of iNPH, pending external validation. These findings offer novel insights into the pathophysiology of iNPH, with implications for improved diagnosis.

neuroscience↗

bioRxiv2023

A fluid biomarker reveals loss of TDP-43 splicing repression in pre-symptomatic ALS

Loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well-documented in postmortem tissues of amyotrophic lateral sclerosis (ALS), yet whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects functional loss of TDP-43, and thus detection of cryptic exon-encoded peptides in cerebrospinal fluid (CSF) could reveal the earliest stages of TDP-43 dysregulation in patients. Here, we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in C9ORF72-associated ALS, including pre-symptomatic mutation carriers. In contrast to neurofilament light and heavy chain proteins, cryptic HDGFL2 accumulates in CSF at higher levels during early stages of disease. Our findings indicate that loss of TDP-43 splicing repression occurs early in disease progression, even pre-symptomatically, and that detection of HDGFL2s cryptic neoepitope may serve as a prognostic test for ALS which should facilitate patient recruitment and measurement of target engagement in clinical trials.

molecular biology↗

bioRxiv2019

Tau pathology in cognitively normal older adults: Associations with brain atrophy and cognitive decline

INTRODUCTIONTau pathology, a hallmark of Alzheimers disease, is observed in the brains of virtually all individuals over 70.\n\nMETHODSUsing 18F-AV-1451 (18F-flortaucipir) PET, we evaluated tau pathology in 54 cognitively normal participants (mean age 77.5, SD 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between PET signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status.\n\nRESULTSGreater age, male sex, black race, and amyloid positivity were associated with higher 18F-AV-1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume ({beta} = -1.124, SE = 0.485, p = 0.025) and a steeper decline in memory performance ({beta} = -0.086, SE = 0.039, p = 0.029).\n\nDISCUSSIONAssessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimers disease.

neuroscience↗

bioRxiv2018

Identifying Changepoints in Biomarkers During the Preclinical Phase of AD

ObjectiveSeveral models have been proposed for the evolution of Alzheimers disease (AD) biomarkers. The aim of this study was to identify changepoints in a range of biomarkers during the preclinical phase of AD.\n\nMethodsWe examined nine measures based on cerebrospinal fluid (CSF), magnetic resonance imaging (MRI) and cognitive testing, obtained from 306 cognitively normal individuals, a subset of whom subsequently progressed to the symptomatic phase of AD. A changepoint model was used to determine which of the measures had a significant change in slope in relation to clinical symptom onset.\n\nResultsAll nine measures had significant changepoints, all of which preceded symptom onset, however the timing of these changepoints varied considerably. A single measure, CSF-tau, had an early changepoint (40 years prior to symptom onset). A group of measures, including the remaining CSF measures (CSF-Abeta and phosphorylated tau) and all cognitive tests had changepoints 10-15 years prior to symptom onset. A second group is formed by medial temporal lobe shape composite measures, with a five-year time difference between the right and left side (respectively nine and three years prior to symptom onset).\n\nConclusionsThese findings highlight the long period of time prior to symptom onset during which AD pathology is accumulating in the brain. There are several significant findings, including the early changes in cognition and the laterality of the MRI findings. Additional work is needed to clarify their significance.

neuroscience↗