Biology subjects

D'Souza, D. C.

Publications and source records attributed to D'Souza, D. C..

5 recordsLinked to original sources

bioRxiv2025

Optimized reference region and the effect on test-retest reliability and detection of Parkinson's disease with UCB-J.

[11C]UCB-J is a radioligand targeting synaptic vesicle glycoprotein 2A, used to image synaptic density. For quantification, a small-volume centrum semiovale area was previously optimized as a [11C]UCB-J reference region (CS2mL); however, its high variability resulted in reduced reliability. Herin, we evaluated an alternative reference region method to assess longitudinal test-retest reliability and detection of Parkinsons disease (PD). For estimating distribution volume ratio (DVR), CS2mL and eleven white matter (WM) reference regions (range: 0.5-200 mL) were generated using the Freesurfer WM map. Same-day and longitudinal test-retest variability (TRV) were assessed (24 healthy subjects (HS); n=10 same-day and n=20 longitudinal HRRT scans, range: 7-1028 days). Each reference region was used to evaluate the substantia nigra (SN) and caudate DVRs in HS (n=25) and PD (n=20). The 10mL WM reference region yielded [11C]UCB-J DVR measurements with reduced variability in TRV (same-day: 10mL: 1.2{+/-}5.7%, same-day: CS2mL: -0.9{+/-}9.2% longitudinal: 10mL: 1.5{+/-}7.0%, CS2mL: 1.6{+/-}11.9%,) while maintaining <10% volume of distribution difference, compared to CS2mL. Further, a significant difference between PD and HS groups in SN and caudate DVRs was found using 10mL, with greater effect size (Cohens d 0.61 for SN and 0.66 for caudate) compared to CS2mL (0.38 for SN and 0.43 for caudate).

neuroscience↗

bioRxiv2025

Opposing Modulation of EEG Aperiodic Component by Ketamine and Thiopental: Implications for the Noninvasive Assessment of Cortical E/I Balance in Humans

The balance between excitatory and inhibitory (E/I) activity is critical for brain function, and its disruption is implicated in neuropsychiatric disorders. Electrophysiological signals can be decomposed into periodic (oscillatory) and aperiodic components. In the power spectrum, the periodic component appears as narrowband peaks, while the aperiodic component underlies its characteristic 1/fx power-law decay. Computational models predict that shifts in E/I balance alter the exponent{chi} in specific directions. In a randomized, double-blind, placebo-controlled, within-subject study, healthy volunteers received subanesthetic doses of ketamine and thiopental during an EEG oddball task. These drugs have opposite effects on E/I balance but comparable sedative profiles. Ketamine reduced the PSD exponent, while thiopental increased it, consistent with computational predictions. Changes in the exponent were associated with subjective and cognitive effects. These findings suggest that the PSD exponent has potential as a noninvasive EEG biomarker sensitive to transient shifts in cortical E/I balance.

neuroscience↗

bioRxiv2020

Analysis of Circulating Exosomes Reveals a Peripheral Signature of Astrocytic Pathology in Schizophrenia

BackgroundThere is considerable interest in identifying peripheral biomarkers that reflect neuropathological changes in schizophrenia. Extracellular vesicles, including exosomes can cross the blood brain barrier with their contents intact and their cargo, including lipids, proteins and genetic materials can be assayed peripherally. Circulating exosomes have been studied in other neurodegenerative disorders, but there is scarce data in schizophrenia. MethodsWe examined neuropathology relevant protein biomarkers in circulating exosomes from patients with schizophrenia and age and gender matched healthy controls using methods consistent with the recommended "Minimal information for studies of extracellular vesicles 2018" (MISEV2018) guidelines. Nanoparticle tracking analysis was used to determine the size and concentration of exosomes. Exosomal membrane marker (CD9) and specific target cargo proteins (glial fibrillary acid protein[GFAP], synaptophysin and -II-spectrin) immunopositivity was examined using Western blot analyses and band intensity quantified. ResultsNo group differences were observed between schizophrenia and control samples in plasma exosomal concentration and size or in CD9 or calnexin positivity. Exosomal GFAP concentration was significantly higher and -II-spectrin expression significantly lower in schizophrenia samples and there were no group differences observed for exosomal synaptophysin concentration. ConclusionsOur results demonstrate for the first time, a differential pattern of exosomal protein expression in schizophrenia compared to matched healthy controls, consistent with the hypothesized astro-glial pathology in this disorder. These results warrant further examination of circulating exosomes as vehicles of novel peripheral biomarkers of disease in schizophrenia and other neuropsychiatric disorders.

neuroscience↗

bioRxiv2019

Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans

Delta 9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, is also known to modulate immune response in peripheral cells. The mechanisms of THCs effects on gene expression in human immune cells remains poorly understood. Combining a within-subject design with single cell transcriptome mapping, we report that administration of THC acutely alters gene expression in 15,973 human blood immune cells. Controlled for high inter-individual transcriptomic variability, we identified 294 transcriptome-wide significant genes among eight cell types including 69 common genes and 225 cell-type specific genes affected by acute THC administration, including those genes involving not only in immune response, cytokine production, but signal transduction, and cell proliferation and apoptosis. We revealed distinct transcriptomic sub-clusters affected by THC in major immune cell types where THC perturbed cell type-specific intracellular gene expression correlations. Gene set enrichment analysis further supports the findings of THCs common and cell-type specific effects on immune response and cell toxicity. We found that THC alters the correlation of cannabinoid receptor gene, CNR2, with other genes in B cells, in which CNR2 showed the highest level of expression. This comprehensive cell-specific transcriptomic profiling identified novel genes regulated by THC and provides important insights into THCs acute effects on immune function that may have important medical implications.

genetics↗

bioRxiv2018

Rapamycin, an Immunosuppressant and mTORC1 Inhibitor, Triples the antidepressant Response Rate of Ketamine at 2 Weeks Following Treatment: A double-blind, placebo-controlled, cross-over, randomized clinical trial

BACKGROUNDKetamine exerts rapid and robust antidepressant effects thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine.\n\nMETHODSTwenty-three patients suffering a major depressive episode were randomized to oral rapamycin (6 mg) or placebo, each was followed 2 hours later by ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-[A]sberg Depression Rating Scale (MADRS). Antidepressant response was defined as a MADRS improvement of 50% or more.\n\nRESULTSOver the two-week follow-up, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), reflecting prolonged antidepressant effects post rapamycin+ketamine treatment. At 2 weeks, we found a significantly higher response rate following rapamycin+ketamine (41%) compared to placebo+ketamine (13%, p = 0.04). However, rapamycin pretreatment did not alter the acute effects of ketamine.\n\nCONCLUSIONUnexpectedly, pretreatment with rapamycin prolonged rather than blocked the acute antidepressant effects of ketamine. This observation raises questions about the role of mTORC1 in the antidepressant effects of keta-mine, raises the possibility that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that limit the duration of ketamine effects. The supplementing of ketamine with rapamycin may be a treat-ment strategy for reducing the frequency of ketamine infusions during maintenance treatment.

neuroscience↗