Velayudhan, L. | bioRxiv Science

bioRxiv2022

Neuroanatomical substrates in Parkinson's Disease psychosis and their association with serotonergic receptor gene expression: A coordinate-based meta-regression analysis.

BackgroundCommon neural underpinning of Parkinsons Disease (PD) psychosis across different structural magnetic resonance imaging (MRI) studies remains unclear to this day with few studies and even fewer meta-analyses available. ObjectivesOur meta-analysis aimed to identify and summarise studies using MRI approach to identify PD psychosis-specific brain regions and examine the relation between cortical volume loss and dopaminergic and serotonergic receptor density. MethodsPubMed, Web of Science and Embase were searched for MRI studies of PD psychosis (PDP) compared to PD patients without psychosis (PDnP). Seed-based d Mapping with Permutation of Subject Images was applied in the meta-analysis where coordinates were available. Multiple linear regressions to examine the relationship between grey matter volume loss in PDP and receptor gene expression density (extracted from the Allen Human Brain Atlas) were conducted in R. ResultsWe observed lower grey matter volume in parietal-temporo-occipital regions from our meta-analysis (N studies =10, PDP n=211, PDnP, n=298). These results remained significant after adjusting for PD medications and for cognitive scores. Grey matter volume loss in PDP was associated with local expression of 5-HT1a (b=0.109, p=0.012) and 5-HT2a receptors (b=-0.106, p=0.002) also after adjusting for PD medications (5-HT1a, p = 0.005; 5-HT2a, p = 0.001). ConclusionsWidespread cortical volume loss in the parieto-temporo-occipital regions involved in information processing and integration, as well as attention, could result in PD psychosis symptoms. Neurobiological mechanisms implicating serotonergic receptors may also contribute to this condition.

neuroscience↗

bioRxiv2020

Integrated lipidomics and proteomics network analysis highlights lipid and immunity pathways associated with Alzheimer's disease

INTRODUCTIONThere is an urgent need to understand the molecular mechanisms underlying Alzheimers Disease (AD) to enable early diagnosis and develop effective treatments. Here we aim to investigate Alzheimers dementia using an unsupervised lipid, protein and gene multi-omic integrative approach. METHODSA lipidomics dataset (185 AD, 40 MCI and 185 controls) and a proteomics dataset (201 AD patients, 104 MCI individuals and 97 controls) were utilised for weighted gene co-expression network analyses (WGCNA). An additional proteomics dataset (94 AD, 55 MCI and 100 controls) was included for external proteomics validation. Modules created within each modality were correlated with clinical AD diagnosis, brain atrophy measures and disease progression, as well as with each other. Gene Ontology (GO) enrichment analysis was employed to examine the biological processes and molecular and cellular functions for protein modules associated with AD phenotypes. Lipid species were annotated in the lipid modules associated with AD phenotypes. Associations between established AD risk loci and lipid/protein modules that showed high correlation with AD phenotypes were also explored. RESULTSFive of the 20 identified lipid modules and five of the 17 identified protein modules were correlated with AD phenotypes. Lipid modules comprising of phospholipids, triglycerides, sphingolipids and cholesterol esters, correlated with AD risk loci involved in immune response and lipid metabolism. Five protein modules involved in positive regulation of cytokine production, neutrophil mediated immunity, humoral immune responses were correlated with AD risk loci involved in immune and complement systems. DISCUSSIONWe have shown the first multi-omic study linking genes, proteins and lipids to study pathway dysregulation in AD. Results identified modules of tightly regulated lipids and proteins that were strongly associated with AD phenotypes and could be pathology drivers in lipid homeostasis and innate immunity. Research in ContextO_LILipid and protein modules were preserved amongst Alzheimers disease (AD) patients, participants with mild cognitive impairment (MCI) and controls. Protein modules were also externally validated. C_LIO_LIFive lipid and five protein modules out of a total of thirty-seven correlated with clinical AD diagnosis, brain atrophy measurements and the rate of cognitive decline in AD. C_LIO_LILipid and protein modules associated with AD phenotypes showed associations with established AD risk loci involved in lipid and immune pathways. C_LI

neuroscience↗