COPING AND COMPENSATORY STRATEGY ADOPTED BY AGEING HUMAN BRAIN: EVIDENCE OF DORSO-VENTRAL NEURAL RESILIENCE THROUGH MULTIMODAL NEUROIMAGING AND TRANSCRIPTOMICS FOR DRUG REVERSAL SIGNATURE

Brain ageing and Alzheimer’s disease are contemplated as progressive cognitive decline. Whether cognitive resilience for compensatory mechanisms in elderly brain are regionally constrained is not well defined. Here we investigated the neurorestorative features preserved across nodal hubs of dorsal-and-ventral pathways, integrating macroscale anatomical alteration with molecular/cellular signatures, to identify resilience and therapeutic-intervention. Neuroprotective signatures using multimodal structural/functional brain scans (DWI-T1-fMRI) are obtained from Max Plank Institute open database cohorts: healthy male/female, young: 20-30 years; old: 60-70 years. We estimated the cerebrovascular reactivity. Tract integrity is assessed through axial diffusivity, fractional anisotropy, volumetric changes across the extended dorsal/ventral stream linkages. We obtained Gene-Expression Omnibus (GEO) of postmortem-brain: snRNA-seq and bulk RNA-seq analysis of frontal, occipital and temporal cortex to define region-specific baseline program, disease-associated transcription trajectories, and regulatory pathways. Transcriptional disease signatures were synchronized with perturbational database (CMap) to decipher pathway-level therapeutic reversal signature.Aged-brain exhibits compensatory structural-connectivity across right fronto-occipital, occipito-temporal and left fronto-temporal tracts. From functional-connectivity aspect, we found that the cuneus and inferior-temporal gyrus (functional connectivity) have more centrality and global efficiency in elderly compared to younger-age, coupled by stable cerebrovascular-response. Transcriptomics analysis revealed occipital-cortex/OC enriched for immune-vascular signature, distinct from neuroactivation of Frontal cortex. snRNA-seq in OC identified synaptic-stabilization and neuroprotective factors/SNAP25, with neuron-glia networks. Drug-reversal analysis indicated that restoration mediates through metabolic-inflammatory regulator/proteostasis/proliferation(CDKs).
Ageing-brain is characterized by coexistence of compensatory structural-functional network, and cell-specific reprogramming. Integrating imaging-transcriptomics endows framework for identifying actionable pathways in neuroprotection and resilience.