Hippocampal subfields: volume, neuropathological vulnerability and cognitive decline in Alzheimer's and Parkinson's disease.

Background: The hippocampus is highly affected in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). The relationship between neuropathology and atrophy in hippocampal subfields is complex due to differences in the selective neuronal vulnerability to distinct protein aggregates that underlie cognitive impairment. The aim of the current study was to investigate the relation between hippocampal subfield volumes, neuropathological burden (amyloid-β, p-tau and α-synuclein) and cognitive performance in AD, PD and control brain donors, using a cross-disease and within-subject post-mortem in situ MRI and neuropathology approach.

Methods: A total of 60 brain donors, including 14 non-neurological controls, 27 AD and 19 PD, underwent post-mortem in situ MRI. From 3D-T1 images hippocampal subfield and entorhinal cortex volumes were derived using FreeSurfer-based subfield segmentation. Hippocampal tissue was obtained at subsequent autopsy, fixed and immunostained for amyloid-β, p-tau and pSer129-αSyn. Immunoreactivity in hippocampal subfields was quantified as area% load using QuPath. Clinical Dementia Rating scores were extracted from the clinical files when available.

Results: AD showed atrophy and increased p-tau, but not amyloid-β, burden in the CA1, subiculum and entorhinal cortex compared to controls, however MRI and neuropathology did not correlate. Controls and PD had similar hippocampal subfield volumes and pathology load. In PD, p-tau pathology, rather than pSer129-αSyn, was associated with lower total hippocampal volume (r=-0.68, p = 0.045), predominantly in PD with dementia (PDD) (r=-0.99, p = 0.013). Cross-disease, volume loss of the subiculum (r=-0.68, p = 0.001) and entorhinal cortex (r=-0.73, p = 0.004) strongly associated with cognitive impairment. Moreover, p-tau pathology had the strongest effect on subfield atrophy, most pronounced in the subiculum (β=-0.570, p < 0.001), but could only explain 22-44% of the volumetric variance.

Conclusions: Even though p-tau was the strongest predictor of hippocampal subfield atrophy, AD-pathology (p-tau and amyloid-β) only partially accounted for volumetric differences in hippocampal subfields, highlighting the significance of other pathologies or mechanisms. The increased sensitivity of subicular and entorhinal cortical atrophy compared to total hippocampal atrophy highlights the potential clinical value of incorporating hippocampal subfield atrophy in monitoring disease progression.