Correlations in hippocampal subfield volume and pathological hallmarks in Alzheimer’s and Parkinson’s disease

AbstractBackgroundThe hippocampus is highly vulnerable to protein aggregations and often severly atrophic in Alzheimer’s disease (AD) and related neurodegenerative disoders such as Parkinsons’ disease (PD) with dementia (PDD). This study aims to define the association between MRI‐measured hippocampal subfield volumes and pathology load using a cross‐disease and within‐subject post‐mortem MRI‐pathology approach in clinically‐defined and pathologically‐confirmed AD and PD brain‐donors.MethodWe included 17 typical (amnestic) and 13 atypical (non‐amnestic) AD, 10 PD, 9 PDD and 14 age‐matched control donors. 3T in‐situ MRI 3D‐T1 images were obtained for FreeSurfer‐based subfield segmentation. Hippocampus tissue sections were immunostained for amyloid‐beta (Aβ), p‐tau, and pSer129‐α‐synuclein. Immunoreactivity in manually segmented subfields (DG, CA1 to CA4, (para)subiculum and entorhinal cortex) was quantified as area% load. Clinical Dementia Rating (CDR) scores were obtained from clinical reports. Group differences were analysed with general linear models and regional assocations with partial correlations, corrected for age, sex, postmortem delay and intracranial volume.ResultTotal hippocampal, CA1 and subiculum MRI‐volumes were lower in typical AD compared to all other groups (p<0.03). PD and PDD showed higher volumes in all subregions compared to typical AD, except for CA2/3 and parasubiculum (Fig.1).Typical and atypical AD showed similar p‐tau burden, which was higher compared to other groups in most subfields. CA1 and entorhinal cortex showed the highest Aβ pathology load in AD compared to controls and PD. No significant differences in pSer129‐α‐synuclein pathology were seen between PD and PDD (Fig.2).Cross‐disease, p‐tau negatively correlated with volume in total hippocampus and all subfields (all r←0.30, p<0.025) (Fig.3). In typical AD, no disease‐specific correlations between pathology and volume could be observed. In PD(D), pSer129‐α‐synuclein was negatively associated with volume in CA4, whereas p‐tau negatively correlated with volume in total hippocampus, DG and CA4 in PDD.CDR scores correlated negatively with volume in total hippocampus, subiculum and entorhinal cortex cross‐disease, and in typical AD with p‐tau in total hippocampus, CA1 and CA2.ConclusionAlthough similar pathological burden is observed in typical and atypical AD, typical AD showed more severe hippocampal MRI‐atrophy. Furthermore, p‐tau load is associated with MRI‐atrophy of hippocampal subfields cross‐disease, and is regionally associated with impaired cognition.