Hypothalamic atrophy and structural covariance in amnestic mild cognitive impairment and Alzheimer's dementia

Background: Alzheimer's disease (AD) is characterized by progressive cognitive decline and specific brain atrophy patterns, primarily involving the medial temporal lobes. A number of studies have discussed hypothalamic involvement in AD with consecutive metabolic and/or autonomic disturbances yet only few studies have investigated hypothalamic atrophy in AD and its early stages in particular. Methods: We applied semi-automated volumetry of the hypothalamus (HTH) in 3 T MRI in a sample N = 175 participants [age 74.9 +/- 7.22; gender 85 m/90f; cognitively normal controls (CN; N = 56); amnestic mild cognitive impairment (MCI; N = 78); AD (N = 41)] from the Alzheimer's Disease Neuroimaging Initiative (ADNI). In addition, we used voxel-based morphometry (VBM), cortical thickness (CTH) analyses and source-based morphometry (SBM) derived networks of structural covariance to investigate brain structural covariance patterns of the HTH under consideration of diagnostic groups, beta-amyloid (AB) positivity and apolipoprotein E (APOE) epsilon 4 status. Results: Hypothalamic atrophy was observed in both early and advanced disease stages (i.e. hypothalamic volume CN > MCI > AD). VBM, CTH analysis and SBM revealed positive associations between hypothalamic volume (HV) and AD- vulnerable regions, largely corresponding to the Papez circuit and brain regions implicated in autonomic regulation, however, group differences regarding HTH structural covariance were not observed. Similar observations were made in carriers and non-carriers of the epsilon 4 allele, yet more pronounced in epsilon 4 carriers. Although not reaching significance, comparisons of AB positive vs. negative subjects indicated stronger HTH atrophy in biomarker positive participants. HV was not associated with body mass index or longitudinal weight change. Conclusions: : Our findings support early structural changes of the HTH in AD. HV covaries with regional volumes of AD-vulnerable regions. This could point to secondary atrophy of the HTH following atrophy of the hippo- campus and other structures of the Papez circuit in AD.