Hypothalamic Functional Connectivity and Apathy in People with Alzheimer's Disease and Cognitively Normal Healthy Controls

Abstract

Background: Earlier studies have described the neural markers of apathy in Alzheimer's disease (AD) and mild cognitive impairment (MCI), but few focused on the motivation circuits. Here, we targeted hypothalamus, a hub of the motivation circuit.

Objective: To examine hypothalamic resting state functional connectivity (rsFC) in relation to apathy.

Methods: We performed whole-brain regression of hypothalamic rsFC against Apathy Evaluation Scale (AES) total score and behavioral, cognitive, and emotional subscores in 29 patients with AD/MCI and 28 healthy controls (HC), controlling for age, sex, education, cognitive status, and depression. We evaluated the results at a corrected threshold and employed path analyses to assess possible interaction between hypothalamic rsFCs, apathy and depression/memory. Finally, we re-examined the findings in a subsample of amyloid-β-verified AD.

Results: AES total score correlated negatively with hypothalamic precuneus (PCu)/posterior cingulate cortex (PCC) and positively with left middle temporal gyrus (MTG) and supramarginal gyrus rsFCs. Behavioral subscore correlated negatively with hypothalamic PCu/PCC and positively with middle frontal gyrus rsFC. Cognitive subscore correlated positively with hypothalamic MTG rsFC. Emotional subscore correlated negatively with hypothalamic calcarine cortex rsFC. In path analyses, hypothalamic-PCu/PCC rsFC negatively modulated apathy and, in turn, depression. The model where hypothalamic MTG rsFC and memory independently modulated apathy also showed a good fit. The findings of diminished hypothalamic-PCu/PCC rsFC in relation to apathy and, in turn, depression were confirmed in amyloid-verified AD.

Conclusion: The findings together support a role of altered hypothalamic connectivity in relation to apathy and depression, and modulation of apathy by memory dysfunction.

Keywords: Alzheimer’s disease; apathy; depression; hypothalamus; memory; resting state functional connectivity.

Fig. 1.

Whole-brain multiple regression of hypothalamus (HT) resting state functional connectivity (rsFC) with (A) AES-total score in all (HC and AD/MCI) sample. Warm and winter color bars represent T-values of positive and negative correlations, respectively. B) Scatterplot of AES-total and HT rsFCs (β) with regression line shown separately for HC and AD/MCI. Note that the scatterplots show values in residuals (res.) and the t- and p-values show slope test between HC and AD-MCI for the corresponding correlations. For all regressions, we controlled for age, sex, education, MMSE, and BDI-II. MTG, middle temporal gyrus; PCu, precuneus; PCC, posterior cingulate cortex; SMG, supramarginal gyrus.

Fig. 2.

Whole-brain multiple regression of hypothalamus (HT) resting state functional connectivity (rsFC) with (A) AES behavioral, cognitive, and emotional subscores across all subjects. Color bars indicate voxel T values (warm/cool: positive/negative correlation). MFG, middle frontal gyrus; MTG, middle temporal gyrus; PCu, Precuneus; PCC, posterior cingulate cortex; Calc, calcarine cortex. The bottom row shows the scatterplots of AES (B) behavioral, (C) cognitive, and (D) emotional sub-scores versus extracted HT rsFCs (β) with regression lines shown separately for HC and AD/MCI. Note that the scatterplot represents values in residuals (res.) and the t- and p-values are of the slope tests of HC versus AD/MCI for the corresponding correlations. For all analyses, we controlled for age, sex, education, MMSE, and BDI-II.

Fig. 3.

Models showing a good fit in path analyses. Hypothalamus (HT)-middle frontal gyrus (MFG) rsFC and HT-middle temporal gyrus (MTG) rsFC both negatively modulated HT-precuneus (PCu)/posterior cingulate cortex (PCC) rsFC which (A) negatively affected AES score and, in turn, BDI-II score; and (B) negatively modulated AES score, with BDI-II independently facilitating apathy. In both models, HT-MTG rsFC also significantly and positively modulated AES score. C) In the model of HT rsFC, apathy and memory, HT-PCu/PCC did not significantly affect AES score. HT-MTG rsFC positively and LMI score negatively modulated apathy. The β (path) coefficients and p-values were obtained from regression analyses using maximum likelihood method. The solid and dashed line each represents a significant and non-significant path coefficient.