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

Article type: Research Article

Authors: Chaudhary, Shefali^a | Zhornitsky, Simon^a | Chao, Herta H.^{b; c} | van Dyck, Christopher H.^{a; d; e; f} | Li, Chiang-Shan R.^{a; e; f; g; *}

Affiliations: [a] Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA | [b] VA Connecticut Healthcare System, West Haven, CT, USA | [c] Department of Medicine & Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA | [d] Alzheimer’s Disease Research Unit, Yale University School of Medicine, New Haven, CT, USA | [e] Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA | [f] Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, CT, USA | [g] Wu Tsai Institute, Yale University, New Haven, CT, USA

Correspondence: [*] Correspondence to: Chiang-Shan R. Li, Professor of Psychiatry and of Neuroscience, Connecticut Mental Health Center S112, 34 Park Street, New Haven, CT 06519, USA. Tel.: +1 203 974 7354; E-mail: [email protected].

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

DOI: 10.3233/JAD-220708

Journal: Journal of Alzheimer's Disease, vol. 90, no. 4, pp. 1615-1628, 2022