Cerebral Volumetric Correlates of Apathy in Alzheimer’s Disease and Cognitively Normal Older Adults: Meta-Analysis, Label-Based Review, and Study of an Independent Cohort

Article type: Research Article

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

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

Correspondence: [*] Correspondence to: Chiang-Shan R. Li, MD, PhD, 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:Affecting nearly half of the patients with Alzheimer’s disease (AD), apathy is associated with higher morbidity and reduced quality of life. Basal ganglia and cortical atrophy have been implicated in apathy. However, the findings have varied across studies and left unclear whether subdomains of apathy may involve distinct neuroanatomical correlates. Objective:To identify neuroanatomical correlates of AD-associated apathy. Methods:We performed a meta-analysis and label-based review of the literature. Further, following published routines of voxel-based morphometry, we aimed to confirm the findings in an independent cohort of 19 patients with AD/mild cognitive impairment and 25 healthy controls assessed with the Apathy Evaluation Scale. Results:Meta-analysis of 167 AD and 56 healthy controls showed convergence toward smaller basal ganglia gray matter volume (GMV) in apathy. Label-based review showed anterior cingulate, putamen, insula, inferior frontal gyrus (IFG) and middle temporal gyrus (MTG) atrophy in AD apathy. In the independent cohort, with small-volume-correction, right putamen and MTG showed GMVs in negative correlation with Apathy Evaluation Scale total, behavioral, and emotional scores, and right IFG with emotional score (p < 0.05 family-wise error (FWE)-corrected), controlling for age, education, intracranial volume, and depression. With the Mini-Mental State Examination scores included as an additional covariate, the correlation of right putamen GMV with behavioral and emotional score, right MTG GMV with total and emotional score, and right IFG GMV with emotional score were significant. Conclusion:The findings implicate putamen, MTG and IFG atrophy in AD associated apathy, potentially independent of cognitive impairment and depression, and suggest potentially distinct volumetric correlates of apathy.

Keywords: Activation likelihood estimation, Alzheimer-type dementia, Alzheimer’s disease, emotional apathy, gray matter, inferior frontal gyrus, meta-analysis, middle temporal gyrus, striatum

DOI: 10.3233/JAD-215316

Journal: Journal of Alzheimer's Disease, vol. 85, no. 3, pp. 1251-1265, 2022