Mediation of Reduced Hippocampal Volume by Cerebral Amyloid Angiopathy in Pathologically Confirmed Patients with Alzheimer’s Disease

Article type: Research Article

Authors: Nagaraja, Nandakumar^{a; 1; *} | Wang, Wei-en^b | Duara, Ranjan^c | DeKosky, Steven T.^{a; d} | Vaillancourt, David^{b; e}

Affiliations: [a] Department of Neurology, College of Medicine, University of Florida, Gainesville, FL, USA | [b] Laboratory for Rehabilitation Neuroscience, Department of Applied Physiology and Kinesiology, University of Florida, Gainesville, FL, USA | [c] Department of Neurology, Mount Sinai Medical Center, Miami Beach, FL, USA | [d] McKnight Brain Institute, University of Florida, Gainesville, FL, USA | [e] Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA

Correspondence: [*] Correspondence to: Nandakumar Nagaraja, MD, MS, FAHA, Department of Neurology, Penn State College of Medicine, Milton S. Hershey Medical Center, 30 Hope Drive, Suite 2800, PO Box 859, EC037, Hershey, PA 17033, USA. Tel.: +1 717 531 0003 /Ext 289694; Fax: +1 717 531 0384; E-mail: nnagaraja@pennstatehealth.psu.edu.

Note: [1] Present address: Department of Neurology, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, PA, USA.

Abstract: Background:Hippocampal atrophy in cerebral amyloid angiopathy (CAA) has been reported to be similar to that in Alzheimer’s disease (AD). Objective:To evaluate if CAA pathology partly mediates reduced hippocampal volume in patients with AD. Methods:Patients with a clinical diagnosis of AD and neuropathological confirmation of AD+/-CAA in the National Alzheimer’s Coordinating Center database were included in the study. The volumes of temporal lobe structures were calculated on T1-weighted imaging (T1-MRI) using automated FreeSurfer software, from images acquired on average 5 years prior to death. Multivariate regression analysis was performed to compare brain volumes in four CAA groups. The hippocampal volume on T1-MRI was correlated with Clinical Dementia Rating sum of boxes (CDRsb) score, apolipoprotein E (APOE) genotype, and hippocampal atrophy at autopsy. Results:The study included 231 patients with no (n = 45), mild (n = 70), moderate (n = 67), and severe (n = 49) CAA. Among the four CAA groups, patients with severe CAA had a smaller mean left hippocampal volume (p = 0.023) but this was not significant when adjusted for APOE ɛ4 (p = 0.07). The left hippocampal volume on MRI correlated significantly with the hippocampal atrophy grading on neuropathology (p = 0.0003). Among patients with severe CAA, the left hippocampal volume on T1-MRI: (a) decreased with an increase in the number of APOE ɛ4 alleles (p = 0.04); but (b) had no evidence of correlation with CDRsb score (p = 0.57). Conclusion:Severe CAA was associated with smaller left hippocampal volume on T1-MRI up to five years prior to death among patients with neuropathologically confirmed AD. This relationship was dependent on APOE ɛ4 genotype.

Keywords: Alzheimer’s disease, trophy, cerebral amyloid angiopathy, hippocampus

DOI: 10.3233/JAD-220624

Journal: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 495-507, 2023