Volumetric Analysis of Hippocampal Subregions and Subfields in Left and Right Predominant Semantic Dementia

Abstract Two variants of semantic dementia are recognized based on the laterality of temporal lobe involvement: a left-predominant variant associated with verbal knowledge impairment and a right-predominant variant associated with behavioral changes and non-verbal knowledge loss. This cross-sectional clinicoradiologic study aimed to assess whole hippocampal, subregion, and/or subfield volume loss in semantic dementia versus controls and across its variants. Thirty-five semantic dementia participants and 15 controls from the Neurodegenerative Research Group at Mayo Clinic who had completed 3.0-T volumetric MRI and 18F-fluorodeoxyglucose-PET were included. Classification as left-predominant (n=25) or right-predominant (n=10) variant was based on temporal lobe hypometabolism. Volumes of hippocampal subregions (head, body, tail) and subfields (parasubiculum, presubiculum, subiculum, CA1, CA3, CA4, dentate gyrus, molecular layer, hippocampal-amygdaloid transition area, fimbria) were obtained using FreeSurfer7. Subfield volumes were measured separately from head and body subregions. We fit linear mixed effects models using log-transformed whole hippocampal/subregion/subfield volumes as dependent variables; age, sex, total intracranial volume, hemisphere and a group-by-hemisphere interaction as fixed effects; and subregion/subfield nested within hemisphere as a random effect. Significant results (P<0.05) are hereby reported. At the whole hippocampal level, the dominant (predominantly involved) hemisphere of both variants showed 23%-27% smaller volumes than controls. The non-dominant (less involved) hemisphere of right-predominant variant also showed volume loss versus controls and left-predominant variant. At the subregional level, both variants showed 17%-28% smaller dominant hemisphere head, body, and tail than controls, with right-predominant variant also showing 8%-12% smaller non-dominant hemisphere head than controls and left-predominant variant. At the subfield level, left-predominant variant showed 12%-36% smaller volumes across all dominant hemisphere subfields and 14%-15% smaller non-dominant hemisphere parasubiculum, presubiculum-head, presubiculum-body, subiculum-head, and hippocampal-amygdaloid transition area than controls. Right-predominant variant showed 16%-49% smaller volumes across all dominant hemisphere subfields and 14%-22% smaller parasubiculum, presubiculum, subiculum, CA3, hippocampal-amygdaloid transition area (all from head) and fimbria of non-dominant hemisphere versus controls. Comparison of dominant hemispheres showed 16%-29% smaller volumes of the parasubiculum, presubiculum-head, and fimbria in right-predominant than left-predominant variant; comparison of non-dominant hemispheres showed 12%-15% smaller CA3, CA4, dentate gyrus, hippocampal-amygdaloid transition area (all from head) and CA1, CA3, CA4 (all from body) in right-predominant variant. All hippocampal subregion/subfield volumes are affected in semantic dementia, although some are more affected in both dominant and non-dominant hemispheres of right-predominant than left-predominant variant by the time of presentation. Involvement of hippocampal structures is apparently more subregion-dependent than subfield-dependent, indicating possible superiority of subregion volumes as disease biomarkers.