Dissecting medial temporal lobe from diencephalic sub-volumes: The amnesia dichotomy revisited

Severe episodic memory deficits have historically been categorized as diencephalic amnesia, like in Korsakoff's Syndrome (KS), or as medial temporal lobe (MTL) amnesia, like in Alzheimer's Disease (AD). However, recent research has highlighted that both MTL and thalamus contribute to episodic memory. We aimed to challenge the traditional distinction by assessing whether subregional volume loss in the MTL and diencephalon reflects the distinct amnesia profiles traditionally associated with KS and AD. This cross-sectional observational study includes 203 subjects, comprising 81 healthy control participants. Of the 122 patients, 42 had amnesia: 18 patients with KS and 24 patients with AD at a dementia stage (dAD); and 80 had mild cognitive disorders: 50 patients with severe alcohol use disorder (AUD) without KS and 30 patients with amnestic mild cognitive impairment (aMCI). High-resolution T1-weighted MRI was used to quantify MTL subregions (anterior/posterior hippocampus, entorhinal cortex, parahippocampal cortex) using the ASHS-T1 pipeline and key diencephalic structures (anterior/mediodorsal thalamic nuclei, mammillothalamic tract) using the HIPS-THOMAS toolbox. Volume loss among patients and regions were compared using a linear mixed model. For each region, correlations between episodic memory and volumes loss were assessed and compared between aMCI/dAD and AUD/KS patients. Results showed no volume difference between patient groups for the anterior and posterior hippocampus and parahippocampal cortex. Entorhinal cortex was more altered in aMCI and dAD than in AUD and KS. KS and AUD patients showed disproportionate structural alterations in thalamic nuclei and mammillothalamic tracts compared with MTL subregions. KS patients showed more severe alterations than all other groups, except for anterior thalamic nuclei for which volume did not differ between KS and dAD. Episodic memory performance of AUD and KS patients correlated with volumes loss in the anterior and mediodorsal thalamic nuclei and mammillothalamic tract, while that of aMCI and dAD patients correlated with volume loss in the anterior hippocampus. Alterations in the MTL and diencephalon are not as clearly dissociated as traditionally proposed in the classification of amnesia. While KS pathology is characterized by more severe diencephalic alterations, only the entorhinal cortex is more damaged in AD than in KS. Neither hippocampal nor anterior thalamic volume loss appears to distinguish between the two types of amnesia, suggesting that structural changes in these two regions jointly participate to the pathophysiology of amnesia whatever the etiology. However, these alterations are not similarly involved in memory deficits, which suggests different architectural and/or functional implications of same-scale volume loss.