Abstract
Despite accruing evidence for relative preservation of episodic memory in the semantic variant of primary progressive aphasia (previously semantic dementia), the neural basis for this remains unclear, particularly in light of their well-established hippocampal involvement. We recently investigated the Papez network of memory structures across pathological subtypes of behavioral variant frontotemporal dementia and demonstrated severe degeneration of all relay nodes, with the anterior thalamus in particular emerging as crucial for intact episodic memory. The present study investigated the status of key components of Papez circuit (hippocampus, mammillary bodies, anterior thalamus, cingulate cortex) and anterior temporal cortex using volumetric and quantitative cell counting methods in pathologically-confirmed cases with semantic variant of primary progressive aphasia (n=8; 61-83 years; 3 males), behavioral variant frontotemporal dementia with TDP pathology (n=9; 53-82 years; 6 males) and healthy controls (n=8, 50-86 years; 4 males). Behavioral variant frontotemporal dementia cases with TDP pathology were selected because of the association between the semantic variant of primary progressive aphasia and TDP pathology. Our findings revealed that the semantic variant of primary progressive aphasia and behavioral variant frontotemporal dementia show similar degrees of anterior thalamic atrophy. The mammillary bodies and hippocampal body and tail were preserved in the semantic variant of primary progressive aphasia but were significantly atrophic in behavioral variant frontotemporal dementia. Importantly, atrophy in the anterior thalamus and mild progressive atrophy in the body of the hippocampus emerged as the main memory circuit regions correlated with increasing dementia severity in the semantic variant of primary progressive aphasia. Quantitation of neuronal populations in the cingulate cortices confirmed the selective loss of anterior cingulate Von Economo neurons in behavioral variant frontotemporal dementia. We also show that by end-stage these neurons selectively degenerate in the semantic variant of primary progressive aphasia with preservation of neurons in the posterior cingulate cortex. Overall, our findings demonstrate for the first time, severe atrophy, although not necessarily neuronal loss, across all relay nodes of Papez circuit with the exception of the mammillary bodies and hippocampal body and tail in the semantic variant of primary progressive aphasia. Despite the longer disease course in the semantic variant of primary progressive aphasia compared to behavioral variant frontotemporal dementia, we suggest here that the neural preservation of crucial memory relays (hippocampal_mammillary bodies and posterior cingulate_hippocampus) likely reflects the conservation of specific episodic memory components observed in most patients with semantic variant of primary progressive aphasia.