Right Anterior Temporal Degeneration, Emotions, and Loss of Nonverbal Semantics: The Emotional Semantic Variant Frontotemporal Dementia

It has been proposed that focal anterior temporal lobe (ATL) degeneration is a specific, unitary FTLD-TDP-related disease that initially preferentially affects the left or right hemisphere. Patients with early left ATL (lATL) atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia (svPPA) and semantic dementia, prompting appropriate neurological care. There is less consensus regarding the symptoms in right ATL (rATL) predominant cases, who most often present with behavioral and emotional changes leading to a misdiagnosis of a psychiatric disorder, and later of behavioral variant frontotemporal dementia (bvFTD). Uncertainties regarding early symptoms and lack of an overarching framework continues to hinder proper diagnosis and care of patients with rATL disease. Here, we present symptom chronology, cognitive and socioemotional profiles of a large, well-characterized, longitudinally followed cohort of patients with rATL-predominant degeneration and propose new criteria and nosology for the syndrome. We identified individuals with a clinical diagnosis of bvFTD or svPPA and a structural MRI (n=478). Based on neuroimaging criteria, we identified three groups: patients with rATL-predominant atrophy with relative sparing of the frontal lobes (n=46), patients with frontal-predominant atrophy with relative sparing of the rATL (n=79), and patients with lATL-predominant atrophy with relative sparing of the frontal lobes (n=75). Seventy-eight patients had undergone autopsy. We analyzed patients’ clinical, neuropsychological, genetic, anatomical, and pathological profiles. In the rATL-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%), and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in emotional theory of mind, identifying famous people from names and face, and facial affect naming (despite preserved face perception) than the lATL- and frontal-predominant groups. The clinical features were highly sensitive (81%) and specific (84%) in differentiating rATL from bvFTD in the first three years of the disease. FTLD-TDP (84%) was the most common pathology. Our results suggest that rATL-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive loss of semantic memory for concepts of social-emotional relevance. Although this syndrome exists along a clinical, anatomical, and pathological continuum with svPPA, patients present with progressive behavioral changes. To facilitate early identification and care in clinical and research settings, we propose specific diagnostic criteria and the term “emotional semantic variant frontotemporal dementia” to distinguish this syndrome from other forms of frontotemporal dementia. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the National Institutes of Health (NINDS R01NS050915, NIDCD K24DC015544, NIDCD R03DC013403, NIDCD F32DC009145, NIA U01AG052943, NIA P50AG023501, NIA P01AG019724, NIA R01AG038791, NINDS U54NS092089, NIA K08AG052648, NIA R01AG029577, NIA K23-AG021606, NIA P50AG023501), Alzheimer Disease Research Center of California (03- 75271 DHS/ADP/ARCC); Larry L. Hillblom Foundation; John Douglas French Alzheimer Foundation; Koret Family Foundation; Consortium for Frontotemporal Dementia Research; and McBean Family Foundation. LTG is partially funded by NIH K24AG053435. These supporting sources were not involved in the study design, collection, analysis or interpretation of data, nor were they involved in writing the paper or in the decision to submit this report for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: University of California San Francisco Human Research Protection Program. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data for this study is available upon request. * bvFTD : behavioral variant frontotemporal dementia esvFTD : emotional semantic variant frontotemporal dementia FTD : frontotemporal dementia FTLD : frontotemporal lobar degeneration rATL : right anterior temporal lobe lATL : left anterior temporal lobe sd : standard deviation svPPA : semantic variant primary progressive aphasia TDP-43 : transactive response DNA binding protein 43