Right temporal degeneration and socioemotional semantics: semantic behavioural variant frontotemporal dementia

Abstract

Focal anterior temporal lobe (ATL) degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant ATL (lATL) atrophy show severe anomia and verbal semantic deficits and meet criteria for semantic variant primary progressive aphasia (svPPA) and semantic dementia, patients with early right ATL (rATL) atrophy are more difficult to diagnose as their symptoms are less well understood. Focal rATL atrophy is associated with prominent emotional and behavioral changes, and patients often meet, or go on to meet, criteria for behavioral variant frontotemporal dementia (bvFTD). Uncertainty around early symptoms and absence of an overarching clinicoanatomical framework continue to hinder proper diagnosis and care of patients with rATL disease. Here, we examine a large, well-characterized, longitudinal cohort of patients with rATL-predominant degeneration and propose new criteria and nosology. We identified individuals from our database with a clinical diagnosis of bvFTD or svPPA and a structural MRI (n = 478). Based on neuroimaging criteria, we defined three patient groups: rATL-predominant atrophy with relative sparing of the frontal lobes (n = 46), frontal-predominant atrophy with relative sparing of the rATL (n = 79), and lATL-predominant atrophy with relative sparing of the frontal lobes (n = 75). We compared the clinical, neuropsychological, genetic, and pathological profiles of these groups. 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, recognition of famous people (from names and face), and facial affect naming (despite preserved face perception) than the frontal- and lATL-predominant groups. The clinical symptoms in the first three years of the disease alone were highly sensitive (81%) and specific (84%) differentiating rATL-predominant from frontal-predominant groups. FTLD-TDP (84%) was the most common pathology of the rATL-predominant group. rATL-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive decline in semantic memory for concepts of socioemotional relevance. Guided by our results, we outline new diagnostic criteria and propose the name, “semantic behavioral variant frontotemporal dementia” (sbvFTD), which highlights the underlying cognitive mechanism and the predominant symptomatology. These diagnostic criteria will facilitate early identification and care of patients with early, focal rATL degeneration as well as in vivo prediction of FTLD-TDP pathology.

The problematic syndrome of right temporal lobe atrophy: Unweaving the phenotypic rainbow

“…Empathy may, for example, be misplaced and/or caricatured rather than blunted (20). Certain features such as religiosity, musicophilia, obsessions around puzzles, colors or time-keeping, somatising and other odd (sometimes synaesthetic) sensory experiences, while still quite sketchily described, appear to be quite specific for RTLA set against other cases of bvFTD or svPPA (4)(5)(6)(7)(21)(22)(23). Moreover, along with more pervasive disturbances of affect, humor, social awareness, pain sensibility, appetite and circadian rhythms, these behavioral changes often occur early, even well before the onset of cognitive deficits such as prosopagnosia (19,(23)(24)(25)(26)(27)(28).…”

“…The clinically significant way-finding difficulty that sometimes accompanies RTLA superficially resembles the topographical disorientation of Alzheimer's disease but may reflect impaired recognition of topographical landmarks, potentially also encompassing ‘landmark' events in patients' personal timelines ( 9 ). Based on a detailed clinical, neuropsychological, neuroanatomical, neuropathological and genetic analysis of 46 cases, Younes et al ( 4 ) have recently proposed that this syndrome be designated “semantic behavioral variant frontotemporal dementia”, with core diagnostic criteria of loss of empathy, difficulty identifying familiar people and complex compulsions or mental rigidity ( 4 ).…”

“…Complex and profound affective and behavioral disturbances are integral to the RTLA syndrome ( 4 , 5 ), and these features have yet to be fully characterized. Empathy may, for example, be misplaced and/or caricatured rather than blunted ( 20 ).…”

“…Three canonical clinico-anatomical syndromes of FTD are currently recognized: non-fluent variant primary progressive aphasia (nfvPPA), characterized by impaired language output, with predominant anterior left peri-Sylvian atrophy; semantic variant primary progressive aphasia (svPPA), characterized by impaired understanding of words, objects, concepts and socio-emotional signals, with predominantly left-sided antero-mesial temporal lobe atrophy; and behavioral variant frontotemporal dementia (bvFTD), characterized by impaired behavioral regulation and disordered inter-personal conduct and awareness, with a variable atrophy profile. The syndromes of bvFTD and svPPA have an important interface of clinical and neuroanatomical overlap, with a key locus in the right anterior temporal lobe: patients with selective or disproportionate right temporal lobe atrophy (RTLA) may have a distinctive clinical syndrome spanning the bvFTD-svPPA interface, however encapsulating this syndrome has proved both challenging and controversial ( 4 – 6 ).…”

Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort

“…The right temporal variant of FTD (rtvFTD), a rarer clinical phenotype, originally considered a right variant of svFTD, has distinct clinical features and predominantly right hemisphere involvement. Patients with rtvFTD exhibit early behavioral symptoms, particularly empathy deficits and psychiatric disorders ( Ulugut Erkoyun et al, 2020 ), but the diagnosis is challenging, and patients are often misdiagnosed as behavioral variant of FTD (bvFTD; Younes et al, 2022 ). A motor neuron involvement is rare in svFTD, but it has been found in up to 28% of rtvFTD cases in a recent neuropathological cohort ( Ulugut et al, 2021 ).…”