Clinical and neuroanatomical characterization of the semantic behavioral variant of frontotemporal dementia in a multicenter Italian cohort

Abstract

Background: Semantic behavioral variant frontotemporal dementia (sbvFTD) is a neurodegenerative condition presenting with specific behavioral and semantic derangements and predominant atrophy of the right anterior temporal lobe (ATL). The objective was to evaluate clinical, neuropsychological, neuroimaging, and genetic features of an Italian sbvFTD cohort, defined according to recently proposed guidelines, compared to semantic variant primary progressive aphasia (svPPA) and behavioral variant FTD (bvFTD) patients.

Methods: Fifteen sbvFTD, sixty-three bvFTD, and twenty-five svPPA patients and forty controls were enrolled. Patients underwent clinical, cognitive evaluations, and brain MRI. Symptoms of bvFTD patients between onset and first visit were retrospectively recorded and classified as early and late. Grey matter atrophy was investigated using voxel-based morphometry.

Results: sbvFTD experienced early criteria-specific symptoms: world, object and person-specific semantic loss (67%), complex compulsions and rigid thought (60%). Sequentially, more behavioral symptoms emerged (apathy/inertia, loss of empathy) along with non-criteria-specific symptoms (anxiety, suspiciousness). sbvFTD showed sparing of attentive/executive functions, especially compared to bvFTD and better language functions compared to svPPA. All sbvFTD patients failed at the famous face recognition test and more than 80% failed in understanding written metaphors and humor. At MRI, sbvFTD had predominant right ATL atrophy, almost specular to svPPA. Three sbvFTD patients presented pathogenic genetic variants.

Conclusion: We replicated the application of sbvFTD diagnostic guidelines in an independent Italian cohort, demonstrating that the presence of person-specific semantic knowledge loss and mental rigidity, along with preserved executive functions and a predominant right ATL atrophy with sparing of frontal lobes, should prompt a diagnosis of sbvFTD.

Keywords: FTD; MRI; Voxel-based morphometry; rtvFTD; sbvFTD.

Fig. 1

Sample selection and study design. Two hundred eighty-three patients with a suspected diagnosis of FTLD-spectrum disease were enrolled at San Raffaele Hospital between 2017 and 2023. Of these, 236 were confirmed for an FTLD-related disorder. Fifteen patients (6.4%) had sbvFTD. The remaining patients had bvFTD (n = 63, 26.7%), svPPA (n = 25, 10.5%), nfvPPA (n = 21, 8.4%), MND (n = 67, 28.4%), atypical parkinsonism (n = 45, 19%). For the purposes of this study, we included only patients with a diagnosis of sbvFTD, bvFTD or svPPA, for a total number of 103 subjects. Detected genetic mutations are reported in the last pie chart. bvFTD behavioral variant frontotemporal dementia, C9orf72 chromosome 9 open reading frame 72, FTLD frontotemporal lobar degeneration, FUS fused in sarcoma, GRN progranulin, MAPT microtubule associated protein tau, MND motor neuron disease, sbvFTD semantic behavioral variant frontotemporal dementia, svPPA semantic variant primary progressive aphasia, TREM2 triggering receptor expressed on myeloid cells 2

Fig. 2

Symptoms developed by semantic behavioral FTD (sbvFTD) patients. Spider chart depicting the number of sbvFTD patients affected by a given symptom. Blue line represents the first three symptoms reported by caregivers/patients; orange line represents all symptoms reported from disease onset to the time of the visit. “Extra-criteria” symptoms = anxiety, suspiciousness, agitation, irritability or depression

Fig. 3

Patterns of gray matter atrophy in patients with behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), and semantic behavioral frontotemporal dementia (sbvFTD). Results of voxel-based morphometry analysis showing regions of significant GM atrophy in bvFTD patients compared to healthy controls (HC) (A), svPPA compared to HC (B), and sbvFTD compared to HC (C). Composite image showing svPPA and sbvFTD patterns of atrophy, combined with green areas showing regions of overlapping volume loss (D). Significant clusters are overlaid on sections of the Montreal Neurologic Institute standard brain. Analyses were corrected for age, sex, and total intracranial volume. Statistical threshold for significance was p < 0.05, family-wise error corrected for multiple comparisons. bvFTD behavioral variant frontotemporal dementia, sbvFTD semantic behavioral variant frontotemporal dementia, svPPA semantic variant primary progressive aphasia

Fig. 4

Patterns of gray matter atrophy in patients with semantic behavioral variant frontotemporal dementia (sbvFTD) compared to behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA). Results of voxel-based morphometry showing regions of significant GM atrophy in bvFTD compared to sbvFTD (A), sbvFTD compared to bvFTD (B), svPPA compared to sbvFTD (C), sbvFTD compared to svPPA (D). Significant clusters are overlaid on sections of the Montreal Neurologic Institute standard brain. Analyses were corrected for age, sex, and total intracranial volume. Statistical threshold for significance was p < 0.05, family-wise error corrected for multiple comparisons. For uncorrected results, threshold of significance was p < 0.001. bvFTD behavioral variant frontotemporal dementia, sbvFTD semantic behavioral variant frontotemporal dementia, svPPA semantic variant primary progressive aphasia