Differences and similarities between familial and sporadic frontotemporal dementia: An Italian single‐center cohort study

Abstract

Introduction The possibility to generalize our understandings on treatments and assessments to both familial frontotemporal dementia (f‐FTD) and sporadic FTD (s‐FTD) is a fundamental perspective for the near future, considering the constant advancement in potential disease‐modifying therapies that target particular genetic forms of FTD. We aimed to investigate differences in clinical features, cerebrospinal fluid (CSF), and blood‐based biomarkers between f‐FTD and s‐FTD. Methods In this longitudinal cohort study, we evaluated a consecutive sample of symptomatic FTD patients, classified as f‐FTD and s‐FTD according to Goldman scores (GS). All patients underwent clinical, behavioral, and neuropsychiatric symptom assessment, CSF biomarkers and serum neurofilament light (NfL) analysis, and brain atrophy evaluation with magnetic resonance imaging. Results Of 570 patients with FTD, 123 were classified as f‐FTD, and 447 as s‐FTD. In the f‐FTD group, 95 had a pathogenic FTD mutation while 28 were classified as GS = 1 or 2; of the s‐FTD group, 133 were classified as GS = 3 and 314 with GS = 4. f‐FTD and s‐FTD cases showed comparable demographic features, except for younger age at disease onset, age at diagnosis, and higher years of education in the f‐FTD group (all P < .05). f‐FTD showed worse behavioral disturbances as measured with Frontal Behavioral Inventory (FBI) negative behaviors (14.0 ± 7.6 vs. 11.6 ± 7.4, P = .002), and positive behaviors (20.0 ± 11.0 vs. 17.4 ± 11.8, P = .031). Serum NfL concentrations were higher in patients with f‐FTD (70.9 ± 37.9 pg/mL) compared to s‐FTD patients (37.3 ± 24.2 pg/mL, P < .001), and f‐FTD showed greater brain atrophy in the frontal and temporal regions and basal ganglia. Patients with f‐FTD had significantly shorter survival than those with s‐FTD ( P = .004). Discussion f‐FTD and s‐FTD are very similar clinical entities, but with different biological mechanisms, and different rates of progression. The parallel characterization of both f‐FTD and s‐FTD will improve our understanding of the disease, and aid in designing future clinical trials for both genetic and sporadic forms of FTD. Highlights Do clinical features and biomarkers differ between patients with familial frontotemporal dementia (f‐FTD) and sporadic FTD (s‐FTD)? In this cohort study of 570 patients with FTD, f‐FTD and s‐FTD share similar demographic features, but with younger age at disease onset and diagnosis in the f‐FTD group. f‐FTD showed higher serum neurofilament light concentrations, greater brain damage, and shorter survival, compared to s‐FTD. f‐FTD and s‐FTD are very similar clinical entities, but with different cognitive reserve mechanisms and different ra...

The pursuit for markers of disease progression in behavioral variant frontotemporal dementia: a scoping review to optimize outcome measures for clinical trials

“…Increased CSF NfL, in both genetic and sporadic subtypes, has been associated with various progression measures, including CDR, cognition (executive functioning; neuropsychiatry unit cognitive assessment tool), behavioral symptoms (FBI), frontotemporal GM atrophy, WM tract pathophysiology, GABA-ergic deficit, and survival rates ( Scherling et al, 2014 ; Kassubek et al, 2018 ; Steinacker et al, 2018 ; Benussi et al, 2020 ; Spotorno et al, 2020 ; Walia et al, 2022 ). Interestingly, when comparing genetic and sporadic subtypes, a large cross-sectional study concluded that serum NfL concentration is higher in genetic bvFTD ( Benussi et al, 2022 ). Another promising, less validated fluid biomarker is soluble triggering receptor expressed on myeloid cells 2 (sTREM2).…”

Cell type-specific translatome analysis of mouse models of three genetic neurodegenerative diseases

“…Although classified as rare diseases, they are each caused by a well-defined mutation in a single protein. Monogenic neurodegenerative diseases, including genetic forms of Alzheimer's disease 9,10 , Parkinson's disease, and prion diseases have become popular in scientific research as their study offers several advantages 11 : While differences in clinical symptoms and pathological changes exist between genetic and sporadic forms of the same disease, there is also considerable overlap [12][13][14] , suggesting findings may translate between different disease forms. Furthermore, they are easier to replicate in a disease model than sporadic or polygenic diseases, which have a more complex etiology involving interactions of genetic and environmental factors.…”