Redefining the multidimensional clinical phenotypes of frontotemporal lobar degeneration syndromes

Abstract

The syndromes caused by frontotemporal lobar degeneration have highly heterogeneous and overlapping clinical features. There has been great progress in the refinement of clinical diagnostic criteria in the past decade, but we propose that a better understanding of aetiology, pathophysiology and symptomatic treatments can arise from a transdiagnostic approach to clinical phenotype and brain morphometry. In a cross-sectional epidemiological study, we examined 310 patients with a syndrome likely to be caused by frontotemporal lobar degeneration, including behavioural variant frontotemporal dementia, non-fluent, and semantic variants of primary progressive aphasia (PPA), progressive supranuclear palsy and corticobasal syndrome. We included patients with logopenic PPA and those who met criteria for PPA but not a specific subtype. To date, 49 patients have a neuropathological diagnosis. A principal component analysis identified symptom dimensions that broadly recapitulated the core features of the main clinical syndromes. However, the subject-specific scores on these dimensions showed considerable overlap across the diagnostic groups. Sixty-two per cent of participants had phenotypic features that met the diagnostic criteria for more than one syndrome. Behavioural disturbance was prevalent in all groups. Forty-four per cent of patients with corticobasal syndrome had progressive supranuclear palsy-like features and 30% of patients with progressive supranuclear palsy had corticobasal syndrome-like features. Many patients with progressive supranuclear palsy and corticobasal syndrome had language impairments consistent with non-fluent variant PPA while patients with behavioural variant frontotemporal dementia often had semantic impairments. Using multivariate source-based morphometry on a subset of patients (n = 133), we identified patterns of covarying brain atrophy that were represented across the diagnostic groups. Canonical correlation analysis of clinical and imaging components found three key brain-behaviour relationships, with a continuous spectrum across the cohort rather than discrete diagnostic entities. In the 46 patients with follow-up (mean 3.6 years) syndromic overlap increased with time. Together, these results show that syndromes associated with frontotemporal lobar degeneration do not form discrete mutually exclusive categories from their clinical features or structural brain changes, but instead exist in a multidimensional spectrum. Patients often manifest diagnostic features of multiple disorders while deficits in behaviour, movement and language domains are not confined to specific diagnostic groups. It is important to recognize individual differences in clinical phenotype, both for clinical management and to understand pathogenic mechanisms. We suggest that a transdiagnostic approach to the spectrum of frontotemporal lobar degeneration syndromes provides a useful framework with which to understand disease aetiology, progression, and heterogeneity and to target future treatments to a higher proportion of patients.

Social Cognition Deficits Are Pervasive across Both Classical and Overlap Frontotemporal Dementia Syndromes

“…Recently, overlap syndromes are increasingly being recognized; these are characterised by a range of motor features in association with the cognitive-behavioural syndrome of FTD. These include: FTD amyotrophic lateral sclerosis (FTD-ALS), FTD progressive supranuclear palsy (FTD-PSP), and FTD corticobasal syndrome (FTD-CBS) [ 4 , 5 , 6 , 7 , 8 ]. Research indicates that social cognition deficits underlie the complex behavioural problems exhibited by patients with FTD [ 9 ].…”

“…Social cognition impairment has been consistently demonstrated in BvFTD [ 1 , 7 , 8 , 9 , 17 , 18 , 19 , 20 , 21 ]. Impaired emotion recognition and empathy have also been reported in patients with PPA [ 22 , 23 , 24 , 25 , 26 ].…”

Metabolomic changes associated with frontotemporal lobar degeneration syndromes

“…We therefore examined blood-based metabolic biomarkers in four clinical syndromes associated with FTLD. We studied the four syndromes together, in view of their potential commonalities in clinical and neuropathological features [1,7,8].…”

Frontal Pole Hypometabolism Linked to Reduced Prosocial Sexual Behaviors in Frontotemporal Dementia and Corticobasal Syndrome

“…Patients were evaluated sequentially within an ongoing research study on FTD and CBS in the [17][18][19][20]. Participants were excluded if they were pregnant, or if they had behavioral symptoms or other medical or social conditions that would preclude the gathering of data for the study.…”