Predicting loss of independence and mortality in frontotemporal lobar degeneration syndromes

Abstract

Objective To test the hypothesis that in syndromes associated with frontotemporal lobar degeneration, behavioural impairment predicts loss of functional independence and motor clinical features predict mortality, irrespective of syndrome subtype. Method We used a transdiagnostic approach to survival in an epidemiological cohort, testing the association between clinical features, independence and survival in patients with clinical diagnoses of behavioural variant frontotemporal dementia (n=64), non-fluent variant primary progressive aphasia (n=36), semantic variant primary progressive aphasia (n=25), progressive supranuclear palsy (n=101) and corticobasal syndrome (n=68). A principal components analysis identified six dimensions of clinical features. Using Cox proportional hazards and logistic regression we identified the association between each of these dimensions and functionally independent survival (time from clinical assessment to care home admission), and absolute survival (time to death). Analyses adjusted for the covariates of age, gender and diagnostic group. Secondary analysis excluded specific diagnostic groups. Results Behavioural disturbance, including impulsivity and apathy, was associated with reduced functionally independent survival (OR 2.46, p<0.001), even if patients with bvFTD were removed from the analysis. Motor impairments were associated with reduced absolute survival, even if patients with PSP and CBS were removed from the analysis. Conclusion Our results may help individualised prognostication and planning of disease-modifying trials and support a transdiagnostic approach to symptomatic treatment trials in patients with clinical syndromes associated with frontotemporal lobar degeneration.

GABA and glutamate deficits from frontotemporal lobar degeneration are associated with disinhibition

“…Behavioural change is a common feature of the syndromes associated with frontotemporal lobar degeneration (FTLD) pathology, including behavioural variant frontotemporal dementia (bvFTD) and progressive supranuclear palsy (PSP) ( Gerstenecker et al , 2013 ; Bang et al , 2015 ; Lansdall et al , 2017 ; Murley et al , 2020 a ). This is associated with loss of functional independence ( Agarwal et al , 2019 ; Murley et al , 2020 b ) and increased mortality ( Lansdall et al , 2019 ) in both disorders. Better treatment of behavioural symptoms might therefore improve both functionally independent survival and quality of life for patients and their families.…”

Proton magnetic resonance spectroscopy in frontotemporal lobar degeneration-related syndromes

“…Such symptomatic treatment is a priority given the severe sequelae of cognitive impairment in FTLD. 7,23,26 However, it remains unclear to what extent our findings reflect a potentially reversible deficit of synaptic glutamate. MRS measures the total pool of unbound glutamate, involved in neuron and glia metabolism, protein synthesis and neurotransmission.…”

“…Our cohort has limited pathological confirmation of the diagnosis but clinicopathological correlations in the PIPPIN study as whole match those found elsewhere. 6,7 Therefore, while spectroscopy may be a valuable measure of early disease and/or disease progression it is unlikely to differentiate FTLD syndromes according to their underlying proteinopathies. Third, due to small numbers we grouped non-fluent, semantic and logopenic variants of PPA together, although these sub-groups have different clinical and neuropathological features.…”

“…[2][3][4][5] However the clinical phenotypes associated with FTLD are heterogeneous and overlapping in their features 6 , and include higher cognitive changes which cause a high burden on the patient and their families and carers. 7,8 . There is a pressing need for a better mechanistic understanding of their pathophysiology, in support of new treatment strategies.…”