Mendelian forms of disease and age at onset affect survival in frontotemporal dementia

Cosseddu, Maura; Benussi, Alberto; Gazzina, Stefano; Turrone, Rosanna; Archetti, Silvana; Bonomi, Elisa; Biasiotto, Giorgio; Zanella, Isabella; Ferrari, Raffaele; Cotelli, Maria Sofia; Alberici, Antonella; Padovani, Alessandro; Borroni, Barbara

doi:10.1080/21678421.2017.1384020

Cited by 13 publications

(17 citation statements)

References 32 publications

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“…Presence of a known pathogenic mutation in the three well‐recognized FTD genes was the strongest predictor of progression. This is in keeping with emerging evidence , although the individual contributions of the specific genotypes remain unclear. There is considerable heterogeneity in the length of survival in FTD associated with the C9orf72 repeat expansions , whereas in ALS, C9orf72 expansions seem to be more consistently associated with shorter survival .…”

Section: Discussionsupporting

confidence: 84%

Predictors of survival and progression in behavioural variant frontotemporal dementia

Agarwal

D‘Mello

Foxe

et al. 2019

Euro J of Neurology

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Background and purpose Predicting the course of behavioural variant frontotemporal dementia (bvFTD) remains a major clinical challenge. This study aimed to identify factors that predict survival and clinical progression in bvFTD. Methods Consecutive patients with clinically probable bvFTD were prospectively followed up over an 8‐year period. Baseline neuropsychological variables, presence of a known pathogenic frontotemporal dementia gene mutation and a systematic visual magnetic resonance imaging assessment at baseline were examined as candidate predictors using multivariate modelling. Results After screening 121 cases, the study cohort consisted of 75 patients with probable bvFTD, with a mean age of 60.8 ± 8.5 years, followed up for a mean duration of 7.2 ± 3.5 years from symptom onset. Median survival time from disease onset was 10.8 years and median survival, prior to transition to nursing home, was 8.9 years. A total of 25 of the 75 patients died during the study follow‐up period. Survival without dependence was predicted by shorter disease duration at presentation (hazard ratio, 0.49, P = 0.001), greater atrophy in the anterior cingulate cortex (hazard ratio, 1.75, P = 0.047), older age (hazard ratio, 1.07, P = 0.026) and a higher burden of behavioural symptoms (hazard ratio, 1.04, P = 0.015). In terms of disease progression, presence of a known pathogenic frontotemporal dementia mutation (β = 0.46, P < 0.001) was the strongest predictor of progression. Deficits in letter fluency (β = −0.43, P = 0.017) and greater atrophy in the motor cortex (β = 0.51, P = 0.03) were also associated with faster progression. Conclusions This study provides novel clinical predictors of survival and progression in bvFTD. Our findings are likely to have an impact on prognostication and care planning in this difficult disease.

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Section: Discussionsupporting

confidence: 84%

Predictors of survival and progression in behavioural variant frontotemporal dementia

Agarwal

D‘Mello

Foxe

et al. 2019

Euro J of Neurology

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“…Although much has been learned over the past decade about the clinical features of these genetic forms of frontotemporal demen tia, most studies explor ing age at symptom onset and disease duration have been small and geographic ally restricted. [4][5][6] In particular, although indivi dual case series have suggested that such phenotypic characteristics can be quite variable, no studies have syste matically investi gated these factors across all the differ ent genetic groups and the different mutations found within these groups.…”

Section: Implications Of All the Available Evidencementioning

confidence: 99%

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

Moore

Nicholas

Grossman

et al. 2020

The Lancet Neurology

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Background Frontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72. Methods In this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried. Findings Data were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49•5 years (SD 10•0; onset) and 58•5 years (11•3; death) in the MAPT group, 58•2 years (9•8; onset) and 65•3 years (10•9; death) in the C9orf72 group, and 61•3 years (8•8; onset) and 68•8 years (9•7; death) in the GRN group. Mean disease duration was 6•4 years (SD 4•9) in the C9orf72 group, 7•1 years (3•9) in the GRN group, and 9•3 years (6•4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0•45 between individual and parental age at onset, r=0•63 between individual and mean family age at onset, r=0•58 between individual and parental age at death, and r=0•69 between individual and mean family age at death) than in either the C9orf72 group (r=0•32 individual and parental age at onset, r=0•36 individual and mean family age at onset, r=0•38 individual and parental age at death, and r=0•40 individual and mean family age at death) or the GRN group (r=0•22 individual and parental age at onset, r=0•18 individual and mean family age at onset, r=0•22 individual and parental age at death, and r=0•32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even mor...

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“…Predicting the clinical course or progression in FTD remains problematic and several studies have identified markers of poor outcome, as the presence of a known pathogenic mutation [35,36], an early age at disease onset [36], increased frontal and temporal atrophy [37,38], increased tau or neurofilaments levels in cerebrospinal fluid (CSF) [39,40], and the presence of concurrent motor neuron disease [41]. However, several of these observations have not been confirmed or have led to conflicting results, while others have been shown to account for only a small variation in disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…Only SICI (b ¼ 5.0, p < 0.001) and SICF (b ¼ À1. 36, p ¼ 0.004) were retained in the stepwise multiple regression model, which significantly predicted functional decline at 12 months (p < 0.001, adjusted R 2 ¼ 0.73). Including only SICI in the linear regression analysis model, which was the most significant variable, it accounted for 72.5% of the variation in DFTLD-CDR scores at 12 months with adjusted R 2 ¼ 0.72, a large size effect according to Cohen [24].…”

Section: Neurophysiological Measures As Predictors Of Functional Declinementioning

confidence: 99%

TMS for staging and predicting functional decline in frontotemporal dementia

et al. 2020

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a b s t r a c tObjective: To evaluate if transcranial magnetic stimulation (TMS) measures correlate with disease severity and predict functional decline in frontotemporal dementia (FTD) phenotypes. Methods: Paired-pulse TMS was used to investigate the activity of different intracortical circuits in 171 FTD patients (122 bvFTD, 31 avPPA, 18 svPPA) and 74 healthy controls. Pearson's correlations were used to analyze the association between TMS measures and disease severity, while multiple regression analysis was used to identify the best clinical or neurophysiological measure to predict functional decline at 12 months. Results: We observed significant strong correlations between TMS measures [short interval intracortical inhibition-facilitation (SICI-ICF) and long interval intracortical inhibition (LICI)], and disease severity (evaluated with the FTLD-CDR) (all r > 0.5, p < 0.005). SICI-ICF, short interval intracortical facilitation (SICF) and LICI were also significant predictors of functional decline, evaluated as the change in FTLD-CDR scores at 12 months (all p < 0.005), while at the stepwise multiple regression analysis, SICI was the best predictor of disease progression, accounting for 72.5% of the variation in FTLD-CDR scores at 12 months (adjusted R 2 ¼ 0.72, p < 0.001). Conclusions:The present study has shown that the dysfunction of inhibitory and facilitatory intracortical circuits, evaluated with TMS, correlates with disease severity and progression, accurately predicting functional decline at 12 months, better than any other investigated marker.

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Mendelian forms of disease and age at onset affect survival in frontotemporal dementia

Abstract: Our findings suggest that monogenic disease and age at onset are independent predictors of survival and should be considered in future clinical intervention trials and in patients' and caregivers' counselling.

Cited by 13 publications

References 32 publications

Predictors of survival and progression in behavioural variant frontotemporal dementia

Predictors of survival and progression in behavioural variant frontotemporal dementia

Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study

TMS for staging and predicting functional decline in frontotemporal dementia

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