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...
The progressive aging of the world's population makes a higher prevalence of neurodegenerative diseases inevitable. The necessity for an accurate, but at the same time, inexpensive and minimally invasive, diagnostic test is urgently required, not only to confirm the presence of the disease but also to discriminate between different types of dementia to provide the appropriate management and treatment. In this study, attenuated total reflection FTIR (ATR-FTIR) spectroscopy combined with chemometric techniques were used to analyze blood plasma samples from our cohort. Blood samples are easily collected by conventional venepuncture, permitting repeated measurements from the same individuals to monitor their progression throughout the years or evaluate any tested drugs. We included 549 individuals: 347 with various neurodegenerative diseases and 202 age-matched healthy individuals. Alzheimer's disease (AD; n = 164) was identified with 70% sensitivity and specificity, which after the incorporation of apolipoprotein e4 genotype (APOE e4) information, increased to 86% when individuals carried one or two alleles of e4, and to 72% sensitivity and 77% specificity when individuals did not carry e4 alleles. Early AD cases (n = 14) were identified with 80% sensitivity and 74% specificity. Segregation of AD from dementia with Lewy bodies (DLB; n = 34) was achieved with 90% sensitivity and specificity. Other neurodegenerative diseases, such as frontotemporal dementia (FTD; n = 30), Parkinson's disease (PD; n = 32), and progressive supranuclear palsy (PSP; n = 31), were included in our cohort for diagnostic purposes. Our method allows for both rapid and robust diagnosis of neurodegeneration and segregation between different dementias.Alzheimer's disease | dementia with Lewy bodies | apolipoprotein E | differential diagnosis | spectroscopy
Background A proportion of patients with behavioural variant frontotemporal dementia (bvFTD) develop amyotrophic lateral sclerosis (ALS). It is currently unknown whether the behavioural and cognitive syndrome in bvFTD with ALS (ALS-FTD) is indistinguishable from that of bvFTD alone. Methods A retrospective cohort of 241 patients with clinical diagnoses of bvFTD (n=185) or ALS-FTD (n=56) was examined with respect to behavioural, cognitive and neuropsychiatric symptoms. Features were rated as present or absent based on information recorded from clinical interviews and detailed neuropsychological assessment. Results A number of behavioural and affective changes were reported more frequently in bvFTD than ALS-FTD: social disinhibition (p<0.001), inertia (p<0.001), loss of sympathy and empathy (p=0.008), repetitive behaviours (p<0.001) and dietary changes (p<0.001). Warmth of affect demonstrated in the clinic setting was reported more often in ALS-FTD than bvFTD (p<0.001). Executive impairments occurred equally in both groups. Language impairments were more common in ALS-FTD than bvFTD: agrammatism (p<0.017) and impaired sentence comprehension (p<0.036). Psychotic features were relatively rare and did not distinguish the groups. Conclusions Our findings suggest differences between bvFTD and ALS-FTD. In particular, while changes in social behaviour are prominent in bvFTD alone, there may be a comparatively greater degree of language impairment in ALS-FTD. Prospective exploration of the pattern of differences between these groups will be essential. Identification of a distinct neuropsychological phenotype in ALS-FTD may have clinical implications for early diagnosis, disease management and care planning and theoretical implications for our understanding of the relationship between ALS and FTD.
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