The clinical diagnosis of corticobasal degeneration should depend on a specific pattern of impaired cognition as well as an extrapyramidal motor disorder, reflecting the neuroanatomic distribution of disease in frontal and parietal cortices and the basal ganglia.

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...

Objective-To evaluate the diagnostic value of CSF biomarkers in patients with known pathology due to frontotemporal lobar degeneration (FTLD). Background-It is important to distinguish FTLD from other neurodegenerative diseases likeAlzheimer disease (AD), but this may be difficult clinically because of atypical presentations.

Objective: To investigate the neural basis for the behavioral symptoms of frontotemporal lobar degeneration (FTLD) that cause the greatest caregiver distress. Background: FTLD is a progressive neurodegenerative disease associated with behavioral disturbances. Group studies have related these behaviors to volume loss on MRI. Methods: Forty caregivers of patients with the clinical diagnosis of FTLD completed the Neuropsychiatric Inventory. Twelve neuropsychiatric symptoms and the associated caregiver distress were assessed. Optimized voxel-based morphometry identified significant atrophy in subgroups of FTLD patients with isolated behavioral symptoms corresponding to the most distressing behaviors, and we correlated cortical atrophy directly with these distressing behavioral disorders in an unbiased group analysis. Results: The greatest stressors for caregivers were apathy and disinhibition (p < 0.005 for both contrasts). Partially distinct areas of cortical atrophy were associated with these behaviors in both individual patients with these symptoms and group-wide analyses, including the dorsal anterior cingulate cortex and dorsolateral prefrontal cortex in apathetic patients, and the medial orbital frontal cortex in disinhibited patients. Conclusions: Caregiver stress in families of FTLD patients is due in large part to apathy and disinhibition. The anatomic distribution of cortical loss corresponding to these distressing social behaviors includes partially distinct areas within the frontal lobe.

Neurodegeneration in Alzheimer’s disease (AD) is closely associated with accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro which was impaired by the p.Asp395Gly mutation. Additionafsupplly, intracerebral microinjection of pathologic tau led to increased tau aggregates in p.Asp395Gly VCP knock-in mice compared to injected wild-type mice. These findings suggest that p.Asp395Gly VCP is an autosomal dominant genetic mutation associated with neurofibrillary degeneration in part due to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.