Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.

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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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Objective Patients with probable dementia with Lewy bodies (DLB) often have Alzheimer’s disease (AD)-related pathology. Our objective was to determine the pattern of positron emission tomography (PET) tau tracer AV-1451 uptake in patients with probable DLB, compared to AD, and its relationship to β-amyloid deposition on PET. Methods Consecutive patients with clinically probable DLB (n = 19) from the Mayo Clinic Alzheimer’s Disease Research Center underwent magnetic resonance imaging, AV-1451, and Pittsburgh compound-B (PiB) PET examinations. Age- and sex-matched groups of AD dementia (n = 19) patients and clinically normal controls (n = 95) from an epidemiological cohort served as a comparison groups. Atlas- and voxel-based analyses were performed. Results The AD dementia group had significantly higher AV-1451 uptake than the probable DLB group, and medial temporal uptake completely distinguished AD dementia from probable DLB. Patients with probable DLB had greater AV-1451 uptake in the posterior temporoparietal and occipital cortex compared to clinically normal controls, and in probable DLB, the uptake in these regions correlated with global cortical PiB uptake (Spearman rho = 0.63; p = 0.006). Interpretation Medial temporal lobe AV-1451 uptake distinguishes AD dementia from probable DLB, which may be useful for differential diagnosis. Elevated posterior temporoparietal and occipital AV-1451 uptake in probable DLB and its association with global cortical PiB uptake suggest an atypical pattern of tau deposition in DLB.

Few studies have been published regarding the neuropsychological characteristics of patients with essential tremor (ET), but preliminary findings suggest that mild attentional and executive dysfunction accompany the disorder. A consecutive series of 101 patients with ET referred for thalamotomy and/or thalamic deep brain stimulation candidacy work-up also underwent neuropsychological evaluation. Average neuropsychological test scores were calculated, along with the proportions of subjects whose scores fell within or more than one SD above or below the mean (using demographically corrected normative data). Significantly lower than average (T-score of 50) scores were evident on measures of complex auditory attention, visual attention and response inhibition, recall of a word list, verbal fluency, and visual confrontation naming. A significantly greater proportion of patients (ranging from about 34 to 60%) than might be expected on the basis of a normal distribution obtained scores more than one SD below the normative mean on select measures of attention, verbal fluency, immediate word list recall, semantic encoding, and facial matching. Consistent with prior research, notable, albeit clinically subtle, deficits in attention and select executive functions are evident in patients with ET. Although not specific to ET or cerebellar dysfunction, the observed pattern of cognitive deficits is consistent with cerebello-thalamo-cortical circuit dysfunction.

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Previous research suggests that lexical and semantic verbal fluency are differentially sensitive to the effects of cortical and subcortical dementias, but little is known about action fluency performance in dementias. The present study compared lexical, semantic, and action fluency in groups of patients with Parkinson's disease (PD) with and without dementia and an elderly control group. Findings revealed an interaction between fluency type and subject group. Although the demented PD (PDD) group performed significantly more poorly than their non-demented counterparts and normal controls on all three fluency tasks, a disproportionate disparity in scores was noted on the action fluency task. The findings suggest that action fluency may be particularly sensitive to PD-associated dementia and may be an early indicator of the conversion from PD to PDD. As reported elsewhere, PD without dementia was not associated with significant impairment on any of the fluency tasks.