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...

We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7–24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.

Background: Frontotemporal dementia (FTD) is frequently caused by genetic mutations in GRN, C9orf72 and MAPT. Neurofilament light chain (NfL) is a promising blood biomarker in genetic FTD, with elevated levels in symptomatic mutation carriers. A better understanding of NfL dynamics is essential for its use in upcoming therapeutic trials. We investigated longitudinal serum NfL trajectories in presymptomatic and symptomatic genetic FTD. over time was associated with atrophy rate in several grey matter regions, but not with rate of change in clinical parameters. Interpretation: This study confirms the value of blood NfL as a disease progression biomarker in genetic FTD and indicates that longitudinal NfL measurements could help identify mutation carriers approaching symptom onset and capture the rate of brain atrophy. The stable levels in C9orf72-and MAPT-associated FTD offer potential for NfL as a marker of treatment effect in therapeutic trials.

Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24–3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1298-7) contains supplementary material, which is available to authorized users.

Background: Several lines of evidence in the literature have shown that inflammation is involved in the pathogenesis of Alzheimer’s disease (AD). However, the results from the evaluation of serum inflammatory markers in AD patients have been controversial. Objective: To determine if any differences exist in the monocytic secretion pattern of IL-1β, IL-6, IL-12 and TNF-α from mild cognitive impairment (MCI) and AD patients, when compared with healthy age-matched controls. Methods: To evaluate the percentage of peripheral monocytes secreting IL-1β, IL-6, IL-12 and TNF-α along with the relative levels of these proteins, a cytofluorimetric analysis was conducted under basal conditions and after lipopolysaccharide-induced cell activation. Results: We found, in AD and MCI patients, a significant raise in the percentage of monocytes producing the studied cytokines (under basal conditions and after the exposure to an inflammatory stimulus), as well as a decreased competence of these cells to respond to inflammatory challenges, when compared with controls. Conclusions: These results agree with a persistent inflammatory status in AD, reinforcing the hypothesis of a progressive impairment of the immune response in this disorder and suggesting that monocytes may be good targets to study the progression from MCI to AD.

BackgroundRecently, two large genome wide association studies in Alzheimer disease (AD) have identified variants in three different genes (CLU, PICALM and CR1) as being associated with the risk of developing AD. The strongest association was reported for an intronic single nucleotide polymorphism (SNP) in CLU.Methodology/Principal FindingsTo further characterize this association we have sequenced the coding region of this gene in a total of 495 AD cases and 330 healthy controls. A total of twenty-four variants were found in both cases and controls. For the changes found in more than one individual, the genotypic frequencies were compared between cases and controls. Coding variants were found in both groups (including a nonsense mutation in a healthy subject), indicating that the pathogenicity of variants found in this gene must be carefully evaluated. We found no common coding variant associated with disease. In order to determine if common variants at the CLU locus effect expression of nearby (cis) mRNA transcripts, an expression quantitative loci (eQTL) analysis was performed. No significant eQTL associations were observed for the SNPs previously associated with AD.Conclusions/SignificanceWe conclude that common coding variability at this locus does not explain the association, and that there is no large effect of common genetic variability on expression in brain tissue. We surmise that the most likely mechanism underpinning the association is either small effects of genetic variability on resting gene expression, or effects on damage induced expression of the protein.

Background: Pathological brain iron deposition has been implicated as a source of neurotoxic reactive oxygen species in Alzheimer (AD) and Parkinson diseases (PD). Iron metabolism is associated with the gene hemochromatosis (HFE Human genome nomenclature committee ID:4886), and mutations in HFE are a cause of the iron mismetabolism disease, hemochromatosis. Several reports have tested the association of HFE variants with neurodegenerative diseases, such as AD and PD with conflicting results.

The International Working Group on Alzheimer's disease (AD) suggested the free and cued selective reminding test (FCSRT) to assess memory, as it showed high sensitivity and specificity in the differentiation of AD from healthy controls and other dementias. The FCSRT involves the use of selective reminding with semantic cueing in memory assessment. This study aims to validate the FCSRT for mild cognitive impairment (MCI) and AD through the analysis of the diagnostic accuracy and the suggestion of cut-off scores. Patients were classified into two groups according to standard criteria: MCI (n = 100) and AD (n = 70). A matched control group (n = 101) of cognitively healthy subjects was included. The reliability and the validity of the FCSRT were analysed on the immediate (IR) and delayed (DR) recalls. The Cronbach's alpha was 0.915 for the IR and 0.879 for the DR. The total recall measures revealed good areas under the curve for MCI (IR: .818; DR: .828) and excellent for AD (IR: .987; DR: .991). Furthermore, the MCI group was subdivided with respect to a non-similar/similar AD pattern of impairment, with almost half of the subjects showing an AD-like decline. This analysis represents a novel contribution regarding the properties of the FCSRT in illustrating the heterogeneity of MCI at baseline. The FCSRT has proved to be a very useful tool in the characterization of the memory impairment of the AD spectrum.