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Background: Dentatorubral-pallidoluysian atrophy is a hereditary neurodegenerative disease prevalently reported in Japan but rare in Caucasians. The objective of this study was to reconstruct the pedigree of Italian dentatorubral-pallidoluysian atrophy familial cases describing their clinical features., Methods: We investigated 6 apparently unrelated dentatorubral-pallidoluysian atrophy families comprising a total of 51 affected individuals: 13 patients were clinically examined, and for 38 patients clinical data were collected from clinical sources. The dentatorubral-pallidoluysian atrophy diagnosis was genetically confirmed in 18 patients. Genealogical data from historical archives were analyzed., Results: All 6 families were unified in a large pedigree deriving from a founder couple originating from Monte San Giuliano (Italy) in the late 1500s, with 51 affected subjects over the last 4 generations. Wide phenotypical variability in age at onset and clinical features was confirmed. Epilepsy was more frequent in juvenile cases than in late adults, with cognitive/psychiatric and motor disorders observed regardless of age at onset., Conclusions: We have described the largest Caucasian dentatorubral-pallidoluysian atrophy pedigree from a single founder couple. The introduction of the dentatorubral-pallidoluysian atrophy gene in Italy could have arisen as a result of trade relationships between the Spanish or Portuguese and the Japanese in the 1500s. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10 -7 ), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10 -4 ) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10 -8 ) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10 -10 , odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 -10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 -14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

We identified the novel PSEN1 pathogenic mutation M84V in 3 patients belonging to a large kindred affected by autosomal dominant Alzheimer's disease (AD). The clinical phenotype was characterized by early onset dementia in 14 affected subjects over 3 generations. Detailed clinical, imaging and genetic assessment was performed. We highlighted the presence of unusual symptoms such as frontal executive syndrome, psychosis and spastic paraparesis in these patients. Spastic paraparesis has been reported in other PSEN1 mutations in adjacent codons, suggesting that the position of the genetic defect may affect the clinical expression, although this phenotype can occur in mutations throughout the whole PSEN1 gene. Brain magnetic resonance imaging showed diffuse cortical atrophy, but also atrophy of cerebellar lobules, mainly involving Crus I, in 2 patients without cerebellar motor deficits. These neuroimaging results were consistent with recent findings about the association between sporadic AD and distinct and circumscribed cerebellar atrophy. The present work acknowledged the novel PSEN1 pathogenic mutation M84V and might contribute to the ongoing debate about the involvement of cerebellum in AD., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Several neurological and systemic diseases can cause dementia, beyond Alzheimer's disease. Rare genetic causes are often responsible for dementia with atypical features. Recently, mutations causative for Niemann-Pick type C disease (NPC) have also been implicated in neurodegenerative diseases. NPC is an autosomal recessive lipid storage disorder caused by mutations in NPC1 and NPC2 genes. In adults, clinical presentation mimicking other neurodegenerative diseases makes diagnosis difficult. Recent evidence suggests that heterozygous mutations in NPC genes may take on etiological significance., Objective: To investigate the presence of NPC1 and NPC2 mutations in adults affected by neurodegenerative dementia plus., Methods: We performed a genetic screening on 50 patients using a wide clinical and biochemical approach to characterize the phenotype of mutated patients., Results: Sequencing analysis revealed four different and known heterozygous mutations in NPC1 and NPC2 genes. Patient 1 carried the p. F284LfsX26 in NPC1 and was affected by progressive supranuclear palsy-like syndrome. The remaining three patients showed a corticobasal syndrome and harbored the c.441+1G>A variant of NPC2 (patient 2), the missense p.N222 S mutation associated with the c.1947+8G>C variant in the splice region of intron 12 in NPC1 (patient 3), and the p.V30M mutation in NPC2 (patient 4), respectively. Filipin staining was abnormal in patients 1 and 2. mRNA analysis revealed an altered splicing of the NPC2 gene in patient 2., Conclusions: Heterozygous mutations of NPC1 and NPC2 genes could contribute to dementia plus, at least in a subset of patients. We highlight the occurrence of NPC1 and NPC2 heterozygous variants in dementia-plus as pathological event.

In frontotemporal dementia (FTD), age at disease onset (AAO) is unpredictable in both early and late-onset cases; AAO variability is found even in autosomal dominant FTD. The present study was aimed at identifying genetic modifiers modulating AAO in a large cohort of Italian FTD patients. We conducted an association analysis on 411 FTD patients, belonging to 7 Italian Centers, and for whom AAO was available. Population structure was evaluated by principal component analysis to infer continuous axes of genetic variation, and single linear regression models were applied. A genetic score (GS) was calculated on the basis of suggestive single nucleotide polymorphisms (SNPs) found by association analyses. GS showed genome-wide significant slope decrease by -3.86 (95% CI: -4.64 to -3.07, p < 2×10-16) per standard deviation of the GS for 6 SNPs mapping to genes involved in neuronal development and signaling, axonal myelinization, and glutamatergic/GABA neurotransmission. An increase of the GS was associated with a decrease of the AAO. Our data indicate that there is indeed a genetic component that underpins and modulates up to 14.5% of variability of AAO in Italian FTD. Future studies on genetic modifiers in FTD are warranted.

Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer's disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel single nucleotide polymorphisms (SNPs)-to-genes approach and functional annotation analysis. We identified 2 novel potential loci for FTD. Suggestive SNPs reached p-values ∼10(-7) and odds ratio > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of -cis genes such as RFNG and AATK involved in neuronal genesis and differentiation and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation, and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-genome-wide association study. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To report, for the first time, a large autosomal dominant Alzheimer disease (AD) family in which the APP A713T mutation is present in the homozygous and heterozygous state. To date, the mutation has been reported as dominant, and in the heterozygous state associated with familial AD and cerebrovascular lesions., Methods: The family described here has been genealogically reconstructed over 6 generations dating back to the 19th century. Plasma β-amyloid peptide was measured. Sequencing of causative AD genes was performed., Results: Twenty-one individuals, all but 1 born from 2 consanguineous unions, were studied: 8 were described as affected through history, 5 were studied clinically and genetically, and 8 were asymptomatic at-risk subjects. The A713T mutation was detected in the homozygous state in 3 patients and in the heterozygous state in 8 subjects (6 asymptomatic and 2 affected)., Conclusions: Our findings, also supported by the β-amyloid plasma assay, confirm (1) the pathogenic role of the APP A713T mutation, (2) the specific phenotype (AD with cerebrovascular lesions) associated with this mutation, and (3) the large span of age at onset, not influenced by APOE, TOMM40, and TREM2 genes. No substantial differences concerning clinical phenotype were evidenced between heterozygous and homozygous patients, in line with the classic definition of dominance. Therefore, in this study, AD followed the classic definition of a dominant disease, contrary to that reported in a previously described AD family with recessive APP mutation. This confirms that genetic AD may be considered a disease with dominant and recessive traits of inheritance., (© 2015 American Academy of Neurology.)

The most common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) is a G4C2-repeat expansion in C9orf72. However, the lower limit for pathological repeats has not been established and expansions with different sizes could have different pathological consequences. One of the implicated disease mechanisms is haploinsufficiency. Previously, we identified expansion-specific hypermethylation at the 5' CpG-island near the G4C2-repeat, but only in a fraction of carriers (up to 36 %). Here, we tested the hypothesis that the G4C2-repeat itself could be the main site of methylation. To evaluate (G4C2)n -methylation, we developed a novel assay, which was validated by an independent methylation-sensitive restriction enzyme assay. Notably, both assays are qualitative but not quantitative. Blood DNA was available for 270 unrelated individuals, including 71 expansion carriers. In addition, we investigated blood DNA from family members of 16 probands, and 38 DNA samples from multiple tissues of 10 expansion carriers. Finally, we tested DNA from different tissues of an ALS patient carrying a somatically unstable 90-repeat. We demonstrated that the G4C2-expansion is generally methylated in unrelated carriers of alleles >50 repeats (97 %), while small (<22 repeats) or intermediate (22-90 repeats) alleles were completely unmethylated. The presence of (G4C2)n -methylation does not separate the C9orf72-phenotypes (ALS vs. ALS/FTLD vs. FTLD), but has the potential to predict large vs. intermediate repeat length. Our results suggest that (G4C2)n -methylation might sometimes spread to the 5'-upstream region, but not vice versa. It is stable over time, since (G4C2)n -methylation was detected in carriers with a wide range of ages (24-74 years). It was identified in both blood and brain tissues for the same individual, implying its potential use as a biomarker. Furthermore, our findings may open up new perspectives for studying disease mechanisms, such as determining whether methylated and unmethylated repeats have the same ability to form a G-quadruplex configuration.

The G₄C₂-repeat expansion in C9orf72 is a common cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). C9orf72 transcription is reduced in expansion carriers implicating haploinsufficiency as one of the disease mechanisms. Indeed, our recent ALS study revealed that the expansion was associated with hypermethylation of the CpG-island (5'of the repeat) in DNA samples obtained from different tissues (blood, brain and spinal cord). However, the link between FTLD and methylation of the CpG-island is unknown. Hence, we investigated the methylation profile of the same CpG-island by bisulfite sequencing of DNA obtained from blood of 34 FTLD expansion carriers, 166 FTLD non-carriers and 103 controls. Methylation level was significantly higher in FTLD expansion carriers than non-carriers (P = 7.8E-13). Our results were confirmed by two methods (HhaI-assay and sequencing of cloned bisulfite PCR products). Hypermethylation occurred only in carriers of an allele with >50 repeats, and was not detected in non-carriers or individuals with an intermediate allele (22-43 repeats). As expected, the position/number of methylated CpGs was concordant between the sense and anti-sense DNA strand, suggesting that it is a stable epigenetic modification. Analysis of the combined ALS and FTLD datasets (82 expansion carriers) revealed that the degree of methylation of the entire CpG-island or contribution of specific CpGs (n = 26) is similar in both syndromes, with a trend towards a higher proportion of ALS patients with a high methylation level (P = 0.09). In conclusion, we demonstrated that hypermethylation of the CpG-island 5'of the G₄C₂-repeat is expansion-specific, but not syndrome-specific (ALS versus FTLD)., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Beta-amyloid accumulation in brain is a driving force for Alzheimer's disease pathogenesis. Apolipoprotein E (ApoE) represents a critical player in beta-amyloid homeostasis, but its role in disease progression is controversial. We previously reported that the acute-phase protein haptoglobin binds ApoE and impairs its function in cholesterol homeostasis. The major aims of this study were to characterize the binding of haptoglobin to beta-amyloid, and to evaluate whether haptoglobin affects ApoE binding to beta-amyloid. Haptoglobin is here reported to form a complex with beta-amyloid as shown by immunoblotting experiments with purified proteins, or by its immunoprecipitation in brain tissues from patients with Alzheimer's disease. The interaction between ApoE and beta-amyloid was previously shown to be crucial for limiting beta-amyloid neurotoxicity and for promoting its clearance. We demonstrate that haptoglobin, rather than impairing ApoE binding to beta-amyloid, promotes to a different extent the formation of the complex between beta-amyloid and ApoE2 or ApoE3 or ApoE4. Our data suggest that haptoglobin and ApoE functions in brain should be evaluated taking into account their mutual interaction with beta-amyloid. Hence, the risk of developing Alzheimer's disease might not only be linked to the different ApoE isoforms, but also rely on the level of critical ligands, such as haptoglobin.

Frontotemporal dementia (FTD) has a strong genetic basis, with familial forms occurring in 30-50% of cases. Causative genes have been identified, with an autosomal dominant pattern of inheritance. Notwithstanding, in a number of cases with positive family history no pathogenetic mutation has been reported, and the role of genetics in sporadic cases is still unclear. In the present study, we aim to estimate the genetic contribution to FTD using concordance among parent-offspring pairs. Heritability of early-onset (EO, <65 years) and late-onset (LO, ≥65 years) FTD was estimated by examining the concordance between parents and offspring. Probands with at least one parent whose dementia status was known were recruited from 15 Italian centers, and the presence or absence of dementia was considered in siblings. Different prevalence estimates, as available by literature data, were tested. A total of 260 probands and 1619 family members were considered in this study. We found that parent-offspring concordance in FTD was 6.25%, resulting in hereditability of 98.5% (95% confidence interval (CI): 85.0%-100.0%). Equal heritability for both sexes regardless of parental gender was reported. EO-FTD showed hereditability of 86.3% (95% CI: 77.0%-95.0%) and LO-FTD of 75.7% (95% CI: 65.0%-86.0%). Estimating the contribution of genetics in FTD may help in driving future genetic studies to identify new pathogenetic determinants. We suggest that in most of the cases FTD is a genetic-based disease, even in the elderly. Different inheritance modality might be considered in future work, beyond autosomal dominant disease.

OBJECTIVE To estimate the allele frequency of C9orf72 (G4C2) repeats in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer disease (AD), and Parkinson disease (PD). DESIGN The number of repeats was estimated by a 2-step genotyping strategy. For expansion carriers, we sequenced the repeat flanking regions and obtained APOE genotypes and MAPT H1/H2 haplotypes. SETTING Hospitals specializing in neurodegenerative disorders. SUBJECTS We analyzed 520 patients with FTLD, 389 patients with ALS, 424 patients with AD, 289 patients with PD, 602 controls, 18 families, and 29 patients with PD with the LRRK2 G2019S mutation. MAIN OUTCOME MEASURE The expansion frequency. RESULTS Based on a prior cutoff (&gt;30 repeats), the expansion was detected in 9.3% of patients with ALS, 5.2% of patients with FTLD, and 0.7% of patients with PD but not in controls or patients with AD. It was significantly associated with family history of ALS or FTLD and age at onset of FTLD. Phenotype variation (ALS vs FTLD) was not associated with MAPT, APOE, or variability in the repeat flanking regions. Two patients with PD were carriers of 39 and 32 repeats with questionable pathological significance, since the 39-repeat allele does not segregate with PD. No expansion or intermediate alleles (20-29 repeats) were found among the G2019S carriers and AD cases with TAR DNA-binding protein 43-positive inclusions. Surprisingly, the frequency of the 10-repeat allele was marginally increased in all 4 neurodegenerative diseases compared with controls, indicating the presence of an unknown risk variation in the C9orf72 locus. CONCLUSIONS The C9orf72 expansion is a common cause of ALS and FTLD, but not of AD or PD. Our study raises concern about a reliable cutoff for the pathological repeat number, which is important in the utility of genetic screening.

A clinical and molecular overlap between Alzheimer's disease (AD) and frontotemporal dementia (FTD) has been reported. Presenilins have been associated with FTD or with FTD-like phenotype, while mutations in the MAPT gene have been linked to a clinical phenotype of AD. We performed a clinical and genetic examination in two FTD siblings and their family tree has been reconstructed. We identified a novel Val75Ala MAPT mutation in one patient and in the other the Arg62His Presenilin2 mutation. The DNA variations identified, defined mutations by frequency, per se are not causative of the disease. These mutations, possibly in association with other unknown environmental and genetic factors, may contribute to neurodegeneration. In this family, the disease might result from a genetically interconnected spectrum of altered pathways that could link most neurodegenerative disorders. Moreover, the novel mutation identified merits further functional studies that would contribute to the unravelling of such a complex field.

Background: Frontotemporal dementia is a clinically and genetically heterogeneous syndrome. Mutations in two genes, Microtubule Associated Protein Tau (MAPT) and Progranulin (PGRN), and rarely Presenilin mutations, have been causally linked to this disorder., Objective: To investigate the presence of PGRN, PSEN1, PSEN2 and APP mutations in a group of familial early-onset frontotemporal dementia (f-EOFTD) patients negative for MAPT gene mutations., Subjects and Methods: We prospectively studied 17 unrelated subjects diagnosed with f-EOFTD (one case neuropathologically confirmed as FTD-Ub+). Among these subjects eight belonged to eight autosomal dominant families unrelated to each other, and nine had at least one first degree relative affected by dementia., Results: We identified two novel heterozygous mutations in two unrelated patients, Cys139Arg in the PGRN gene and Val412Ile in the PSEN1 gene., Conclusions: Early-onset f-FTD remains a heterogeneous disorder from a genetic point of view. PGRN mutation frequency was low in our sample. The presence of a novel PSEN1 mutation suggests that presenilin molecular studies should be performed when screening for MAPT and PGRN genes is negative.

Frontotemporal dementia (FTD) is a complex dementing syndrome whose genetic/non genetic risk factors are mostly unknown. Aim of the present work was to investigate whether APOE and/or tau gene variability does affect the risk of FTD. A sample of FTD cases (sporadic: n = 54; familial: n = 46, one subject per family) was collected in a genetically homogeneous population (Calabria, southern Italy) and analyzed in comparison with an age- and sex-matched control group (n = 180) extracted from the same population. Logistic regression analysis showed that APOE gene variability affects the probability of disease, with allele epsilon4 increasing (exp(beta1) = 2.68 with [1.51-4.76] 95% confidence interval; p = 0.001) and allele epsilon2 decreasing (exp(beta1) = 0.28 with [0.12-0.66] 95% confidence interval; p = 0.003) the risk of FTD. On the contrary, tau gene variability was ineffectual (exp(beta1) non significantly different from 1 for either H1 or H2 haplotypes), although a small effect was observed by the H1 haplotype in increasing the protective effect of the epsilon2 allele (p = 0.007).

Frontotemporal dementia (FTD) displays significant neuropathological and genetic heterogeneity among and within affected families. An early diagnosis is often difficult because cognitive symptoms are manifest only at a late stage of the disease. We have been studying a large pedigree segregating frontotemporal dementia (FTD) to which belong 34 identified affected persons, 11 of whom were personally examined. The kindred has been genealogically reconstructed; all FTD patients have been linked to the same ancestors who lived in the early 18(th) century (11 generations before the present one). Autosomal dominant transmission was evident. Clinical features were uniform within the kindred and met the Lund-Manchester criteria. Personality changes with absence of insight, lack of empathy and of social awareness manifested up to 5 years before medical advice was sought. Loss of fluency was the earliest neuropsychological sign, in the absence of memory, orientation and praxis deficits, which evolved late, together with hyperorality. Akinesia was observed early, rigidity appeared late, tremor was absent. Two patients showed myoclonus late in their evolution. No ALS signs were observed in this kindred. Mutations of the MAPt gene, coding for the Tau protein, were not detected in affected family members. Linkage studies excluded chromosomes 3 and 9 and gave indeterminate results that were model dependent for chromosome 17.