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Surgery, needle fasciotomy, and collagenase injection are used to treat Dupuytren contracture, with limited data on long-term comparative effectiveness. The article presents 2-year interim results of DETECT (DupuytrEn Treatment EffeCtiveness Trial), an ongoing randomized comparative effectiveness trial of these therapies for the treatment of participants with treatment-naive Dupuytren contracture. Visual Abstract. Surgery, Needle Fasciotomy, or Collagenase Injection for Dupuytren Contracture: Surgery, needle fasciotomy, and collagenase injection are used to treat Dupuytren contracture, with limited data on long-term comparative effectiveness. The article presents 2-year interim results of DETECT (DupuytrEn Treatment EffeCtiveness Trial), an ongoing randomized comparative effectiveness trial of these therapies for the treatment of participants with treatment-naive Dupuytren contracture. Background: Surgery, needle fasciotomy, and collagenase injection are used to treat Dupuytren contracture. The treatment decision requires balancing initial morbidity and costs of surgery against its potential long-term benefits over needle fasciotomy and collagenase. Objective: To compare the effectiveness of surgery, needle fasciotomy, and collagenase injection at 3 months and 2 years (secondary time points of the trial). Design: A multicenter, randomized, outcome assessor–blinded, superiority trial. (ClinicalTrials.gov: NCT03192020) Setting: 6 public hospitals in Finland. Participants: 302 persons with treatment-naive Dupuytren contracture (contracture angle <135°). Intervention: Surgery (n  = 101), needle fasciotomy (n  = 101), or collagenase (n  = 100). Measurements: The primary outcome was the success rate, defined as greater than 50% contracture release and patients reaching the patient acceptable symptom state. Secondary outcomes included hand function, pain, quality of life, patient satisfaction, residual contracture angle, finger flexion, risk for retreatment, and serious adverse events. Results: A total of 292 (97%) and 284 (94%) participants completed the 3-month and 2-year follow-ups. Success rates were similar at 3 months: 71% (95% CI, 62% to 80%) for surgery, 73% (CI, 64% to 82%) for needle fasciotomy, and 73% (CI, 64% to 82%) for collagenase. At 2 years, surgery had superior success rates compared with both needle fasciotomy (78% vs. 50%; adjusted risk difference [aRD], 0.30 [CI, 0.17 to 0.43]) and collagenase (78% vs. 65%; aRD, 0.13 [CI, 0.01 to 0.26]). Secondary analyses paralleled with the primary analysis. Limitation: Participants were not blinded. Conclusion: Initial outcomes are similar between the treatments, but at 2 years success rates were maintained in the surgery group but were lower with both needle fasciotomy and collagenase despite retreatments. Primary Funding Source: Research Council of Finland. [ABSTRACT FROM AUTHOR]

Background: The most common genetic cause of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) has been linked to a hexanucleotide repeat expansion in the C9ORF72 gene. The frequency of the C9ORF72 expansion in Finland is among the highest in the world. Methods: We assessed 73 Finnish patients with FTLD in order to examine the clinical characteristics associated with the expanded C9ORF72. Demographic and clinical features were evaluated. As a potential disease modifier, the apolipoprotein E (APOE) genotype was also assessed. Neuropathological analysis was available on 2 expansion carriers and 1 non-carrier. Results: The C9ORF72 expansion was present in 20 of 70 (29%) probands. Significant associations with the C9ORF72 expansion were observed for concomitant ALS and positive family history of dementia or ALS. Psychoses were detected in both carriers and non-carriers (21 vs. 10%, p = 0.25). The APOE ε4 allele did not cluster among expansion carriers. Numerous p62-positive neuronal inclusions were detected in the cerebellar cortex of the 2 expansion carriers. Conclusion: In line with the suggested C9ORF72 core phenotype, we also detected a high frequency of neuropsychiatric symptoms; however, these symptoms seem not be specific to C9ORF72-associated FTLD. FTLD should be considered in cases of middle-age-onset psychosis.

Abstract Background Frontotemporal lobar degeneration (FTLD) consists of a clinically and neuropathologically heterogeneous group of syndromes affecting the frontal and temporal lobes of the brain. Mutations in microtubule-associated protein tau (MAPT), progranulin (PGRN) and charged multi-vesicular body protein 2B (CHMP2B) are associated with familial forms of the disease. The prevalence of these mutations varies between populations. The H1 haplotype of MAPT has been found to be closely associated with tauopathies and with sporadic FTLD. Our aim was to investigate MAPT mutations and haplotype frequencies in a clinical series of patients with FTLD in Northern Finland. Methods MAPT exons 1, 2 and 9–13 were sequenced in 59 patients with FTLD, and MAPT haplotypes were analysed in these patients, 122 patients with early onset Alzheimer's disease (eoAD) and 198 healthy controls. Results No pathogenic mutations were found. The H2 allele frequency was 11.0% (P = 0.028) in the FTLD patients, 9.8% (P = 0.029) in the eoAD patients and 5.3% in the controls. The H2 allele was especially clustered in patients with a positive family history (P = 0.011) but did not lower the age at onset of the disease. The ApoE4 allele frequency was significantly increased in the patients with eoAD and in those with FTLD. Conclusion We conclude that although pathogenic MAPT mutations are rare in Northern Finland, the MAPT H2 allele may be associated with increased risks of FTLD and eoAD in the Finnish population.

A hexanucleotide expansion in chromosome 9 open-reading frame 72 (C9ORF72) has been found to be a major cause of frontotemporal lobar degeneration (FTLD). We describe a 20-year follow-up of a unique case with very slowly progressive FTLD caused by theC9ORF72repeat expansion. In serial neuropsychological examinations, the patient’s cognitive decline was exceptionally slow and after 20 years the patient still was mainly independent in activities of daily living. Our case indicates that there is great individual variation in the progression and duration ofC9ORF72-associated FTLD, and also language variants or mixed phenotypes may be present. [ABSTRACT FROM AUTHOR]

Key Clinical Message Neuromyelitis optica is a rare inflammatory, demyelinating disease of the central nervous system that predominantly targets the optic nerves and spinal cord. Our case represents an unusual and severe course of neuromyelitis optica. Despite several forms of treatment, our patient died after a severe and short-term attack. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal lobar degeneration (FTLD) consists of a clinically and neuropathologically heterogeneous group of syndromes affecting the frontal and temporal lobes of the brain. Mutations in microtubule-associated protein tau (MAPT), progranulin (PGRN) and charged multi-vesicular body protein 2B (CHMP2B) are associated with familial forms of the disease. The prevalence of these mutations varies between populations. The H1 haplotype of MAPT has been found to be closely associated with tauopathies and with sporadic FTLD. Our aim was to investigate MAPT mutations and haplotype frequencies in a clinical series of patients with FTLD in Northern Finland.Methods: MAPT exons 1, 2 and 9-13 were sequenced in 59 patients with FTLD, and MAPT haplotypes were analysed in these patients, 122 patients with early onset Alzheimer's disease (eoAD) and 198 healthy controls.Results: No pathogenic mutations were found. The H2 allele frequency was 11.0% (P = 0.028) in the FTLD patients, 9.8% (P = 0.029) in the eoAD patients and 5.3% in the controls. The H2 allele was especially clustered in patients with a positive family history (P = 0.011) but did not lower the age at onset of the disease. The ApoE4 allele frequency was significantly increased in the patients with eoAD and in those with FTLD.Conclusion: We conclude that although pathogenic MAPT mutations are rare in Northern Finland, the MAPT H2 allele may be associated with increased risks of FTLD and eoAD in the Finnish population. [ABSTRACT FROM AUTHOR]

A hexanucleotide repeat expansion (HRE) in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Human brain imaging and experimental studies indicate early changes in brain structure and connectivity in C9-ALS/FTD, even before symptom onset. Because these early disease phenotypes remain incompletely understood, we generated iPSC-derived cerebral organoid models from C9-ALS/FTD patients, presymptomatic C9ORF72-HRE (C9-HRE) carriers, and controls. Our work revealed the presence of all three C9-HRE-related molecular pathologies and developmental stage-dependent size phenotypes in cerebral organoids from C9-ALS/FTD patients. In addition, single-cell RNA sequencing identified changes in cell type abundance and distribution in C9-ALS/FTD organoids, including a reduction in the number of deep layer cortical neurons and the distribution of neural progenitors. Further, molecular and cellular analyses and patch-clamp electrophysiology detected various changes in synapse structure and function. Intriguingly, organoids from all presymptomatic C9-HRE carriers displayed C9-HRE molecular pathology, whereas the extent to which more downstream cellular defects, as found in C9-ALS/FTD models, were detected varied for the different presymptomatic C9-HRE cases. Together, these results unveil early changes in 3D human brain tissue organization and synaptic connectivity in C9-ALS/FTD that likely constitute initial pathologies crucial for understanding disease onset and the design of therapeutic strategies. [ABSTRACT FROM AUTHOR]

Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR–induced toxicity and improved the survival of iPSC–derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72. Editor's summary: Repeat expansions in the gene C9ORF72 frequently cause the neurodegenerative diseases ALS and frontotemporal dementia. Using neurons derived from patients, Dong et al. found that repeats of glycine-arginine (poly-GR) encoded by mutant C9ORF72 RNA stalled the translational machinery, which caused ribosomes to collide. The resulting ribotoxic stress response induced neuronal death. Blocking this response by inhibiting the kinases ZAKα or p38 MAPK increased the survival of patient-derived neurons in culture. The approach might have therapeutic potential to preserve neurons in patients. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective: This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods: A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results: Four known pathogenic or likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO, and DCTN1, were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions: There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. Objective: To evaluate psychopharmacological medication use at the time of FTD diagnosis. Methods: Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer's disease (AD) patients was used as a neurodegenerative disease reference group. Results: Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. Conclusion: Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis. [ABSTRACT FROM AUTHOR]

Background: Recently, Sigma nonopioid intracellular receptor 1 (SIGMAR1) variants have been shown harboring C9orf72 pathogenic repeat expansions in some frontotemporal dementia (FTD) cases. However, no SIGMAR1 genotype analysis has been reported in a cohort absent of C9orf72 pathogenic repeat expansions to date. Objective: The present study investigated the contribution of SIGMAR1 independent of C9orf72 gene status to FTD spectrum syndromes. Methods: We directly sequencing the entire coding region and a minimum of 50 bp from each of the flanking introns of SIGMAR1 gene in 82 sporadic FTD patients (female: male = 42 : 40) and 417 controls. For the patient carrying SIGMAR1 variant, a follow-up 3T MR imaging was performed in the study. Results: Gene sequencing of SIGMAR1 revealed a rare 3′UTR nucleotide variation rs192856872 in a male patient with semantic dementia independent of C9orf72 gene status. The MR imaging showed asymmetrical atrophy in the anterior temporal lobes and the degeneration extends caudally into the posterior temporal lobes as the disease progresses. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores, which is predicted to affect normal splicing. Conclusion: We found a novel SIGMAR1 variant independent of C9orf72 gene status associated with semantic dementia phenotype. [ABSTRACT FROM AUTHOR]

As an important part in international disease, mental disorders seriously damage human health and social stability, which show the complex pathogenesis and increasing incidence year by year. In order to analyze the pathogenesis of mental disorders as soon as possible and to look for the targeted drug treatment for psychiatric diseases, a more reasonable animal model is imperious demands. Benefiting from its high homology with the human genome, its brain tissue is highly similar to that of humans, and it is easy to realize whole-body optical visualization and high-throughput screening; zebrafish stands out among many animal models of mental disorders. Here, valuable qualified zebrafish mental disorders models could be established through behavioral test and sociological analysis, which are simulated to humans, and combined with molecular analyses and other detection methods. This review focuses on the advances in the zebrafish model to simulate the human mental disorders; summarizes the various behavioral characterization means, the use of equipment, and operation principle; sums up the various mental disorder zebrafish model modeling methods; puts forward the current challenges and future development trend, which is to contribute the theoretical supports for the exploration of the mechanisms and treatment strategies of mental disorders. [ABSTRACT FROM AUTHOR]

This article examines the evolution in understanding of frontotemporal dementia (FTD) during the last four decades. A central theme is the recognition of heterogeneity. Originally construed as a disorder of behaviour and executive impairment, FTD is now known also to be associated with alterations in language, conceptual knowledge and praxis. An absence of neurological signs is the hallmark of many FTD patients, but there is also an established association with motor neurone disease (MND), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). FTD is commonly defined as an early onset dementia, yet about a quarter of patients present after the age of 65. The underlying pathological protein is tau, TDP‐43 or more rarely fused‐in‐sarcoma (FUS). Distinct genetic mutations have been identified in familial FTD. There are predictable relationships between clinical phenotype, pathological substrate and genetic mutation. For example, a circumscribed semantic disorder predicts TDP‐43 pathology, and speech or limb apraxia tau pathology. The co‐occurrence of MND predicts TDP‐43 pathology, and PSP and CBD tau pathology. FUS pathology is associated with very youthful onset, stereotyped behaviours and caudate atrophy. Non‐fluent aphasia is linked to progranulin (GRN) mutations and MND and psychosis to repeat expansions in the C9orf72 gene. Despite striking worldwide consensus in findings there remain some issues of contention, largely related to the classification of FTD and its sub‐variants. Understanding the diverse nature of FTD is crucial for effective diagnosis, management and the development of targeted therapies. [ABSTRACT FROM AUTHOR]

The term frontotemporal dementia (FTD) refers to a group of progressive neurodegenerative disorders characterized mainly by atrophy of the frontal and anterior temporal lobes. Based on clinical presentation, three main clinical syndromes have traditionally been described: behavioral variant frontotemporal dementia (bvFTD), non-fluent/agrammatic primary progressive aphasia (nfPPA), and semantic variant PPA (svPPA). However, over the last 20 years, it has been recognized that cognitive phenotypes often overlap with motor phenotypes, either motor neuron diseases or parkinsonian signs and/or syndromes like progressive supranuclear palsy (PSP) and cortico-basal syndrome (CBS). Furthermore, FTD-related genes are characterized by genetic pleiotropy and can cause, even in the same family, pure motor phenotypes, findings that underlie the clinical continuum of the spectrum, which has pure cognitive and pure motor phenotypes as the extremes. The genotype-phenotype correlation of the spectrum, FTD-motor neuron disease, has been well defined and extensively investigated, while the continuum, FTD-parkinsonism, lacks a comprehensive review. In this narrative review, we describe the current knowledge about the genotype-phenotype correlation of the spectrum, FTD-parkinsonism, focusing on the phenotypes that are less frequent than bvFTD, namely nfPPA, svPPA, PSP, CBS, and cognitive-motor overlapping phenotypes (i.e. PPA + PSP). From a pathological point of view, they are characterized mainly by the presence of phosphorylated-tau inclusions, either 4 R or 3 R. The genetic correlate of the spectrum can be heterogeneous, although some variants seem to lead preferentially to specific clinical syndromes. Furthermore, we critically review the contribution of genome-wide association studies (GWAS) and next-generation sequencing (NGS) in disentangling the complex heritability of the FTD-parkinsonism spectrum and in defining the genotype-phenotype correlation of the entire clinical scenario, owing to the ability of these techniques to test multiple genes, and so to allow detailed investigations of the overlapping phenotypes. Finally, we conclude with the importance of a detailed genetic characterization and we offer to patients and families the chance to be included in future randomized clinical trials focused on autosomal dominant forms of FTLD. [ABSTRACT FROM AUTHOR]

Background Low uptake of presymptomatic testing and medically assisted reproduction in families impacted by neurogenetic diseases prompted us to investigate how reproductive options are considered and whether there is a relationship with perceived severity of the disease. We hypothesised that self-estimated severity would influence opinion on reproductive options and that prenatal/preimplantation diagnosis would be a motivation to inform relatives about their risk. Methods We invited people impacted by neurogenetic diseases to evaluate the severity of their familial disease using analogic visual scales and to answer questionnaires about reproductive choices and intrafamilial communication. We compared answers between diseases and with the perceived severity of each disease. Results We analysed 562 questionnaires. Participants were impacted by Huntington disease (n=307), spinocerebellar ataxias (n=114), Steinert myotonic dystrophy (n=82) and amyotrophic lateral sclerosis/frontotemporal dementia (n=59). Self-estimated severity differed between pathologies (p<0.0001). Overall, participants considered prenatal diagnosis (78.0±34.4 out of 100) and preimplantation diagnosis (75.2±36.1 out of 100) justified more than termination of pregnancy (68.6±38.5 out of 100). They were less in favour of gamete donation (48.3±39.8 out of 100) or pregnancy abstention (43.3±40.3 out of 100). The greater the perceived severity of the disease, the more reproductive options were considered justified, except for gamete donation. Prenatal/preimplantation diagnosis was a motivation to inform relatives for only 55.3% of participants (p=0.01). Conclusion Self-estimated severity minimally impacts opinions towards reproductive options. Medically assisted reproduction procedures are rarely sought and do not motivate familial communication. [ABSTRACT FROM AUTHOR]

Hexanucleotide repeat expansions in C9ORF72 are the most common genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Studies have shown that the hexanucleotide expansions cause the noncanonical translation of C9ORF72 transcripts into neurotoxic dipeptide repeat proteins (DPRs) that contribute to neurodegeneration. We show that a cell-penetrant peptide blocked the nuclear export of C9ORF72-repeat transcripts in HEK293T cells by competing with the interaction between SR-rich splicing factor 1 (SRSF1) and nuclear export factor 1 (NXF1). The cell-penetrant peptide also blocked the translation of toxic DPRs in neurons differentiated from induced neural progenitor cells (iNPCs), which were derived from individuals carrying C9ORF72-linked ALS mutations. This peptide also increased survival of iNPC-differentiated C9ORF72-ALS motor neurons cocultured with astrocytes. Oral administration of the cell-penetrant peptide reduced DPR translation and rescued locomotor deficits in a Drosophila model of mutant C9ORF72-mediated ALS/FTD. Intrathecal injection of this peptide into the brains of ALS/FTD mice carrying a C9ORF72 mutation resulted in reduced expression of DPRs in mouse brains. These findings demonstrate that disrupting the production of DPRs in cellular and animal models of ALS/FTD might be a strategy to ameliorate neurodegeneration in these diseases. House arrest for toxic C9ORF72 hexanucleotide repeat expanded RNAs: Hexanucleotide repeat expansions in the C9ORF72 gene, and translation of these repeat transcripts into toxic dipeptide repeat proteins (DPRs) causes neurodegeneration in some forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Castelli et al. report that a peptide that prevents the nuclear exit of pathological C9ORF72-repeat RNAs inhibits the production of DPRs in rat and human cell models. The peptide also blocked neurotoxic DPR production in flies and mice in vivo and ameliorated locomotor deficits in a fly disease model. This suggests that blocking nuclear export of toxic C9ORF72-repeat RNAs could be a potential therapeutic strategy to reduce neurodegeneration in ALS and FTD. —DN [ABSTRACT FROM AUTHOR]

Poly-glycine-alanine (poly-GA) proteins are widely believed to be one of the main toxic dipeptide repeat molecules associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia diseases. Using discontinuous molecular dynamics simulation and an all-atom model of the proteins, we study folding, stability, and aggregation of poly-GA. The results demonstrate that poly-GA is an aggregation-prone protein that, after a long enough time, forms β-sheet-rich aggregates that match recent experiment data and that two unique helical structures are formed very frequently, namely, β-helix and double-helix. The details of the two structures are analyzed. The analysis indicates that such helical structures are stable and share the characteristics of both α-helices and β-sheets. Molecular simulations indicate that identical phenomena also occur in the aggregation of poly-glycine-arginine (poly-GR). Therefore, we hypothesize that proteins of type (GX)n in which X may be any non-glycine amino acid and n is the repeat length may share the same folding structures of β-helix and double-helix and that it is the glycine in the repeat that contributes the most to this characteristic. Molecular dynamics simulation with continuous interaction potentials and explicit water molecules as the solvent supports the hypothesis. To our knowledge, this is the first molecular dynamics simulation of the phenomena involving poly-GA and poly-GR proteins. [ABSTRACT FROM AUTHOR]

Background: Currently, there are few studies considering possible modifiable risk factors of frontotemporal dementia (FTD).Objective: In this retrospective case-control study, we evaluated whether a history of traumatic brain injury (TBI) associates with a diagnosis of FTD or modulates the clinical phenotype or onset age in FTD patients.Methods: We compared the prevalence of prior TBI between individuals with FTD (N = 218) and age and sex-matched AD patients (N = 214) or healthy controls (HC; N = 100). Based on the patient records, an individual was categorized to the TBI+ group if they were reported to have suffered from TBI during lifetime. The possible associations of TBI with age of onset and disease duration were also evaluated in the whole FTD patient group or separately in the sporadic and genetic FTD groups.Results: The prevalence of previous TBI was the highest in the FTD group (19.3%) when compared to the AD group (13.1%, p = 0.050) or HC group (12%, p = 0.108, not significant). Preceding TBI was more often associated with the sporadic FTD cases than the C9orf72 repeat expansion-carrying FTD cases (p = 0.003). Furthermore, comparison of the TBI+ and TBI- FTD groups indicated that previous TBI was associated with an earlier onset age in the FTD patients (B = 3.066, p = 0.010).Conclusion: A preceding TBI associates especially with sporadic FTD and with earlier onset of symptoms. The results of this study suggest that TBI may be a triggering factor for the neurodegenerative processes in FTD. However, understanding the precise underlying mechanisms still needs further studies. [ABSTRACT FROM AUTHOR]

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Genetic frontotemporal lobar degeneration (FTLD) is characterized by heterogeneous phenotypic expression, with a disease onset highly variable even in patients carrying the same mutation. Herein we investigated if variants in lysosomal genes modulate the age of onset both in FTLD due to GRN null mutations and C9orf72 expansion. In a total of 127 subjects (n = 74 GRN mutations and n = 53 C9orf72 expansion carriers), we performed targeted sequencing of the top 98 genes belonging to the lysosomal pathway, selected based on their high expression in multiple brain regions. We described an earlier disease onset in GRN/C9orf72 pedigrees in subjects carrying the p.Asn521Thr variant (rs1043424) in PTEN-induced kinase 1 (PINK1), a gene that is already known to be involved in neurodegenerative diseases. We found that: (i) the PINK1 rs1043424 C allele is significantly associated with the age of onset; (ii) every risk C allele increases hazard by 2.11%; (iii) the estimated median age of onset in homozygous risk allele carriers is 10–12 years earlier than heterozygous/wild type homozygous subjects. A replication study in GRN/C9orf72 negative FTLD patients confirmed that the rs1043424 C allele was associated with earlier disease onset (−5.5 years in CC versus A carriers). Understanding the potential mechanisms behind the observed modulating effect of the PINK1 gene in FTLD might prove critical for identifying biomarkers and/or designing drugs to modify the age of onset, especially in GRN/C9orf72-driven disease. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) covers a spectrum of neurodegenerative disorders with various clinical and neuropathological subtypes. The two major pathological proteins accumulating in the brains of FTD patients, depending on their genetic background, are TDP-43 and tau. We aimed to evaluate whether total TDP-43 levels measured from the serum associate with the genotype or clinical phenotype of the FTD patients and whether serum TDP-43 provides prognostic or diagnostic value in the FTD spectrum disorders. Methods: The study cohort included 254 participants with a clinical diagnosis of FTD (including all major genotypes and clinical phenotypes) and 105 cognitively healthy controls. Serum total TDP-43 levels measured with a single-molecule array (Simoa) were compared within the FTD group according to the genotype, clinical phenotype, and predicted neuropathological subtype of the patients. We also evaluated the associations between the TDP-43 levels and disease severity or survival in FTD. Results: Total TDP-43 levels in the serum were significantly lower in the FTD group as compared to the healthy control group (275.3 pg/mL vs. 361.8 pg/mL, B = 0.181, 95%CI = 0.014–0.348, p = 0.034). The lowest TDP-43 levels were observed in the subgroup of FTD patients harboring predicted TDP-43 brain pathology (FTD-TDP, 241.4 pg/mL). The low levels in the FTD-TDP group were especially driven by C9orf72 repeat expansion carriers (169.2 pg/mL) and FTD patients with concomitant motoneuron disease (FTD-MND, 113.3 pg/mL), whereas GRN mutation carriers did not show decreased TDP-43 levels (328.6 pg/mL). Serum TDP-43 levels showed no correlation with disease severity nor progression in FTD. Conclusions: Our results indicate that the total levels of TDP-43 in the serum are decreased especially in FTD patients with the C9orf72 repeat expansion or FTD-MND phenotype, both subtypes strongly associated with TDP-43 type B brain pathology. Serum-based measurement of TDP-43 could represent a useful tool in indicating C9orf72 repeat expansion and FTD-MND-related TDP-43 neuropathology for future diagnostics and intervention studies. [ABSTRACT FROM AUTHOR]

Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72, play a critical role in C9ORF72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR–induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD. Bringing the target up to PAR: The most common genetic form of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/LTD) is caused by repeat expansion of the hexanucleotide G4C2 in the C9ORF72 gene, the subsequent production of arginine-rich dipeptide repeat proteins (R-DPRs) ultimately resulting in neurodegeneration. Here, Gao et al. investigated how R-DPR formation could lead to neuronal loss and showed that the polymer poly(ADP)-ribose (PAR) interacts with R-DPR and promotes stress granule formation and TDP-43 aggregation in fly models. Similar effects were found in samples from patients with ALS/FTD, suggesting that targeting PAR could reduce the deleterious effects of R-DPR in C9ORF72-mediated ALS/FTD. [ABSTRACT FROM AUTHOR]