Use of Multimodal Imaging and Clinical Biomarkers in Presymptomatic Carriers of C9orf72 Repeat Expansion.
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ABSTRACT:
SUBMITTER: De Vocht J
PROVIDER: S-EPMC7417970 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Use of Multimodal Imaging and Clinical Biomarkers in Presymptomatic Carriers of C9orf72 Repeat Expansion.
De Vocht Joke J Blommaert Jeroen J Devrome Martijn M Radwan Ahmed A Van Weehaeghe Donatienne D De Schaepdryver Maxim M Ceccarini Jenny J Rezaei Ahmadreza A Schramm Georg G van Aalst June J Chiò Adriano A Pagani Marco M Stam Daphne D Van Esch Hilde H Lamaire Nikita N Verhaegen Marianne M Mertens Nathalie N Poesen Koen K van den Berg Leonard H LH van Es Michael A MA Vandenberghe Rik R Vandenbulcke Mathieu M Van den Stock Jan J Koole Michel M Dupont Patrick P Van Laere Koen K Van Damme Philip P
JAMA neurology 20200801 8
<h4>Importance</h4>During a time with the potential for novel treatment strategies, early detection of disease manifestations at an individual level in presymptomatic carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) is becoming increasingly relevant.<h4>Objectives</h4>To evaluate changes in glucose metabolism before symptom onset of amyotrophic lateral sclerosis or frontotemporal dementia in preSxC9 using simultaneous fluorine 18-labeled fluorodeoxyglucose ([18F]FDG po ...[more]
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Project description:Hexanucleotide repeat expansions in C9ORF72 are the most common known genetic cause of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis. Previous work has shown that patients with behavioral variant frontotemporal dementia due to C9ORF72 show salience and sensorimotor network disruptions comparable to those seen in sporadic behavioral variant frontotemporal dementia, but it remains unknown how early in the lifespan these and other changes in brain structure and function arise. To gain insights into this question, we compared 15 presymptomatic carriers (age 43.7 ± 10.2 years, nine females) to matched healthy controls. We used voxel-based morphometry to assess gray matter, diffusion tensor imaging to interrogate white matter tracts, and task-free functional MRI to probe the salience, sensorimotor, default mode, and medial pulvinar thalamus-seeded networks. We further used a retrospective chart review to ascertain psychiatric histories in carriers and their non-carrier family members. Carriers showed normal cognition and behavior despite gray matter volume and brain connectivity deficits that were apparent as early as the fourth decade of life. Gray matter volume deficits were topographically similar though less severe than those in patients with behavioral variant frontotemporal dementia due to C9ORF72, with major foci in cingulate, insula, thalamus, and striatum. Reduced white matter integrity was found in the corpus callosum, cingulum bundles, corticospinal tracts, uncinate fasciculi and inferior longitudinal fasciculi. Intrinsic connectivity deficits were detected in all four networks but most prominent in salience and medial pulvinar thalamus-seeded networks. Carrier and control groups showed comparable relationships between imaging metrics and age, suggesting that deficits emerge during early adulthood. Carriers and non-carrier family members had comparable lifetime histories of psychiatric symptoms. Taken together, the findings suggest that presymptomatic C9ORF72 expansion carriers exhibit functionally compensated brain volume and connectivity deficits that are similar, though less severe, to those reported during the symptomatic phase. The early adulthood emergence of these deficits suggests that they represent aberrant network patterning during development, an early neurodegeneration prodrome, or both.
| S-EPMC5349617 | biostudies-literature
Project description:Clinical and neuropathological characteristics associated with G4C2 repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, are highly variable. To gain insight on the molecular basis for the heterogeneity among C9ORF72 mutation carriers, we evaluated associations between features of disease and levels of two abundantly expressed "c9RAN proteins" produced by repeat-associated non-ATG (RAN) translation of the expanded repeat. For these studies, we took a departure from traditional immunohistochemical approaches and instead employed immunoassays to quantitatively measure poly(GP) and poly(GA) levels in cerebellum, frontal cortex, motor cortex, and/or hippocampus from 55 C9ORF72 mutation carriers [12 patients with ALS, 24 with frontotemporal lobar degeneration (FTLD) and 19 with FTLD with motor neuron disease (FTLD-MND)]. We additionally investigated associations between levels of poly(GP) or poly(GA) and cognitive impairment in 15 C9ORF72 ALS patients for whom neuropsychological data were available. Among the neuroanatomical regions investigated, poly(GP) levels were highest in the cerebellum. In this same region, associations between poly(GP) and both neuropathological and clinical features were detected. Specifically, cerebellar poly(GP) levels were significantly lower in patients with ALS compared to patients with FTLD or FTLD-MND. Furthermore, cerebellar poly(GP) associated with cognitive score in our cohort of 15 patients. In the cerebellum, poly(GA) levels similarly trended lower in the ALS subgroup compared to FTLD or FTLD-MND subgroups, but no association between cerebellar poly(GA) and cognitive score was detected. Both cerebellar poly(GP) and poly(GA) associated with C9ORF72 variant 3 mRNA expression, but not variant 1 expression, repeat size, disease onset, or survival after onset. Overall, these data indicate that cerebellar abnormalities, as evidenced by poly(GP) accumulation, associate with neuropathological and clinical phenotypes, in particular cognitive impairment, of C9ORF72 mutation carriers.
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Project description:The temporal variant of frontotemporal dementia (tv-FTD) is a progressive neurodegenerative disease with a complex clinical picture mainly characterized by behavioral and language disorders. In this work, we describe clinical, genetic, neuroanatomical and neuropathological (only in one case) features of two patients with tv-FTD carrying C9orf72 repeat expansion. The first patient (AB) presented with a 1-year disease duration showing focal right anterior temporal lobe (ATL) atrophy on magnetic resonance imaging (MRI). The second patient (BC) came to medical attention 13 years after disease onset and showed a prominent bilateral ATL involvement. Both patients showed naming deficits, impairment in identifying known faces and proper names, and personality changes with new onset behavioral rigidity, and progressing language difficulties to single-word and sentence comprehension difficulties. They were classified as tv-FTD. Clinical, cognitive and MRI follow-up were performed. As cognitive impairment progressed, MRI atrophy worsened in ATL and frontotemporal areas in both patients. Both cases had clear family histories of neurological and/or psychiatric disease. Genetic testing revealed a C9orf72 hexanucleotide repeat expansion in both cases. BC passed away after 15 years of disease and autopsy showed the expected TDP-type B pathology. These genetic cases of tv-FTD highlight the susceptibility of ATL to C9orf72-related pathology and emphasize the importance of genetical testing in FTD-spectrum disorders, regardless of the clinical phenotype.
| S-EPMC7467111 | biostudies-literature
Project description:ObjectiveTo determine the frequency of a hexanucleotide repeat expansion in C9ORF72, a gene of unknown function implicated in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), in Australian FTD patient cohorts and to examine the clinical and neuropathologic phenotypes associated with this expansion.MethodsWe examined a clinically ascertained FTD cohort (n = 89) and a neuropathologically ascertained cohort of frontotemporal lobar degeneration cases with TDP-43 pathology (FTLD-TDP) (n = 22) for the C9ORF72 hexanucleotide repeat expansion using a repeat primed PCR assay. All expansion-positive patients were genotyped for rs3849942, a surrogate marker for the chromosome 9p21 risk haplotype previously associated with FTD and ALS.ResultsThe C9ORF72 repeat expansion was detected in 10% of patients in the clinically diagnosed cohort, rising to 29% in those with a positive family history of early-onset dementia or ALS. The prevalence of psychotic features was significantly higher in expansion-positive cases (56% vs 14%). In the pathology cohort, 41% of TDP-43-positive cases harbored the repeat expansion, and all exhibited type B pathology. One of the 17 expansion-positive probands was homozygous for the "nonrisk" G allele of rs3849942.ConclusionsThe C9ORF72 repeat expansion is a relatively common cause of FTD in Australian populations, and is especially common in those with FTD-ALS, psychotic features, and a strong family history. Detection of a repeat expansion on the 9p21 putative "nonrisk" haplotype suggests that not all mutation carriers are necessarily descended from a common founder and indicates that the expansion may have occurred on multiple haplotype backgrounds.
| S-EPMC3430710 | biostudies-literature
Project description:Importance:The c9orf72 repeat expansion (c9 or c9orf72RE) confers a survival disadvantage in amyotrophic lateral sclerosis (ALS); its effect on prognosis in frontotemporal dementia (FTD) remains uncertain. Data on prognostic factors in c9orf72RE disorders could inform patient care, genetic counseling, and trial design. Objective:To examine prognostic factors in c9ALS, c9FTD, c9ALS-FTD, and atypical phenotypes. Data Sources:The MEDLINE, Embase, Amed, ProQuest, PsychINFO, CINAHL, and LILACS databases were searched between January 2011 and January 2019. Keywords used were c9orf72 and chromosome 9 open reading frame 72. Reference lists, citations of eligible studies, and review articles were also searched by hand. Study Selection:Studies reporting disease duration for patients with a confirmed c9orf72RE and a neurological and/or psychiatric disorder were included. A second author independently reviewed studies classified as irrelevant by the first author. Analysis began in January 2019. Data Extraction and Synthesis:Data were extracted by 1 author; a further author independently extracted 10% of data. Data were synthesized in univariate and multivariable Cox regression and are displayed as hazard ratios (HR) and 95% confidence intervals. Main Outcomes and Measures:Survival after symptom onset. Results:Overall, 206 studies reporting on 1060 patients were included from 2878 publications identified (c9ALS: n?=?455; c9FTD: n?=?296; c9ALS-FTD: n?=?198; atypical phenotypes: n?=?111); 197 duplicate cases were excluded. The median (95% CI) survival (in years) differed significantly between patients with c9ALS (2.8 [2.67-3.00]), c9FTD (9.0 [8.09-9.91]), and c9ALS-FTD (3.0 [2.73-3.27]); survival in atypical phenotypes varied substantially. Older age at onset was associated with shorter survival in c9ALS (HR, 1.03; 95% CI, 1.02-1.04; P?<?.001), c9FTD (HR, 1.04; 95% CI, 1.02-1.06; P?<?.001), and c9ALS-FTD (HR, 1.02; 95% CI, 1.004-1.04; P?=?.016). Bulbar onset was associated with shorter survival in c9ALS (HR, 1.64; 95% CI, 1.27-2.08; P?<?.001). Age at onset and bulbar onset ALS remained significant in multivariable regression including variables indicating potential diagnostic ascertainment bias, selection bias, and reporting bias. Family history, sex, study continent, FTD subtype, or the presence of additional pathogenic sequence variants were not significantly associated with survival. Clinical phenotypes in patients with neuropathologically confirmed frontotemporal lobar degeneration-TDP-43, motor neuron disease-TDP-43 and frontotemporal lobar degeneration-motor neuron disease-TDP-43 were heterogenous and impacted on survival. Conclusions and Relevance:Several factors associated with survival in c9orf72RE disorders were identified. The inherent limitations of our methodological approach must be considered; nonetheless, the reported prognostic factors were not significantly associated with the bias indicators examined.
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Project description:Variants in transmembrane protein 106 B (TMEM106B) modify the disease penetrance of frontotemporal dementia (FTD) in carriers of progranulin (GRN) mutations. We investigated whether TMEM106B is also a genetic modifier of disease in carriers of chromosome 9 open reading frame 72 (C9ORF72) expansions. We assessed the genotype of 325 C9ORF72 expansion carriers (cohort 1), 586 FTD patients lacking C9ORF72 expansions [with or without motor neuron disease (MND); cohort 2], and a total of 1,302 controls for TMEM106B variants (rs3173615 and rs1990622) using MassArray iPLEX and Taqman genotyping assays. For our primary analysis, we focused on functional variant rs3173615, and employed a recessive genotypic model. In cohort 1, patients with C9ORF72 expansions showed a significantly reduced frequency of carriers homozygous for the minor allele as compared to controls [11.9 vs. 19.1 %, odds ratio (OR) 0.57, p = 0.014; same direction as carriers of GRN mutations]. The strongest evidence was provided by FTD patients (OR 0.33, p = 0.009) followed by FTD/MND patients (OR 0.38, p = 0.017), whereas no significant difference was observed in MND patients (OR 0.85, p = 0.55). In cohort 2, the frequency of carriers homozygous for the minor allele was not significantly reduced in patients as compared to controls (OR 0.77, p = 0.079); however, a significant reduction was observed when focusing on those patients with frontotemporal lobar degeneration and TAR DNA-binding protein 43 inclusions (FTLD-TDP; OR 0.26, p < 0.001). Our study identifies TMEM106B as the first genetic factor modifying disease presentation in C9ORF72 expansion carriers. Homozygosity for the minor allele protects carriers from developing FTD, but not from developing MND; similar effects are seen in FTLD-TDP patients with yet unknown genetic causes. These new findings show that the protective effects of TMEM106B are not confined to carriers of GRN mutations and might be relevant for prognostic testing, and as a promising therapeutic target for the entire spectrum of FTLD-TDP.
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Project description:In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 frontotemporal lobar degeneration (FTLD) patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-frontotemporal dementia (FTD) and 2 FTD-amyotrophic lateral sclerosis [ALS]) out of 53 patients and 1 neurologically normal control. Interestingly, 2 of the C9ORF72 expansion carriers also carried 2 novel missense mutations in GRN (Y294C) and in PSEN-2(I146V). Further, 1 of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TAR (trans-activation response) DNA-binding protein (TDP)-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD, or FTD-ALS and occasional comorbid conditions such as Alzheimer's disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.
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Project description:The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
| S-EPMC4800742 | biostudies-literature
Project description:Previous cross-sectional imaging studies found differences in brain structure and in resting state networks between presymptomatic carriers of mutations in C9orf72 (C9+) and healthy controls. We carried out a prospective longitudinal study of clinical and resting state functional imaging in a cohort of 15 presymptomatic C9+ carriers to determine whether differences in resting state connectivity prior to developing symptoms reflect static developmental differences or ongoing low-grade degenerative changes. Presymptomatic C9+ carriers were scanned at baseline with follow-up scanning at 6- and 18-months and compared to a cohort of 14 healthy controls scanned longitudinally. Resting state networks associated with manifest disease were visualized by comparing 27 symptomatic C9+ carriers to 34 healthy controls. Motor, salience, thalamic, and speech production networks were visualized using a seed-based analysis. Neurofilament light chain was measured in serum obtained at the time of the scans. Neither clinical measures of motor, cognitive, and behavioral function nor neurofilament levels changed over follow-up in presymptomatic C9+ carriers. In thalamic networks, there was a reduction in connectivity in presymptomatic carriers at all timepoints with a constant difference compared to healthy controls. In contrast, precuneus/posterior cingulate regions exhibited declining functional connectivity compared to controls over the 18-month follow-up, particularly in motor networks. These were regions that also exhibited reduced functional connectivity in symptomatic C9+ carriers. Reduced connectivity over time also occurred in small regions of frontal and temporal cortex within salience and thalamic networks in presymptomatic C9+ carriers. A few areas of increased connectivity occurred, including cortex near the motor seed and within the speech production network. Overall, changes in functional connectivity over time favor the explanation of ongoing low-grade alterations in presymptomatic C9+ carriers in most networks, with the exception of thalamic networks where functional connectivity reductions were stable over time. The loss of connectivity to parietal cortex regions in several different networks may be a distinct feature of C9orf72-related degeneration. Longitudinal studies of carriers who phenoconvert will be important to determine the prognostic significance of presymptomatic functional connectivity alterations.
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