Dataset Information

Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers.

ABSTRACT: 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.

SUBMITTER: Lee SE

PROVIDER: S-EPMC5349617 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers.

Lee Suzee E SE Sias Ana C AC Mandelli Maria Luisa ML Brown Jesse A JA Brown Alainna B AB Khazenzon Anna M AM Vidovszky Anna A AA Zanto Theodore P TP Karydas Anna M AM Pribadi Mochtar M Dokuru Deepika D Coppola Giovanni G Geschwind Dan H DH Rademakers Rosa R Gorno-Tempini Maria Luisa ML Rosen Howard J HJ Miller Bruce L BL Seeley William W WW

NeuroImage. Clinical 20161210

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 str ...[more]

PMID: 28337409

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Project description:ImportanceDuring 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.ObjectivesTo 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 positron emission tomographic (PET) and magnetic resonance imaging as well as the mutation's association with clinical and fluid biomarkers.Design, setting, and participantsA prospective, case-control study enrolled 46 participants from November 30, 2015, until December 11, 2018. The study was conducted at the neuromuscular reference center of the University Hospitals Leuven, Leuven, Belgium.Main outcomes and measuresNeuroimaging data were spatially normalized and analyzed at the voxel level at a height threshold of P < .001, cluster-level familywise error-corrected threshold of P < .05, and statistical significance was set at P < .05 for the volume-of-interest level analysis, using Benjamini-Hochberg correction for multiple correction. W-score maps were computed using the individuals serving as controls as a reference to quantify the degree of [18F]FDG PET abnormality. The threshold for abnormality on the W-score maps was designated as an absolute W-score greater than or equal to 1.96. Neurofilament levels and performance on cognitive and neurologic examinations were determined. All hypothesis tests were 1-sided.ResultsOf the 42 included participants, there were 17 with the preSxC9 mutation (12 women [71%]; mean [SD] age, 51 [9] years) and 25 healthy controls (12 women [48%]; mean [SD] age, 47 [10] years). Compared with control participants, significant clusters of relative hypometabolism were found in frontotemporal regions, basal ganglia, and thalami of preSxC9 participants and relative hypermetabolism in the peri-Rolandic region, superior frontal gyrus, and precuneus cortex. W-score frequency maps revealed reduced glucose metabolism with local maxima in the insular cortices, central opercular cortex, and thalami in up to 82% of preSxC9 participants and increased glucose metabolism in the precentral gyrus and precuneus cortex in up to 71% of preSxC9 participants. Other findings in the preSxC9 group were upper motor neuron involvement in 10 participants (59%), cognitive abnormalities in 5 participants (29%), and elevated neurofilament levels in 3 of 16 individuals (19%) who underwent lumbar puncture.Conclusions and relevanceThe results suggest that [18F]FDG PET can identify glucose metabolic changes in preSxC9 at an individual level, preceding significantly elevated neurofilament levels and onset of symptoms.

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.

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.

Project description:ImportancePresymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation, the most frequent genetic cause of frontotemporal lobar degeneration and amyotrophic lateral sclerosis, represent the optimal target population for the development of disease-modifying drugs. Preclinical biomarkers are needed to monitor the effect of therapeutic interventions in this population.ObjectivesTo assess the occurrence of cognitive, structural, and microstructural changes in presymptomatic C9orf72 carriers.Design, setting, and participantsThe PREV-DEMALS study is a prospective, multicenter, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Eighty-four participants entered the study between October 2015 and April 2017; 80 (95%) were included in cross-sectional analyses of baseline data. All participants underwent neuropsychological testing and magnetic resonance imaging; 63 (79%) underwent diffusion tensor magnetic resonance imaging. Gray matter volumes and diffusion tensor imaging metrics were calculated within regions of interest. Anatomical and microstructural differences between individuals who carried the C9orf72 mutation (C9+) and those who did not carry the C9orf72 mutation (C9-) were assessed using linear mixed-effects models. Data were analyzed from October 2015 to April 2017.Main outcomes and measuresDifferences in neuropsychological scores, gray matter volume, and white matter integrity between C9+ and C9- individuals.ResultsOf the 80 included participants, there were 41 C9+ individuals (24 [59%] female; mean [SD] age, 39.8 [11.1] years) and 39 C9- individuals (24 [62%] female; mean [SD] age, 45.2 [13.9] years). Compared with C9- individuals, C9+ individuals had lower mean (SD) praxis scores (163.4 [6.1] vs 165.3 [5.9]; P = .01) and intransitive gesture scores (34.9 [1.6] vs 35.7 [1.5]; P = .004), atrophy in 8 cortical regions of interest and in the right thalamus, and white matter alterations in 8 tracts. When restricting the analyses to participants younger than 40 years, compared with C9- individuals, C9+ individuals had lower praxis scores and intransitive gesture scores, atrophy in 4 cortical regions of interest and in the right thalamus, and white matter alterations in 2 tracts.Conclusions and relevanceCognitive, structural, and microstructural alterations are detectable in young C9+ individuals. Early and subtle praxis alterations, underpinned by focal atrophy of the left supramarginal gyrus, may represent an early and nonevolving phenotype related to neurodevelopmental effects of C9orf72 mutation. White matter alterations reflect the future phenotype of frontotemporal lobar degeneration/amyotrophic lateral sclerosis, while atrophy appears more diffuse. Our results contribute to a better understanding of the preclinical phase of C9orf72 disease and of the respective contribution of magnetic resonance biomarkers.Trial registrationclinicaltrials.gov Identifier: NCT02590276.

Project description:BackgroundPhysiological disturbances in cortical network excitability and plasticity are established and widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those harbouring the C9ORF72 repeat expansion (C9ORF72RE) mutation - the most common genetic impairment causal to ALS and FTD. Noting that perturbations in cortical function are evidenced pre-symptomatically, and that the cortex is associated with widespread pathology, cortical dysfunction is thought to be an early driver of neurodegenerative disease progression. However, our understanding of how altered network function manifests at the cellular and molecular level is not clear.MethodsTo address this we have generated cortical neurons from patient-derived iPSCs harbouring C9ORF72RE mutations, as well as from their isogenic expansion-corrected controls. We have established a model of network activity in these neurons using multi-electrode array electrophysiology. We have then mechanistically examined the physiological processes underpinning network dysfunction using a combination of patch-clamp electrophysiology, immunocytochemistry, pharmacology and transcriptomic profiling.ResultsWe find that C9ORF72RE causes elevated network burst activity, associated with enhanced synaptic input, yet lower burst duration, attributable to impaired pre-synaptic vesicle dynamics. We also show that the C9ORF72RE is associated with impaired synaptic plasticity. Moreover, RNA-seq analysis revealed dysregulated molecular pathways impacting on synaptic function. All molecular, cellular and network deficits are rescued by CRISPR/Cas9 correction of C9ORF72RE. Our study provides a mechanistic view of the early dysregulated processes that underpin cortical network dysfunction in ALS-FTD.ConclusionThese findings suggest synaptic pathophysiology is widespread in ALS-FTD and has an early and fundamental role in driving altered network function that is thought to contribute to neurodegenerative processes in these patients. The overall importance is the identification of previously unidentified defects in pre and postsynaptic compartments affecting synaptic plasticity, synaptic vesicle stores, and network propagation, which directly impact upon cortical function.

Project description:The majority of the clinico-pathological variability observed in patients harboring a repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) remains unexplained. This expansion, which represents the most common genetic cause of frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND), results in a loss of C9orf72 expression and the generation of RNA foci and dipeptide repeat (DPR) proteins. The C9orf72 protein itself plays a role in vesicular transport, serving as a guanine nucleotide exchange factor that regulates GTPases. To further elucidate the mechanisms underlying C9orf72-related diseases and to identify potential disease modifiers, we performed an extensive RNA sequencing study. We included individuals for whom frontal cortex tissue was available: FTLD and FTLD/MND patients with (n?=?34) or without (n?=?44) an expanded C9orf72 repeat as well as control subjects (n?=?24). In total, 6706 genes were differentially expressed between these groups (false discovery rate [FDR]?<?0.05). The top gene was C9orf72 (FDR?=?1.41E-14), which was roughly two-fold lower in C9orf72 expansion carriers than in (disease) controls. Co-expression analysis revealed groups of correlated genes (modules) that were enriched for processes such as protein folding, RNA splicing, synaptic signaling, metabolism, and Golgi vesicle transport. Within our cohort of C9orf72 expansion carriers, machine learning uncovered interesting candidates associated with clinico-pathological features, including age at onset (vascular endothelial growth factor A [VEGFA]), C9orf72 expansion size (cyclin dependent kinase like 1 [CDKL1]), DPR protein levels (eukaryotic elongation factor 2 kinase [EEF2K]), and survival after onset (small G protein signaling modulator 3 [SGSM3]). Given the fact that we detected a module involved in vesicular transport in addition to a GTPase activator (SGSM3) as a potential modifier, our findings seem to suggest that the presence of a C9orf72 repeat expansion might hamper vesicular transport and that genes affecting this process may modify the phenotype of C9orf72-linked diseases.

Dataset Information

Network degeneration and dysfunction in presymptomatic C9ORF72 expansion carriers.

Publications

Network degeneration and dysfunction in presymptomatic <i>C9ORF72</i> expansion carriers.

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