The gene coding for PGC-1α modifies age at onset in Huntington's Disease

Huntington's disease (HD) is one of the most common autosomal dominant inherited, neurodegenerative disorders. It is characterized by progressive motor, emotional and cognitive dysfunction. In addition metabolic abnormalities such as wasting and altered energy expenditure are increasingly recognized as clinical hallmarks of the disease. HD is caused by an unstable CAG repeat expansion in the HD gene (HTT), localized on chromosome 4p16.3. The number of CAG repeats in the HD gene is the main predictor of disease-onset, but the remaining variation is strongly heritable. Transcriptional dysregulation, mitochondrial dysfunction and enhanced oxidative stress have been implicated in the pathogenesis. Recent studies suggest that PGC-1α, a transcriptional master regulator of mitochondrial biogenesis and metabolism, is defective in HD. A genome wide search for modifier genes of HD age-of-onset had suggested linkage at chromosomal region 4p16-4p15, near the locus of PPARGC1A, the gene coding for PGC-1α. We now present data of 2-loci PPARGC1A block 2 haplotypes, showing an effect upon age-at-onset in 447 unrelated HD patients after statistical consideration of CAG repeat lengths in both HTT alleles. Block 1 haplotypes were not associated with the age-at-onset. Homozygosity for the 'protective' block 2 haplotype was associated with a significant delay in disease onset. To our knowledge this is the first study to show clinically relevant effects of the PGC-1α system on the course of Huntington's disease in humans

A Remote Digital Monitoring Platform to Assess Cognitive and Motor Symptoms in Huntington Disease: Cross-sectional Validation Study

BACKGROUND: Remote monitoring of Huntington disease (HD) signs and symptoms using digital technologies may enhance early clinical diagnosis and tracking of disease progression, guide treatment decisions, and monitor response to disease-modifying agents. Several recent studies in neurodegenerative diseases have demonstrated the feasibility of digital symptom monitoring. OBJECTIVE: The aim of this study was to evaluate a novel smartwatch- and smartphone-based digital monitoring platform to remotely monitor signs and symptoms of HD. METHODS: This analysis aimed to determine the feasibility and reliability of the Roche HD Digital Monitoring Platform over a 4-week period and cross-sectional validity over a 2-week interval. Key criteria assessed were feasibility, evaluated by adherence and quality control failure rates; test-retest reliability; known-groups validity; and convergent validity of sensor-based measures with existing clinical measures. Data from 3 studies were used: the predrug screening phase of an open-label extension study evaluating tominersen (NCT03342053) and 2 untreated cohorts-the HD Natural History Study (NCT03664804) and the Digital-HD study. Across these studies, controls (n=20) and individuals with premanifest (n=20) or manifest (n=179) HD completed 6 motor and 2 cognitive tests at home and in the clinic. RESULTS: Participants in the open-label extension study, the HD Natural History Study, and the Digital-HD study completed 89.95% (1164/1294), 72.01% (2025/2812), and 68.98% (1454/2108) of the active tests, respectively. All sensor-based features showed good to excellent test-retest reliability (intraclass correlation coefficient 0.89-0.98) and generally low quality control failure rates. Good overall convergent validity of sensor-derived features to Unified HD Rating Scale outcomes and good overall known-groups validity among controls, premanifest, and manifest participants were observed. Among participants with manifest HD, the digital cognitive tests demonstrated the strongest correlations with analogous in-clinic tests (Pearson correlation coefficient 0.79-0.90). CONCLUSIONS: These results show the potential of the HD Digital Monitoring Platform to provide reliable, valid, continuous remote monitoring of HD symptoms, facilitating the evaluation of novel treatments and enhanced clinical monitoring and care for individuals with HD

Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase

Objective To investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers. Methods The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA. Results CSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (-80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05). Conclusion Our data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome

Different CSF protein profiles in amyotrophic lateral sclerosis and frontotemporal dementia with C9orf72 hexanucleotide repeat expansion

Objectives: The hexanucleotide repeat expansion in the C9orf72 gene is the most common mutation associated with amyotrophic lateral sclerosis (C9-ALS) and frontotemporal dementia (C9-FTD). Until now, it is unknown which factors define whether C9orf72 mutation carriers develop ALS or FTD. Our aim was to identify protein biomarker candidates in the cerebrospinal fluid (CSF) which differentiate between C9-ALS and C9-FTD and might be indicative for the outcome of the mutation. Methods We compared the CSF proteome of 16 C9-ALS and 8 C9-FTD patients and 11 asymptomatic C9orf72 mutation carriers (CAR) by isobaric tags for relative and absolute quantitation. Eleven biomarker candidates were selected from the pool of differentially regulated proteins for further validation by multiple reaction monitoring and single-molecule array in a larger cohort (n=156). Results In total, 2095 CSF proteins were identified and 236 proteins were significantly different in C9-ALS versus C9-FTD including neurofilament medium polypeptide (NEFM) and chitotriosidase-1 (CHIT1). Eight candidates were successfully validated including significantly increased ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1) levels in C9-ALS compared with C9-FTD and controls and decreased neuronal pentraxin receptor (NPTXR) levels in C9-FTD versus CAR. Conclusions: This study presents a deep proteomic CSF analysis of C9-ALS versus C9-FTD patients. As a proof of concept, we observed higher NEFM and CHIT1 CSF levels in C9-ALS. In addition, we also show clear upregulation of UCHL1 in C9-ALS and downregulation of NPTXR in C9-FTD. Significant differences in UCHL1 CSF levels may explain diverging ubiquitination and autophagy processes and NPTXR levels might reflect different synapses organisation processes

Use and subjective experience of the impact of motor-assisted movement exercisers in people with amyotrophic lateral sclerosis: a multicenter observational study

Motor-assisted movement exercisers (MME) are devices that assist with physical therapy in domestic settings for people living with ALS. This observational cross-sectional study assesses the subjective experience of the therapy and analyzes users' likelihood of recommending treatment with MME. The study was implemented in ten ALS centers between February 2019 and October 2020, and was coordinated by the research platform Ambulanzpartner. Participants assessed symptom severity, documented frequency of MME use and rated the subjective benefits of therapy on a numerical scale (NRS, 0 to 10 points, with 10 being the highest). The Net Promotor Score (NPS) determined the likelihood of a participant recommending MME. Data for 144 participants were analyzed. Weekly MME use ranged from 1 to 4 times for 41% of participants, 5 to 7 times for 42%, and over 7 times for 17%. Particularly positive results were recorded in the following domains: amplification of a sense of achievement (67%), diminution of the feeling of having rigid limbs (63%), diminution of the feeling of being immobile (61%), improvement of general wellbeing (55%) and reduction of muscle stiffness (52%). Participants with more pronounced self-reported muscle weakness were more likely to note a beneficial effect on the preservation and improvement of muscle strength during MME treatment (p < 0.05). Overall, the NPS for MME was high (+ 61). High-frequency MME-assisted treatment (defined as a minimum of five sessions a week) was administered in the majority of participants (59%) in addition to physical therapy. Most patients reported having achieved their individual therapeutic objectives, as evidenced by a high level of satisfaction with MME therapy. The results bolster the justification for extended MME treatment as part of a holistic approach to ALS care

A novel CHCHD10 mutation implicates a Mia40-dependent mitochondrial import deficit in ALS

CHCHD10 mutations are linked to amyotrophic lateral sclerosis, but their mode of action is unclear. In a 29-year-old patient with rapid disease progression, we discovered a novel mutation (Q108P) in a conserved residue within the coiled-coil-helix-coiled-coil-helix (CHCH) domain. The aggressive clinical phenotype prompted us to probe its pathogenicity. Unlike the wild-type protein, mitochondrial import of CHCHD10 Q108P was blocked nearly completely resulting in diffuse cytoplasmic localization and reduced stability. Other CHCHD10 variants reported in patients showed impaired mitochondrial import (C122R) or clustering within mitochondria (especially G66V and E127K) often associated with reduced expression. Truncation experiments suggest mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the proposed N-terminal mitochondrial targeting signal. Knockdown of Mia40, which introduces disulfide bonds into CHCH domain proteins, blocked mitochondrial import of CHCHD10. Overexpression of Mia40 rescued mitochondrial import of CHCHD10 Q108P by enhancing disulfide-bond formation. Since reduction in CHCHD10 inhibits respiration, mutations in its CHCH domain may cause aggressive disease by impairing mitochondrial import. Our data suggest Mia40 upregulation as a potential therapeutic salvage pathway

July 2017 ENCALS statement on edaravone

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Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values &gt;0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.</p