Publications by authors named "Ammar Al-Chalabi"

253 Publications

Challenging the Established Order: Innovating Clinical Trials for Amyotrophic Lateral Sclerosis.

Neurology 2021 Jul 27. Epub 2021 Jul 27.

Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, the Netherlands.

Development of effective treatment for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology and methodological design challenges. Here we have evaluated two major themes in the design of pivotal, phase 3 clinical trials for ALS: (1) patient selection and (2) analytical strategy, and discussed potential solutions with the European Medicines Agency (EMA). Several design considerations were assessed using data from five placebo-controlled clinical trials (N = 988), four population-based cohorts (N = 5,100), and 2,436 placebo-allocated patients from the PRO-ACT database. The validity of each proposed design modification was confirmed by means of simulation and illustrated for a hypothetical setting. Compared to classical trial design, the proposed design modifications reduce the sample size by 30.5% and placebo exposure time by 35.4%. By making use of prognostic survival models, one creates a potential to include a larger proportion of the population and maximize generalizability. We propose a flexible design framework which naturally adapts the trial duration when inaccurate assumptions are made at the design stage such as the enrollment or survival rate. In case of futility, the follow-up time is shortened and patient exposure to ineffective treatments or placebo is minimized. For diseases such as ALS, optimizing the use of resources, widening eligibility criteria and minimizing the exposure to futile treatments and placebo is critical to the development of effective treatments. Our proposed design modifications could circumvent important pitfalls and may serve a blueprint for future clinical trials in this population.
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http://dx.doi.org/10.1212/WNL.0000000000012545DOI Listing
July 2021

A HML6 endogenous retrovirus on chromosome 3 is upregulated in amyotrophic lateral sclerosis motor cortex.

Sci Rep 2021 Jul 12;11(1):14283. Epub 2021 Jul 12.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 9NU, UK.

There is increasing evidence that endogenous retroviruses (ERVs) play a significant role in central nervous system diseases, including amyotrophic lateral sclerosis (ALS). Studies of ALS have consistently identified retroviral enzyme reverse transcriptase activity in patients. Evidence indicates that ERVs are the cause of reverse transcriptase activity in ALS, but it is currently unclear whether this is due to a specific ERV locus or a family of ERVs. We employed a combination of bioinformatic methods to identify whether specific ERVs or ERV families are associated with ALS. Using the largest post-mortem RNA-sequence datasets available we selectively identified ERVs that closely resembled full-length proviruses. In the discovery dataset there was one ERV locus (HML6_3p21.31c) that showed significant increased expression in post-mortem motor cortex tissue after multiple-testing correction. Using six replication post-mortem datasets we found HML6_3p21.31c was consistently upregulated in ALS in motor cortex and cerebellum tissue. In addition, HML6_3p21.31c showed significant co-expression with cytokine binding and genes involved in EBV, HTLV-1 and HIV type-1 infections. There were no significant differences in ERV family expression between ALS and controls. Our results support the hypothesis that specific ERV loci are involved in ALS pathology.
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http://dx.doi.org/10.1038/s41598-021-93742-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275748PMC
July 2021

Preventing neurodegenerative disease.

Authors:
Ammar Al-Chalabi

Brain 2021 Jun;144(5):1279-1280

London, UK.

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http://dx.doi.org/10.1093/brain/awab151DOI Listing
June 2021

DGLinker: flexible knowledge-graph prediction of disease-gene associations.

Nucleic Acids Res 2021 07;49(W1):W153-W161

Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King's College London, SE5 8AF, London, UK.

As a result of the advent of high-throughput technologies, there has been rapid progress in our understanding of the genetics underlying biological processes. However, despite such advances, the genetic landscape of human diseases has only marginally been disclosed. Exploiting the present availability of large amounts of biological and phenotypic data, we can use our current understanding of disease genetics to train machine learning models to predict novel genetic factors associated with the disease. To this end, we developed DGLinker, a webserver for the prediction of novel candidate genes for human diseases given a set of known disease genes. DGLinker has a user-friendly interface that allows non-expert users to exploit biomedical information from a wide range of biological and phenotypic databases, and/or to upload their own data, to generate a knowledge-graph and use machine learning to predict new disease-associated genes. The webserver includes tools to explore and interpret the results and generates publication-ready figures. DGLinker is available at https://dglinker.rosalind.kcl.ac.uk. The webserver is free and open to all users without the need for registration.
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http://dx.doi.org/10.1093/nar/gkab449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262728PMC
July 2021

A multicentre validation study of the diagnostic value of plasma neurofilament light.

Nat Commun 2021 06 7;12(1):3400. Epub 2021 Jun 7.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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http://dx.doi.org/10.1038/s41467-021-23620-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185001PMC
June 2021

Does genetic anticipation occur in familial Alexander disease?

Neurogenetics 2021 Jul 28;22(3):215-219. Epub 2021 May 28.

Department of Basic and Clinical Neuroscience, King's College London, London, UK.

Alexander Disease (AxD) is a rare leukodystrophy caused by missense mutations of glial fibrillary acidic protein (GFAP). Primarily seen in infants and juveniles, it can present in adulthood. We report a family with inherited AxD in which the mother presented with symptoms many years after her daughter. We reviewed the age of onset in all published cases of familial AxD and found that 32 of 34 instances of parent-offspring pairs demonstrated an earlier age of onset in offspring compared to the parent. We suggest that genetic anticipation occurs in familial AxD and speculate that genetic mosaicism could explain this phenomenon.
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http://dx.doi.org/10.1007/s10048-021-00642-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241638PMC
July 2021

Facial Onset Sensory and Motor Neuronopathy: New Cases, Cognitive Changes, and Pathophysiology.

Neurol Clin Pract 2021 Apr;11(2):147-157

Universitair Medisch Centrum Utrecht (EMJB, HSG, JI, MP, LHB, JHV, MAE), Department of Neurology, Utrecht, The Netherlands; Brighton and Sussex Medical School (AWB, ME, RB, PNL), Clinical Imaging Sciences Centre, Brighton, United Kingdom; Hurstwood Park Neurological Centre (AWB, ME, SJA, RB, AN), Haywards Heath, United Kingdom; Hospital Universitari i Politècnic La Fe (JFVC), ALS Unit, Department of Neurology, Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) (JFVC), Madrid, Spain; Department of Neurology (JP), Rostock University Medical Center and German Center for Neurodegenerative Diseases (DZNE), Germany; Department of Neurology (CAV), Haukeland University Hospital and Department of Clinical Medicine, Bergen, Norway; Department of Neurology (JPF), Hospital Clínico Universitario de Santiago, Santiago, Spain; Department of Neurology (MPP, MAAA), Hospital Universitari de Bellvitge, Barcelona, Spain; ALS/MND Centre (EDB, GL), 3rd Neurology Unit, Fondazione IRCCS Institute Neurologico Carlo Besta, Milan, Italy; Department of Biomedical and Clinical Sciences "Luigi Sacco" (GL), University of Milan, Milan, Italy; Department of Neurology and Neurosurgery (WBVRP, PVSS, ASBO), Federal University of São Paulo (UNIFESP), São Paulo, Brazil; National Institutes of Health (CT), National Human Genome Research Institute, Bethesda, United States of America; Memorial Sloan Kettering Cancer Center (OH), NY; King's College Hospital NHS Foundation Trust (AA-C), London, United Kingdom; and Department of Neuroscience (PNL), Brighton and Sussex Medical School, Brighton, United Kingdom.

Purpose Of Review: To improve our clinical understanding of facial onset sensory and motor neuronopathy (FOSMN).

Recent Findings: We identified 29 new cases and 71 literature cases, resulting in a cohort of 100 patients with FOSMN. During follow-up, cognitive and behavioral changes became apparent in 8 patients, suggesting that changes within the spectrum of frontotemporal dementia (FTD) are a part of the natural history of FOSMN. Another new finding was chorea, seen in 6 cases. Despite reports of autoantibodies, there is no consistent evidence to suggest an autoimmune pathogenesis. Four of 6 autopsies had TAR DNA-binding protein (TDP) 43 pathology. Seven cases had genetic mutations associated with neurodegenerative diseases.

Summary: FOSMN is a rare disease with a highly characteristic onset and pattern of disease progression involving initial sensory disturbances, followed by bulbar weakness with a cranial to caudal spread of pathology. Although not conclusive, the balance of evidence suggests that FOSMN is most likely to be a TDP-43 proteinopathy within the amyotrophic lateral sclerosis-FTD spectrum.
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http://dx.doi.org/10.1212/CPJ.0000000000000834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032419PMC
April 2021

Intuitive Staging Correlates With King's Clinical Stage.

Amyotroph Lateral Scler Frontotemporal Degener 2021 08 6;22(5-6):336-340. Epub 2021 Apr 6.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.

Clinical stage in amyotrophic lateral sclerosis (ALS) can be assigned using King's staging with a simple protocol based on the number of CNS regions involved and the presence of significant nutritional or respiratory failure. It is important that the assigned clinical stage matches expectations, and generally corresponds with how a health care professional would intuitively stage the patient. We therefore investigated the relationship between King's clinical ALS stage and ALS stage as intuitively assigned by health care professionals. We wrote 17 case vignettes describing people with ALS at different disease stages from very early limited disease involvement through to severe, multi-domain disease. During two workshops, we asked health care professionals to intuitively stage the vignettes and compared the answers with the actual King's clinical ALS stage. There was a good correlation between King's clinical ALS stage and intuitively assigned stage, with a Spearman's Rank correlation coefficient of 0.64 ( < 0.001). There was no difference in the intuitive stages assigned by practitioners of different types or at different levels of experience. Across a spectrum of ALS scenarios, King's clinical ALS stage corresponds to intuitive ALS stage as assigned by a range of health care professionals.
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http://dx.doi.org/10.1080/21678421.2020.1867181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611335PMC
August 2021

Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders.

Genome Biol 2021 Mar 26;22(1):90. Epub 2021 Mar 26.

Centre for Clinical Research, The University of Queensland, Brisbane, QLD, 4019, Australia.

Background: People with neurodegenerative disorders show diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) provides a way to explore this overlap and heterogeneity as it is determined by the combined effects of genetic variation and the environment. In this study, we aim to identify shared blood DNAm differences between controls and people with Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease.

Results: We use a mixed-linear model method (MOMENT) that accounts for the effect of (un)known confounders, to test for the association of each DNAm site with each disorder. While only three probes are found to be genome-wide significant in each MOMENT association analysis of amyotrophic lateral sclerosis and Parkinson's disease (and none with Alzheimer's disease), a fixed-effects meta-analysis of the three disorders results in 12 genome-wide significant differentially methylated positions. Predicted immune cell-type proportions are disrupted across all neurodegenerative disorders. Protein inflammatory markers are correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy aging cohort. In contrast, they are not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights.

Conclusions: We identify shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.
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http://dx.doi.org/10.1186/s13059-021-02275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004462PMC
March 2021

Cross-reactive probes on Illumina DNA methylation arrays: a large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies.

NAR Genom Bioinform 2020 Dec 17;2(4):lqaa105. Epub 2020 Dec 17.

Department of Neurology, UMC Utrecht Brain Center, 3584 CG, Utrecht, the Netherlands.

Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple regions in the genome. Although several studies have reported on this issue, few studies have empirically examined the impact of cross-reactivity in an epigenome-wide association study (EWAS). In this paper, we report on cross-reactivity issues that we discovered in a large EWAS on the presence of the repeat expansion in ALS patients. Specifically, we found that that the majority of the significant probes inadvertently cross-hybridized to the locus. Importantly, these probes were not flagged as cross-reactive in previous studies, leading to novel insights into the extent to which cross-reactivity can impact EWAS. Our findings are particularly relevant for epigenetic studies into diseases associated with repeat expansions and other types of structural variation. More generally however, considering that most spurious associations were not excluded based on pre-defined sets of cross-reactive probes, we believe that the presented data-driven flag and consider approach is relevant for any type of EWAS.
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http://dx.doi.org/10.1093/nargab/lqaa105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745769PMC
December 2020

The Effect of SMN Gene Dosage on ALS Risk and Disease Severity.

Ann Neurol 2021 04 15;89(4):686-697. Epub 2021 Jan 15.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA.

Objective: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency.

Methods: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data.

Results: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63).

Interpretation: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.
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http://dx.doi.org/10.1002/ana.26009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048961PMC
April 2021

Improving clinical trial outcomes in amyotrophic lateral sclerosis.

Nat Rev Neurol 2021 Feb 18;17(2):104-118. Epub 2020 Dec 18.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Individuals who are diagnosed with amyotrophic lateral sclerosis (ALS) today face the same historically intransigent problem that has existed since the initial description of the disease in the 1860s - a lack of effective therapies. In part, the development of new treatments has been hampered by an imperfect understanding of the biological processes that trigger ALS and promote disease progression. Advances in our understanding of these biological processes, including the causative genetic mutations, and of the influence of environmental factors have deepened our appreciation of disease pathophysiology. The consequent identification of pathogenic targets means that the introduction of effective therapies is becoming a realistic prospect. Progress in precision medicine, including genetically targeted therapies, will undoubtedly change the natural history of ALS. The evolution of clinical trial designs combined with improved methods for patient stratification will facilitate the translation of novel therapies into the clinic. In addition, the refinement of emerging biomarkers of therapeutic benefits is critical to the streamlining of care for individuals. In this Review, we synthesize these developments in ALS and discuss the further developments and refinements needed to accelerate the introduction of effective therapeutic approaches.
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http://dx.doi.org/10.1038/s41582-020-00434-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747476PMC
February 2021

Rare Variant Burden Analysis within Enhancers Identifies CAV1 as an ALS Risk Gene.

Cell Rep 2020 12;33(9):108456

Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK. Electronic address:

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease. CAV1 and CAV2 organize membrane lipid rafts (MLRs) important for cell signaling and neuronal survival, and overexpression of CAV1 ameliorates ALS phenotypes in vivo. Genome-wide association studies localize a large proportion of ALS risk variants within the non-coding genome, but further characterization has been limited by lack of appropriate tools. By designing and applying a pipeline to identify pathogenic genetic variation within enhancer elements responsible for regulating gene expression, we identify disease-associated variation within CAV1/CAV2 enhancers, which replicate in an independent cohort. Discovered enhancer mutations reduce CAV1/CAV2 expression and disrupt MLRs in patient-derived cells, and CRISPR-Cas9 perturbation proximate to a patient mutation is sufficient to reduce CAV1/CAV2 expression in neurons. Additional enrichment of ALS-associated mutations within CAV1 exons positions CAV1 as an ALS risk gene. We propose CAV1/CAV2 overexpression as a personalized medicine target for ALS.
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http://dx.doi.org/10.1016/j.celrep.2020.108456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710676PMC
December 2020

Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis.

Mol Brain 2020 11 13;13(1):154. Epub 2020 Nov 13.

Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.

Long interspersed element-1 (LINE-1/L1) is the only autonomous transposable element in the human genome that currently mobilises in both germline and somatic tissues. Recent studies have identified correlations between altered retrotransposon expression and the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a subset of patients. The risk of an individual developing ALS is dependent on an interaction of genetic variants and subsequent modifiers during life. These modifiers could include environmental factors, which can lead to epigenetic and genomic changes, such as somatic mutations, occurring in the neuronal cells that degenerate as the disease develops. There are more than 1 million L1 copies in the human genome today, but only 80-100 L1 loci in the reference genome are considered to be retrotransposition-competent (RC) and an even smaller number of these RC-L1s loci are highly active. We hypothesise that RC-L1s could affect normal cellular function through their mutagenic potential conferred by their ability to retrotranspose in neuronal cells and through DNA damage caused by the endonuclease activity of the L1-encoded ORF2 protein. To investigate whether either an increase in the genomic burden of RC-L1s or epigenetic changes to RC-L1s altering their expression, could play a role in disease development, we chose a set of seven well characterised genomic RC-L1 loci that were reported earlier to be highly active in a cellular L1 retrotransposition reporter assay or serve as major source elements for germline and/or somatic retrotransposition events. Analysis of the insertion allele frequency of five polymorphic RC-L1s, out of the set of seven, for their presence or absence, did not identify an increased number individually or when combined in individuals with the disease. However, we did identify reduced levels of methylation of RC-L1s in the motor cortex of those individuals with both familial and sporadic ALS compared to control brains. The changes to the regulation of the loci encompassing these RC-L1s demonstrated tissue specificity and could be related to the disease process.
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http://dx.doi.org/10.1186/s13041-020-00694-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666467PMC
November 2020

The genetic architecture of ALS.

Neurobiol Dis 2021 01 29;147:105156. Epub 2020 Oct 29.

Department of Basic & Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 9RX, UK; Department of Neurology, King's College Hospital, London SE5 9RS, UK. Electronic address:

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http://dx.doi.org/10.1016/j.nbd.2020.105156DOI Listing
January 2021

Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics.

Cell Rep 2020 10;33(4):108323

Centre for Clinical Research, The University of Queensland, Brisbane QLD, Australia; Department of Neurology, Royal Brisbane and Women's Hospital, Brisbane QLD, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane QLD, Australia.

We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients' fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: -2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: -1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients.
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http://dx.doi.org/10.1016/j.celrep.2020.108323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610013PMC
October 2020

Clinical staging in amyotrophic lateral sclerosis: analysis of Edaravone Study 19.

J Neurol Neurosurg Psychiatry 2021 02 27;92(2):165-171. Epub 2020 Oct 27.

Mitsubishi Tanabe Pharma America, Inc, Jersey City, New Jersey, USA

Objective: This was a post hoc analysis of the Edaravone Phase III Study MCI186-19 ('Study 19') to examine the utility of clinical staging systems as end points in clinical trials in amyotrophic lateral sclerosis (ALS).

Methods: Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised item scores from Study 19 were retrospectively mapped to King's stage and Milano-Torino staging (MiToS) stage. We assessed the percentage of patients who experienced progression in King's and MiToS stages during Study 19. We also assessed disease progression in subgroups of patients according to baseline King's stage.

Results: During double-blind treatment, the percentage of patients who experienced a progression in King's stage was lower for edaravone (42.0%, 95% CI 30.4% to 53.6%) than placebo (55.9%, 95% CI 44.1% to 67.6%). The most pronounced effect was noted among patients who were in stage 1 and was maintained throughout open-label treatment. An analysis of a ≥2-stage progression in MiToS stage showed no difference between treatment arms during double-blind treatment, but during the open-label period, more rapid progression was noted among patients in the placebo-edaravone arm than among those in the edaravone-edaravone arm (log-rank test, p<0.001).

Conclusions: The King's and MiToS staging systems provided utility in assessing clinical progression in Edaravone Study 19. These findings may support the use of staging systems as end points in ALS clinical trials and to understand the timing of benefit as measured by these scales.
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http://dx.doi.org/10.1136/jnnp-2020-323271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841496PMC
February 2021

repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization.

Brain Commun 2020 19;2(2):fcaa064. Epub 2020 May 19.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute and United Kingdom Dementia Research Institute, King's College London, London SE5 9NU, UK.

Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in , polyglutamine expansions in and polyalanine expansions in . Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in , suggested a similar disease association for the repeat expansion in . We, therefore, performed a large-scale international study in 11 700 individuals, in which we showed a significant association between intermediate repeat expansions and amyotrophic lateral sclerosis (=3.33 × 10). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in , further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/braincomms/fcaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425293PMC
May 2020

Motor Neuron Disease Register for England, Wales and Northern Ireland-an analysis of incidence in England.

Amyotroph Lateral Scler Frontotemporal Degener 2021 02 17;22(1-2):86-93. Epub 2020 Sep 17.

Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK.

Introduction: Amyotrophic lateral sclerosis (ALS) has a reported incidence of 1-2/100,000 person-years. It is estimated that there are 5000 people with ALS in the UK at any one time; however, the true figure and geographical distribution, are unknown. In this study, we describe the establishment of a population register for England, Wales, and Northern Ireland and report-estimated incidence. : People with a diagnosis of ALS given by a consultant neurologist and whose postcode of residence is within England, Wales, or Northern Ireland were eligible. The catchment area was based on six data contributors that had been participating since 2016. All centres included in this analysis were in England, and therefore Wales and Northern Ireland are not included in this report. Crude age- and sex-specific incidence rates were estimated using population census records for the relevant postcodes from Office of National Statistics census data. These rates were standardized to the UK population structure using direct standardization. : There were 232 people in the database with a date of diagnosis between 2017 and 2018, when missing data were imputed there were an estimated 287-301 people. The denominator population of the catchment area is 7,251,845 according to 2011 UK census data. Age- and sex-adjusted incidence for complete cases was 1.61/100,000 person-years (95% confidence interval 1.58, 1.63), and for imputed datasets was 2.072/100,000 person-years (95% CI 2.072, 2.073). : We found incidence in this previously unreported area of the UK to be similar to other published estimates. As the MND Register for England, Wales, and Northern Ireland grows we will update incidence estimates and report on further analyses.
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http://dx.doi.org/10.1080/21678421.2020.1812661DOI Listing
February 2021

Relationship between smoking and ALS: Mendelian randomisation interrogation of causality.

J Neurol Neurosurg Psychiatry 2020 12 26;91(12):1312-1315. Epub 2020 Aug 26.

Maurice Wohl Clinical Neuroscience Institute, Department of Basic and Clinical Neuroscience, King's College London, London, UK

Objective: Smoking has been widely studied as a susceptibility factor for amyotrophic lateral sclerosis (ALS), but results are conflicting and at risk of confounding bias. We used the results of recently published large genome-wide association studies and Mendelian randomisation methods to reduce confounding to assess the relationship between smoking and ALS.

Methods: Two genome-wide association studies investigating lifetime smoking (n=463 003) and ever smoking (n=1 232 091) were identified and used to define instrumental variables for smoking. A genome-wide association study of ALS (20 806 cases; 59 804 controls) was used as the outcome for inverse variance weighted Mendelian randomisation, and four other Mendelian randomisation methods, to test whether smoking is causal for ALS. Analyses were bidirectional to assess reverse causality.

Results: There was no strong evidence for a causal or reverse causal relationship between smoking and ALS. The results of Mendelian randomisation using the inverse variance weighted method were: lifetime smoking OR 0.94 (95% CI 0.74 to 1.19), p value 0.59; ever smoking OR 1.10 (95% CI 1 to 1.23), p value 0.05.

Conclusions: Using multiple methods, large sample sizes and sensitivity analyses, we find no evidence with Mendelian randomisation techniques that smoking causes ALS. Other smoking phenotypes, such as current smoking, may be suitable for future Mendelian randomisation studies.
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http://dx.doi.org/10.1136/jnnp-2020-323316DOI Listing
December 2020

Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial.

EBioMedicine 2020 Sep 7;59:102844. Epub 2020 Jul 7.

Department of Biostatistics, Clinical Epidemiology, Public Health and Innovation in Methodology (BESPIM), Nîmes University Hospital, Nîmes, France; Department of Pharmacology, AP-HP.Sorbonne Université, Pitié-Salpêtrière Hospital, 47, Bd de l'Hôpital, F-75013 Paris, France; Department of Pharmacology, Sorbonne Université Médecine, F-75013 Paris, France. Electronic address:

Background: Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects.

Methods: We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4 T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759.

Findings: All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3-4·9) and 1 MIU ES=3·5 (IC95%: 2·1-4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels.

Interpretation: Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression.

Funding: The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA).
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http://dx.doi.org/10.1016/j.ebiom.2020.102844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502670PMC
September 2020

TRICALS: creating a highway toward a cure.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11 9;21(7-8):496-501. Epub 2020 Jul 9.

Department of Neurology, UMC Utrecht Brain Centre, University Medical Centre Utrecht, Utrecht, the Netherlands.

A change in our current approach toward drug development is required to improve the likelihood of finding effective treatment for patients with amyotrophic lateral sclerosis (ALS). The aim of the Treatment Research Initiative to Cure ALS (TRICALS) is to extend the collective effort with industry and consolidate drug development paths. TRICALS has begun a series of meetings on how to best move the field forward collaboratively, thereby addressing five major topics in ALS clinical trials: (1) preclinical research, (2) biomarker development, (3) eligibility criteria, (4) efficacy endpoints and (5) innovative trial design. There is an appetite for ongoing discussions of these major topics in clinical trials between representatives from academia, patient advocacy groups, industry partners and funding bodies. Industry is open to fundamentally change drug development for ALS and shorten the time to effective therapy for patients by implementing promising innovations in biomarker development, trial design, and patient selection. There is however, a pressing need from all stakeholders for regulatory discussions and amendments of current guidelines to successfully adopt innovation in future clinical development lines.
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http://dx.doi.org/10.1080/21678421.2020.1788092DOI Listing
November 2020

Measuring quality of life in ALS/MND: validation of the WHOQOL-BREF.

Amyotroph Lateral Scler Frontotemporal Degener 2020 Jun 27:1-9. Epub 2020 Jun 27.

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

The World Health Organization Quality of Life-BREF Scale (WHOQOL-BREF) is a generic QOL measure with four domains covering Physical, Psychological, Social and Environment. Providing the opportunity to contrast QoL with other conditions, or with population norms, the current study had three aims: 1) can the established domains of the WHOQOL-BREF be validated within a large ALS/MND population; 2) can a total score be validated and 3) can they provide interval level measurement? Data were obtained from the Trajectories of Outcomes in Neurological Conditions study. Internal construct validity was determined by fit of the data to the Rasch measurement model. 636 participants with ALS/MND were included. All domains, except the Social domain, showed satisfactory fit to the Rasch model. All were unidimensional, and showed no Differential Item Functioning by age, gender, or onset type. Finally, a total score was validated from a bi-factor perspective. The WHOQOL-BREF is valid for use in populations with ALS/MND and can be analyzed to yield interval level measurement: It offers a range of domains that reflect QOL, which can be used for parametric analysis and for comparison with other conditions or general populations, two advantages for its inclusion as a trial outcome measure and for observational studies.
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http://dx.doi.org/10.1080/21678421.2020.1752244DOI Listing
June 2020

Focus on the heterogeneity of amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11 25;21(7-8):485-495. Epub 2020 Jun 25.

Mario Negri-ALS Study Group, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.

The clinical manifestations of amyotrophic lateral sclerosis (ALS) are variable in terms of age at disease onset, site of onset, progression of symptoms, motor neuron involvement, and the occurrence of cognitive and behavioral changes. Genetic background is a key determinant of the ALS phenotype. The mortality of the disease also varies with the ancestral origin of the affected population and environmental factors are likely to be associated with ALS at least within some cohorts. Disease heterogeneity is likely underpinned by the presence of different pathogenic mechanisms. A variety of ALS animal models can be informative about the heterogeneity of the neuropathological or genetic aspects of the disease and can support the development of new therapeutic intervention. Evolving biomarkers can contribute to the identification of differing genotypes and phenotypes, and can be used to explore whether genotypic and phenotypic differences in animal models might help to provide a better definition of the heterogeneity of ALS in humans. These include neurofilaments, peripheral blood mononuclear cells, extracellular vesicles, microRNA and imaging findings. These biomarkers might predict not only the development of the disease, but also the variability in progression, although robust validation is required. A promising area of progress in modeling the heterogeneity of human ALS is represented by the use of human induced pluripotent stem cell (iPSCs)-derived motor neurons. Although the translational value of iPSCs remains unclear, this model is attractive in the perspective of replicating the heterogeneity of sporadic ALS as a first step toward a personalized medicine strategy.
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http://dx.doi.org/10.1080/21678421.2020.1779298DOI Listing
November 2020

A Knowledge-Based Machine Learning Approach to Gene Prioritisation in Amyotrophic Lateral Sclerosis.

Genes (Basel) 2020 06 19;11(6). Epub 2020 Jun 19.

Department of Biostatistics & Health Informatics, King's College London, 16 De Crespigny Park, London SE5 8AF, UK.

Amyotrophic lateral sclerosis is a neurodegenerative disease of the upper and lower motor neurons resulting in death from neuromuscular respiratory failure, typically within two to five years of first symptoms. Several rare disruptive gene variants have been associated with ALS and are responsible for about 15% of all cases. Although our knowledge of the genetic landscape of this disease is improving, it remains limited. Machine learning models trained on the available protein-protein interaction and phenotype-genotype association data can use our current knowledge of the disease genetics for the prediction of novel candidate genes. Here, we describe a knowledge-based machine learning method for this purpose. We trained our model on protein-protein interaction data from IntAct, gene function annotation from Gene Ontology, and known disease-gene associations from DisGeNet. Using several sets of known ALS genes from public databases and a manual review as input, we generated a list of new candidate genes for each input set. We investigated the relevance of the predicted genes in ALS by using the available summary statistics from the largest ALS genome-wide association study and by performing functional and phenotype enrichment analysis. The predicted sets were enriched for genes associated with other neurodegenerative diseases known to overlap with ALS genetically and phenotypically, as well as for biological processes associated with the disease. Moreover, using ALS genes from ClinVar and our manual review as input, the predicted sets were enriched for ALS-associated genes (ClinVar = 0.038 and manual review = 0.060) when used for gene prioritisation in a genome-wide association study.
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http://dx.doi.org/10.3390/genes11060668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349022PMC
June 2020

The use of biotelemetry to explore disease progression markers in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11 23;21(7-8):563-573. Epub 2020 Jun 23.

Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Objective: To explore novel, real-world biotelemetry disease progression markers in patients with amyotrophic lateral sclerosis (ALS) and to compare with clinical gold-standard measures. This was an exploratory, non-controlled, non-drug 2-phase study comprising a variable length Pilot Phase (n = 5) and a 48-week Core study Phase (n = 25; NCT02447952). Patients with mild or moderate ALS wore biotelemetry sensors for ∼3 days/month at home, measuring physical activity, heart rate variability (HRV), and speech over 48 weeks. These measures were assessed longitudinally in relation to ALS Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC); assessed by telephone [monthly] and clinic visits [every 12 weeks]). Pilot Phase data supported progression into the Core Phase, where a decline in physical activity from baseline followed ALS progression as measured by ALSFRS-R and FVC. Four endpoints showed moderate or strong between-patient correlations with ALSFRS-R total and gross motor domain scores (defined as a correlation coefficient of ≥0.5 or >0.7, respectively): average daytime active; percentage of daytime active; total daytime activity score; total 24-hour activity score. Moderate correlations were observed between speech endpoints and ALSFRS-R bulbar domain scores; HRV data quality was insufficient for reliable assessment. The sensor was generally well tolerated; 6/25 patients reported mostly mild or moderate intensity skin and subcutaneous tissue disorder adverse events. Biotelemetry measures of physical activity in this Pilot Study tracked ALS progression over time, highlighting their potential as endpoints for future clinical trials. A larger, formally powered study is required to further support activity endpoints as novel disease progression markers.
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http://dx.doi.org/10.1080/21678421.2020.1773501DOI Listing
November 2020

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Circulation 2020 Jul 20;142(4):324-338. Epub 2020 May 20.

Masonic Medical Research Institute, Utica, NY (R.P.).

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.

Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.

Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).

Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Evolution of white matter damage in amyotrophic lateral sclerosis.

Ann Clin Transl Neurol 2020 05 4;7(5):722-732. Epub 2020 May 4.

Department of Neuroscience, Clinical Imaging Sciences Centre, Brighton and Sussex Medical School, University of Sussex, Brighton, East Sussex, United Kingdom.

Objective: To characterize disease evolution in amyotrophic lateral sclerosis using an event-based model designed to extract temporal information from cross-sectional data. Conventional methods for understanding mechanisms of rapidly progressive neurodegenerative disorders are limited by the subjectivity inherent in the selection of a limited range of measurements, and the need to acquire longitudinal data.

Methods: The event-based model characterizes a disease as a series of events, each comprising a significant change in subject state. The model was applied to data from 154 patients and 128 healthy controls selected from five independent diffusion MRI datasets acquired in four different imaging laboratories between 1999 and 2016. The biomarkers modeled were mean fractional anisotropy values of white matter tracts implicated in amyotrophic lateral sclerosis. The cerebral portion of the corticospinal tract was divided into three segments.

Results: Application of the model to the pooled datasets revealed that the corticospinal tracts were involved before other white matter tracts. Distal corticospinal tract segments were involved earlier than more proximal (i.e., cephalad) segments. In addition, the model revealed early ordering of fractional anisotropy change in the corpus callosum and subsequently in long association fibers.

Interpretation: These findings represent data-driven evidence for early involvement of the corticospinal tracts and body of the corpus callosum in keeping with conventional approaches to image analysis, while providing new evidence to inform directional degeneration of the corticospinal tracts. This data-driven model provides new insight into the dynamics of neuronal damage in amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1002/acn3.51035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261765PMC
May 2020
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