To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS.

Background: Adherence to measures that have been adopted during the COVID-19 pandemic is crucial to control the spread of the coronavirus. Methods: Semi-structured telephone interviews were performed with 99 patients with Parkinson’s disease (PD) and 21 controls to explore knowledge, attitudes, practices, and burden in order to elucidate nonadherence to preventive measures. Results: The majority of patients understood the preventive measures and felt sufficiently informed. Analysis of qualitative answers, however, showed that about 30% of patients had an insufficient level of knowledge, which was not associated with educational level, cognitive disorders, or depression. Changes in behaviour were reported by 73 patients (99% performed at least one specific preventive behavior, and 86.9% have reduced social contacts and stayed home). A closer analysis of qualitative answers showed that 27.3% of patients continued to meet relatives face-to-face almost daily. Anxiety and worries about the current situation were reported by 58.6% of patients; 31.3% complained about a decrease in their mobility since the beginning of the restrictions, mainly because of worsening of PD and because regular therapies (e.g., physiotherapy) were canceled. Conclusions: About 30% of PD patients are nonadherent to preventive measures. Use of simple dichotomous questions overestimates adherence to preventive measures in patients with PD.

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, caused by progressive loss of motor neurons. Changes are widespread in the subcortical white matter in ALS. Diffusion tensor imaging (DTI) detects pathological changes in white matter fibres in vivo, based on alterations in the degree (diffusivity, ADC) and directedness (fractional anisotropy, FA) of proton movement.Methods24 patients with ALS and 24 age-matched controls received 1.5T DTI. FA and ADC were analyzed using statistical parametric mapping. In 15 of the 24 ALS patients, a second DTI was obtained after 6 months.ResultsDecreased FA in the corticospinal tract (CST) and frontal areas confirm existing results. With a direct comparison of baseline and follow-up dataset, the progression of upper motor neuron degeneration, reflected in FA decrease, could be captured along the CST and in frontal areas. The involvement of cerebellum in the pathology of ALS, as suspected from functional MRI studies, could be confirmed by a reduced FA (culmen, declive). These structural changes correlated well with disease duration, ALSFRS-R, and physical and executive functions.ConclusionDTI detects changes that are regarded as prominent features of ALS and thus, shows promise in its function as a biomarker. Using the technique herein, we could demonstrate DTI changes at follow-up which correlated well with clinical progression.

Background and Purpose-Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. Methods-Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396) *Drs Rolfs, Fazekas and Grittner contributed equally to this work. Authors contributions: Dr Rolfs has conceptualized, initiated, and designed and organized the study, has been involved in the recruitment of the patients, and wrote significant parts of the manuscript. Dr Fazekas was involved in the study planning and has done together with Drs Enzinger and Schmidt the analysis of all MRI scans; this group was mainly involved in the statistical analysis of the MRI data. Drs Martus, Grittner, Holzhausen have taken responsibility for all statistical analysis and for the data structure of the total data bank. Drs Dichgans, Böttcher, Tatlisumak, Tanislav, Jungehulsing, Putaala, Huber, Bodechtel, Lichy, Hennerici, Kaps, Meyer, Kessler have been most active in the recruitment of the patients, drafting the manuscript and significantly influencing the scientific discussion. Dr Heuschmann was involved in drafting the manuscript and influencing the scientific discussion. Dr Norrving chaired the steering and publication committees of sifap, has written parts of the manuscript, and has significantly influenced the scientific discussions. Drs Lackner and Paschke, H. Mascher, Dr Riess have been involved in the laboratory analyses. Dr Kolodny has mostly contributed to the discussion of the Fabry cases. Dr Giese assisted in writing and editing the manuscript. All authors have reviewed, critically revised and approved the final version of the manuscript.The sponsors of the study had no role in the study design, data collection, data analysis, interpretation, writing of the manuscript, or the decision to submit the manuscript for publication. The academic authors had unrestricted access to the derived dataset, and assume full responsibility for the completeness, integrity, and interpretation of the data, as well as writing the study report and the decision to submit for publication.†Listed in Appendix I in the online-only Data Supplement. Jeffrey L. Saver, MD, was guest editor for this article.

BackgroundIdiopathic cervical dystonia is characterized by involuntary spasms, tremors or jerks. It is not restricted to a disturbance in the basal ganglia system because non-conventional voxel-based MRI morphometry (VBM) and diffusion tensor imaging (DTI) have detected numerous regional changes in the brains of patients.In this study scans of 24 patients with cervical dystonia and 24 age-and sex-matched controls were analysed using VBM, DTI and magnetization transfer imaging (MTI) using a voxel-based approach and a region-of-interest analysis. Results were correlated with UDRS, TWSTRS and disease duration.ResultsWe found structural alterations in the basal ganglia; thalamus; motor cortex; premotor cortex; frontal, temporal and parietal cortices; visual system; cerebellum and brainstem of the patients with dystonia.ConclusionsCervical dystonia is a multisystem disease involving several networks such as the motor, sensory and visual systems.

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. Although the etiology remains unclear, disturbances in calcium homoeostasis and protein folding are essential features of neurodegeneration in this disorder. Here, we review recent research findings on the interaction between endoplasmic reticulum (ER) and mitochondria, and its effect on calcium signaling and oxidative stress. We further provide insights into studies, providing evidence that structures of the ER mitochondria calcium cycle serve as a promising targets for therapeutic approaches for treatment of ALS.