Background Concerns regarding potential neurological complications of COVID-19 are being increasingly reported, primarily in small series. Larger studies have been limited by both geography and specialty. Comprehensive characterisation of clinical syndromes is crucial to allow rational selection and evaluation of potential therapies. The aim of this study was to investigate the breadth of complications of COVID-19 across the UK that affected the brain. Methods During the exponential phase of the pandemic, we developed an online network of secure rapid-response case report notification portals across the spectrum of major UK neuroscience bodies, comprising the Association of British Neurologists (ABN), the British Association of Stroke Physicians (BASP), and the Royal College of Psychiatrists (RCPsych), and representing neurology, stroke, psychiatry, and intensive care. Broad clinical syndromes associated with COVID-19 were classified as a cerebrovascular event (defined as an acute ischaemic, haemorrhagic, or thrombotic vascular event involving the brain parenchyma or subarachnoid space), altered mental status (defined as an acute alteration in personality, behaviour, cognition, or consciousness), peripheral neurology (defined as involving nerve roots, peripheral nerves, neuromuscular junction, or muscle), or other (with free text boxes for those not meeting these syndromic presentations). Physicians were encouraged to report cases prospectively and we permitted recent cases to be notified retrospectively when assigned a confirmed date of admission or initial clinical assessment, allowing identification of cases that occurred before notification portals were available. Data collected were compared with the geographical, demographic, and temporal presentation of overall cases of COVID-19 as reported by UK Government public health bodies.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases, hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth Type 2 (CMT2). In contrast, ALS associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss of function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

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Neurodegeneration and dementia pose a major public health challenge worldwide owing to their devastating impact on quality of life and the tremendous burden they place on health-care systems 1,2 . The number of adults with a diagnosis of neurodegenerative disease across the globe is set to increase dramatically in the coming decades -the ageing population harbours a potential epidemic of functional disability, pain and loss of independence 3-5 . Among the neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) is the most rapidly fatal 6 -the typical time from symptom onset to death is 2-3 years 7,8 .Research in the past 25 years has improved our understanding of the pathophysiology of ALS, but the translation of this knowledge into effective treatments has been disappointing -even today, most patients with ALS do not have the opportunity to participate in clinical trials 9 . Previously unrecognized bottlenecks in the translational process have been revealed, including a lack of large-scale research infrastructure and of the coordination necessary to initiate trials. In addition, inherent disease characteristics, such as disease heterogeneity, make a one-size-fits-all solution unworkable and long durations of clinical trials are necessary

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