Lancet neurology
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Dominantly inherited spinocerebellar ataxias (SCAs) are associated with phenotypes that range from pure cerebellar to multisystemic. The list of implicated genes has lengthened in the past 5 years with the inclusion of SCA37/DAB1, SCA45/FAT2, SCA46/PLD3, SCA47/PUM1, SCA48/STUB1, SCA50/NPTX1, SCA25/PNPT1, SCA49/SAM9DL, and SCA27B/FGF14. In some patients, co-occurrence of multiple potentially pathogenic variants can explain variable penetrance or more severe phenotypes. ⋯ Treatments tested in phase 2 and phase 3 studies, such as riluzole and transcranial direct current stimulation of the cerebellum and spinal cord, have given conflicting results. To enable early intervention, preataxic carriers of pathogenic variants should be assessed with biomarkers, such as neurofilament light chain and brain MRI; these biomarkers could also be used as outcome measures, given that clinical outcomes are not useful in the preataxic phase. The development of bioassays measuring the concentration of the mutant protein (eg, ataxin-3) might facilitate monitoring of target engagement by gene therapies.
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Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. ⋯ For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis.
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Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neuroimaging 1 (STRIVE-1) categorised and standardised the diverse features of SVD that are visible on structural MRI. ⋯ As the effect of combined SVD imaging features becomes clearer, a key role for quantitative imaging biomarkers to determine sub-visible tissue damage, subtle abnormalities visible at high-field strength MRI, and lesion-symptom patterns, is also apparent. Together with rapidly emerging machine learning methods, these metrics can more comprehensively capture the effect of SVD on the brain than the structural MRI features alone and serve as intermediary outcomes in clinical trials and future routine practice. Using a similar approach to that adopted in STRIVE-1, we updated the guidance on neuroimaging of vascular changes in studies of ageing and neurodegeneration to create STRIVE-2.
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Cerebral amyloid angiopathy, which is defined by cerebrovascular deposition of amyloid β, is a common age-related small vessel pathology associated with intracerebral haemorrhage and cognitive impairment. Based on complementary lines of evidence from in vivo studies of individuals with hereditary, sporadic, and iatrogenic forms of cerebral amyloid angiopathy, histopathological analyses of affected brains, and experimental studies in transgenic mouse models, we present a framework and timeline for the progression of cerebral amyloid angiopathy from subclinical pathology to the clinical manifestation of the disease. Key stages that appear to evolve sequentially over two to three decades are (stage one) initial vascular amyloid deposition, (stage two) alteration of cerebrovascular physiology, (stage three) non-haemorrhagic brain injury, and (stage four) appearance of haemorrhagic brain lesions. This timeline of stages and the mechanistic processes that link them have substantial implications for identifying disease-modifying interventions for cerebral amyloid angiopathy and potentially for other cerebral small vessel diseases.
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Neurological diseases cause physical, psychosocial, and spiritual or existential suffering from the time of their diagnosis. Palliative care focuses on improving quality of life for people with serious illness and their families by addressing this multidimensional suffering. ⋯ Improving this situation requires the deployment of routine screening to identify individual palliative care needs, the integration of palliative care approaches into routine neurological care, and collaboration between neurologists and palliative care specialists. Research, education, and advocacy are also needed to raise standards of care.