Lancet neurology
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Migraine is a leading cause of disability worldwide. Despite the recent approval of several calcitonin gene-related peptide-targeted therapies, many people with migraine do not achieve satisfactory headache improvement with currently available therapies and there continues to be an unmet need for effective and tolerable migraine-specific treatments. ⋯ Animal and human studies show that these targets are expressed in regions of the CNS and peripheral nervous system that are involved in pain processing, indicating that these targets might be regarded as promising for the discovery of new migraine therapies. Future studies will require assessment of whether targets are suitable for therapeutic modulation, including assessment of specificity, affinity, solubility, stability, efficacy, and safety.
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Posterior cortical atrophy is a rare syndrome characterised by early, prominent, and progressive impairment in visuoperceptual and visuospatial processing. The disorder has been associated with underlying neuropathological features of Alzheimer's disease, but large-scale biomarker and neuropathological studies are scarce. We aimed to describe demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy in a large international cohort. ⋯ None.
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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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Migraine is an evolving, and sometimes lifelong disorder. The prevalence of episodic migraine peaks among individuals aged in their late 30s, implying a tendency for the disorder to remit with increasing age thereafter, whereas chronic migraine is more likely to persist into later life. Diagnosis and treatment of migraine in older adults, defined as individuals aged 60 years or older, is rendered more complex by increasing probabilities of atypical clinical features and comorbidities, with patients' comorbidities sometimes limiting their therapeutic options. ⋯ Long-term longitudinal studies of individuals with migraine would be particularly informative, with the potential not only to suggest new research directions, but also to lead to the identification of novel therapeutic agents. Although several novel migraine medications are becoming available, their effectiveness, tolerability, and safety often remain uncertain in older adults, who have commonly been excluded from the evaluation of these agents in randomised controlled trials, or who constitute only a small proportion of study populations. There is a need to recognise these limitations in the available evidence, and the specific, and often unmet, clinical needs of older adults with migraine, not least because older adults constitute an increasing proportion of populations worldwide.
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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.