Lancet neurology
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Orthostatic hypotension is an unusually large decrease in blood pressure on standing that increases the risk of adverse outcomes even when asymptomatic. Improvements in haemodynamic profiling with continuous blood pressure measurements have uncovered four major subtypes: initial orthostatic hypotension, delayed blood pressure recovery, classic orthostatic hypotension, and delayed orthostatic hypotension. Clinical presentations are varied and range from cognitive slowing with hypotensive unawareness or unexplained falls to classic presyncope and syncope. ⋯ Neurogenic orthostatic hypotension might be the earliest clinical manifestation of Parkinson's disease or related synucleinopathies, and often coincides with supine hypertension. The emerging variety of clinical presentations advocates a stepwise, individualised, and primarily non-pharmacological approach to the management of orthostatic hypotension. Such an approach could include the cessation of blood pressure lowering drugs, adoption of lifestyle measures (eg, counterpressure manoeuvres), and treatment with pharmacological agents in selected cases.
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Randomized Controlled Trial Multicenter Study
Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial.
B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines. ⋯ Swedish Research Council.
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Moyamoya disease is a rare cause of stroke, radiologically characterised by progressive stenosis of the terminal portion of the internal carotid arteries and compensatory capillary collaterals. The discovery that RNF213, which encodes an unconventional E3 ubiquitin ligase, is the major susceptibility gene for moyamoya disease in people from east Asia has opened new avenues for investigation into the mechanisms of disease and potential treatment targets. ⋯ Several monogenic moyamoya syndromes possess the radiological characteristics of moyamoya disease and have been associated with multiple genes and pathways involved in moyamoya angiopathy pathogenesis. Further clarification of the genetic and environmental factors that contribute to the emergence of moyamoya angiopathy could enable development of new treatment strategies for moyamoya disease.
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Review
Tau biomarkers in Alzheimer's disease: towards implementation in clinical practice and trials.
Deposition of tau aggregates is a pathological hallmark of Alzheimer's disease that is closely linked both spatially and temporally to emergence of neurodegeneration and manifestation of clinical symptoms. There is an urgent need for accurate PET, CSF, and plasma biomarkers of tau pathology to improve the diagnostic process in clinical practice and the selection of participants and monitoring of treatment effects in trials. ⋯ Innovative second-generation tau-PET tracers with high affinity and selectivity to tau pathology in Alzheimer's disease have enabled detection of tau pathology in medial temporal lobe subregions that are affected in the earliest disease stages. Furthermore, novel but common tau spreading subtypes have been discovered using tau-PET, suggesting much greater interindividual differences in the distribution of tau pathology across the brain than previously assumed. In the CSF biomarker field, novel phosphorylated tau (p-tau) assays have been introduced that better reflect tau tangle load than established CSF biomarkers of tau pathology. The advent of cost-effective and accessible blood-based biomarkers for tau pathophysiology (ie, p-tau181, p-tau217, and p-tau231) might transform the Alzheimer's disease field, as these biomarkers correlate with post-mortem Alzheimer's disease pathology, differentiate Alzheimer's disease from other types of dementia, and predict future progression from normal cognition and mild cognitive impairment to Alzheimer's disease. In controlled investigational settings, improvements in tau-PET and biofluid p-tau markers have led to earlier disease detection, more accurate diagnostic methods, and refinement of prognosis. The anti-tau therapy landscape is rapidly evolving, with multiple ongoing phase 1 and 2 trials of post-translational modification of tau, tau immunotherapy, tau aggregation inhibitors, and targeting production of tau and reduction of intracellular tau levels. Neuroimaging and biofluid tau markers hold potential for optimising such clinical trials by augmenting participant selection, providing evidence of target engagement, and monitoring treatment efficacy. WHERE NEXT?: Major challenges to overcome are the high cost of tau-PET, partial sensitivity to detect early-stage Alzheimer's disease pathology, and off-target tracer binding. Prospective validation studies of biofluid p-tau markers are needed, and assay-related preanalytical and analytical factors need further refinement. Future studies should focus on demonstrating the diagnostic and prognostic accuracy of tau biomarkers-blood-based markers in particular-in non-tertiary settings, such as primary care, which is characterised by a diverse population with medical comorbidities. Large-scale head-to-head studies are needed across different stages of Alzheimer's disease to determine which tau biomarker is optimal in various clinical scenarios, such as early diagnosis, differential diagnosis, and prognosis, and for aspects of clinical trial design, such as proving target engagement, optimising participant selection, and refining monitoring of treatment effects.