Lancet neurology
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Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease and are at very high risk of developing early-onset dementia, which is now the leading cause of death in this population. Diagnosis of dementia remains a clinical challenge because of the lack of validated diagnostic criteria in this population, and because symptoms are overshadowed by the intellectual disability associated with Down syndrome. ⋯ Most importantly, there are no treatments to prevent Alzheimer's disease, even though adults with Down syndrome could be an optimal population in whom to conduct Alzheimer's disease prevention trials. Unprecedented research activity in Down syndrome is rapidly changing this bleak scenario that will translate into disease-modifying therapies that could benefit other populations.
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Manganese is an essential trace metal. The dysregulation of manganese seen in a broad spectrum of neurological disorders reflects its importance in brain development and key neurophysiological processes. ⋯ Moreover, manganese dyshomoeostasis is also implicated in Parkinson's disease and other neurodegenerative conditions, such as Alzheimer's disease and Huntington's disease. Ongoing and future research will facilitate the development of better targeted therapeutical strategies than are currently available for manganese-associated neurological disorders.
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Review
Neocortical development and epilepsy: insights from focal cortical dysplasia and brain tumours.
During the past decade, there have been considerable advances in understanding of the genetic and morphogenic processes underlying cortical malformations and developmental brain tumours. Focal malformations are caused by somatic (postzygotic) variants in genes related to cell growth (ie, in the mTOR pathway in focal cortical dysplasia type 2), which are acquired in neuronal progenitors during neurodevelopment. ⋯ There is also emerging evidence that epigenetic processes underlie a molecular memory in epileptogenesis. This knowledge will together facilitate understanding of why and how patients with these lesions have epilepsy, and could form a basis for a move towards precision medicine for this challenging cohort of patients.
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The enormous societal and financial burden of Alzheimer's disease and related dementias requires the identification of risk factors and pathways to reduce dementia risk. Blood pressure (BP) management and control is one promising area, in which data have been inconclusive. ⋯ However, to date, the results do not concur on the optimal timing and target of BP lowering, and further study in diverse populations is needed. Given the long preclinical phase of dementia and data supporting the importance of BP control earlier in the lifecourse, long-term interventional and observational studies in ethnically and racially diverse populations, with novel imaging and blood-based biomarkers of neurodegeneration and vascular cognitive impairment to understand the pathophysiology, are needed to advance the field.
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Patients with Parkinson's disease present with signs and symptoms of dysregulation of the peripheral autonomic nervous system that can even precede motor deficits. This dysregulation might reflect early pathology and therefore could be targeted for the development of prodromal or diagnostic biomarkers. ⋯ The autonomic innervation of the gut, heart, and skin is affected by α-synuclein pathology in the early stages of the disease and might initiate α-synuclein spread via the autonomic connectome to the CNS. The development of easy-to-use and reliable clinical tests of autonomic nervous system function seems crucial for early diagnosis, and for developing strategies to stop or prevent neurodegeneration in Parkinson's disease.