Journal of neurology, neurosurgery, and psychiatry
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J. Neurol. Neurosurg. Psychiatr. · Nov 2019
ReviewOrthostatic hypotension and REM sleep behaviour disorder: impact on clinical outcomes in α-synucleinopathies.
Review the effect of orthostatic hypotension (OH) and rapid-eye-movement sleep behavioural disorder (RBD) on survival, cognitive impairment and postural stability, and discuss pathogenic mechanisms involved in the association of these two common non-motor features with relevant clinical outcomes in α-synucleinopathies. ⋯ OH and RBD yielded individual and combined negative effects on disability in α-synucleinopathies, reflecting a 'malignant' phenotype of PD with early cognitive impairment and postural instability. Underlying mechanisms may include involvement of selected brainstem cholinergic and noradrenergic nuclei.
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J. Neurol. Neurosurg. Psychiatr. · Nov 2019
ReviewDrug repurposing in neurological diseases: an integrated approach to reduce trial and error.
Identifying effective disease-modifying therapies for neurological diseases remains an important challenge in drug discovery and development. Drug repurposing attempts to determine new indications for pre-existing compounds and represents a major opportunity to address this clinically unmet need. It is potentially more cost-effective and time-efficient than de novo drug development and has yielded notable successes in neurological disorders. ⋯ We provide an overview of the current approach to early-stage drug repurposing and consider the issues contributing to inconclusive, or possibly falsely negative, Phase II and III trial outcomes in neurological diseases by highlighting examples that illustrate the limitations of empirical evidence generation without a strong scientific basis for the dose rationale. We conclude with a framework suggesting a translational, iterative approach, that integrates pharmacological, pharmaceutical and clinical expertise, towards preclinical and early clinical drug development. This ensures appropriate dosing regimen, route of administration and/or formulation are selected for the new indication before their evaluation in prospective clinical trials.
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J. Neurol. Neurosurg. Psychiatr. · Nov 2019
ReviewNeuropathology of dementia in patients with Parkinson's disease: a systematic review of autopsy studies.
Dementia is a common, debilitating feature of late Parkinson's disease (PD). PD dementia (PDD) is associated with α-synuclein propagation, but coexistent Alzheimer's disease (AD) pathology may coexist. Other pathologies (cerebrovascular, transactive response DNA-binding protein 43 (TDP-43)) may also influence cognition. We aimed to describe the neuropathology underlying dementia in PD. ⋯ While significant α-synuclein pathology is the main substrate of dementia in PD, coexistent pathologies are common. In particular, tau and amyloid-β pathologies independently contribute to the development and pattern of cognitive decline in PD. Their presence should be assessed in future clinical trials where dementia is a key outcome measure.
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J. Neurol. Neurosurg. Psychiatr. · Nov 2019
Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease.
A major contributor to dementia in Parkinson disease (PD) is degeneration of the cholinergic basal forebrain. This study determined whether cholinergic nucleus 4 (Ch4) density is associated with cognition in early and more advanced PD. ⋯ In de novo and more advanced PD, lower Ch4 density is associated with impaired global cognition, attention and visuospatial function.