Journal of neurology, neurosurgery, and psychiatry
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J. Neurol. Neurosurg. Psychiatr. · Nov 2020
Associations of APOE e2 genotype with cerebrovascular pathology: a postmortem study of 1275 brains.
We assessed the association of apolipoprotein E (APOE) genotype with cerebrovascular disease (CVD) in a large neuropathological database maintained by the National Alzheimer's Coordinating Center (NACC). Such a comprehensive investigation of APOE and CVD pathology has not heretofore been conducted. We focused on APOE e2, an established neuroprotective genetic variant against Alzheimer's disease. ⋯ In this, the largest study of APOE e2 effects on pathologically verified CVD, e2 was not protective against any CVD pathology compared with e3 homozygotes, including CAA. Regarding the latter pathology, e4 was associated with increases in its severity. Furthermore, and perhaps unexpectedly, e2 significantly increased risk of acute/subacute gross haemorrhage in the presence of CAA. Thus, there were limits to e2 neuroprotection against amyloidosis, despite its known and large protective effects against diffuse and neuritic amyloid plaques compared with e3/e3 and e4 carriers in this very collection.
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J. Neurol. Neurosurg. Psychiatr. · Nov 2020
ReviewData-driven evolution of neurosurgical gene therapy delivery in Parkinson's disease.
Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson's disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. ⋯ The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.
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J. Neurol. Neurosurg. Psychiatr. · Nov 2020
Nusinersen safety and effects on motor function in adult spinal muscular atrophy type 2 and 3.
To retrospectively investigate safety and efficacy of nusinersen in a large cohort of adult Italian patients with spinal muscular atrophy (SMA). ⋯ Our data provide further evidence of nusinersen safety and efficacy in adult SMA2 and SMA3, with the latter appearing to be cumulative over time. In patients with extremely advanced disease, effects on residual motor function are less clear.
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J. Neurol. Neurosurg. Psychiatr. · Nov 2020
Split hand and motor axonal hyperexcitability in spinal and bulbar muscular atrophy.
The 'split hand' sign refers to preferential wasting of the thenar and first dorsal interosseous muscles with relatively sparing of the hypothenar muscles in amyotrophic lateral sclerosis (ALS) and both cortical and spinal/peripheral excitotoxic mechanisms have been proposed. We aimed to study split hand and axonal excitability in spinal and bulbar muscular atrophy (SBMA) in which cortical motor neurons are intact. ⋯ Split hand is not specific to ALS and can be caused by the peripheral mechanism alone in SBMA, whereas the effect of upper motor neuron lesion cannot be excluded in ALS. Our results also suggest that SBMA and ALS share common axonal excitability changes; increased nodal persistent sodium and reduced potassium currents that may accelerate motor neuronal death and differently affect axons-innervating different muscles. Ion channel modulators could be a therapeutic option for both SBMA and ALS.