Brain : a journal of neurology
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Multicenter Study
Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma.
Cortical spreading depolarization causes a breakdown of electrochemical gradients following acute brain injury, and also elicits dynamic changes in regional cerebral blood flow that range from physiological neurovascular coupling (hyperaemia) to pathological inverse coupling (hypoperfusion). In this study, we determined whether pathological inverse neurovascular coupling occurred as a mechanism of secondary brain injury in 24 patients who underwent craniotomy for severe traumatic brain injury. After surgery, spreading depolarizations were monitored with subdural electrode strips and regional cerebral blood flow was measured with a parenchymal thermal diffusion probe. ⋯ Overall, 31% of the pathological inverse responses occurred during ischaemia (<18 ml/100 g/min) thus exacerbating perfusion deficits. Average perfusion was significantly higher in patients with good 6-month outcomes (46.8 ± 6.5 ml/100 g/min) than those with poor outcomes (32.2 ± 3.7 ml/100 g/min, P < 0.05). These results establish inverse neurovascular coupling to spreading depolarization as a novel mechanism of secondary brain injury and suggest that cortical spreading depolarization, the neurovascular response, cerebrovascular autoregulation, and ischaemia are critical processes to monitor and target therapeutically in the management of acute brain injury.
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Multicenter Study
Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment.
Patients with Alzheimer's disease have reduced cerebral blood flow measured by arterial spin labelling magnetic resonance imaging, but it is unclear how this is related to amyloid-β pathology. Using 182 subjects from the Alzheimer's Disease Neuroimaging Initiative we tested associations of amyloid-β with regional cerebral blood flow in healthy controls (n = 51), early (n = 66) and late (n = 41) mild cognitive impairment, and Alzheimer's disease with dementia (n = 24). Based on the theory that Alzheimer's disease starts with amyloid-β accumulation and progresses with symptoms and secondary pathologies in different trajectories, we tested if cerebral blood flow differed between amyloid-β-negative controls and -positive subjects in different diagnostic groups, and if amyloid-β had different associations with cerebral blood flow and grey matter volume. ⋯ The associations of amyloid-β with cerebral blood flow and volume differed across the disease spectrum, with high amyloid-β being associated with greater cerebral blood flow reduction in controls and greater volume reduction in late mild cognitive impairment and dementia. In addition to disease stage, amyloid-β pathology affects cerebral blood flow across the span from controls to dementia patients. Amyloid-β pathology has different associations with cerebral blood flow and volume, and may cause more loss of blood flow in early stages, whereas volume loss dominates in late disease stages.
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Multicenter Study
Natural history of pulmonary function in collagen VI-related myopathies.
The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed 'collagen VI-related myopathies' and include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). ⋯ The relationship between maximal motor ability and forced vital capacity was highly significant (P < 0.0001). This study demonstrates that pulmonary function profiles can be used in combination with motor function profiles to stratify collagen VI-related myopathy patients phenotypically. These findings improve our knowledge of the natural history of the collagen VI-related myopathies, enabling proactive optimization of care and preparing this patient population for clinical trials.
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Multicenter Study
What is influencing the phenotype of the common homozygous polymerase-γ mutation p.Ala467Thr?
Polymerase-γ (POLG) is a major human disease gene and may account for up to 25% of all mitochondrial diseases in the UK and in Italy. To date, >150 different pathogenic mutations have been described in POLG. Some mutations behave as both dominant and recessive alleles, but an autosomal recessive inheritance pattern is much more common. ⋯ In conclusion, our clinical results show that the homozygous p. Ala467Thr POLG mutation does not cause discrete phenotypes, as previously suggested, but rather there is a continuum of clinical symptoms. Our results suggest that the mitochondrial DNA background plays an important role in modifying the disease phenotype but nuclear modifiers, epigenetic and environmental factors may also influence the severity of disease.
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Multicenter Study Comparative Study
Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies.
Lewy bodies are common in the ageing brain and often co-occur with Alzheimer's disease pathology. There is little known regarding the independent role of Lewy body pathology in cognition impairment, decline and fluctuations in community-dwelling older persons. We examined the contribution of Lewy body pathology to dementia, global cognition, cognitive domains, cognitive decline and fluctuations in 872 autopsied subjects (mean age = 87.9 years) from the Rush Religious Order Study (n = 491) and Memory and Aging Project (n = 381) longitudinal community-based clinical-pathological studies. ⋯ Neocortical-type Lewy body pathology is associated with increased odds of dementia; lower and more rapid decline in all cognitive domains including episodic memory and fluctuations in decline in semantic and working memory. Limbic-type Lewy body pathology is specifically associated with lower and more rapid decline in visuospatial skills. The effect of Lewy body pathology on cognition appears to be independent of Alzheimer's disease pathology.