α-tropomyosin gene (TPM3) mutation in an infant with nemaline myopathy

We report a case of neonatal nemaline myopathy with a de novo TPM3 mutation, which has been classified as a likely pathogenic mutation. With the expanding use of genetic testing in congenital myopathies, genotype-phenotype descriptions of novel variants are important to inform clinical care, diagnosis, genetic counseling, and management of disease

Microvessel stenosis, enlarged perivascular spaces, and fibrinogen deposition are associated with ischemic periventricular white matter hyperintensities

Periventricular white matter hyperintensities (pvWMH) are neuroimaging abnormalities surrounding the lateral ventricles that are apparent on magnetic resonance imaging (MRI). They are associated with age, neurodegenerative disease, and cerebrovascular risk factors. While pvWMH ultimately represent a loss of white matter structural integrity, the pathological causes are heterogeneous in nature, and currently, cannot be distinguished using neuroimaging alone. pvWMH could occur because of a combination of small vessel disease (SVD), ependymal loss, blood–brain barrier dysfunction, and microgliosis. In this study we aimed to characterize microvascular stenosis, fibrinogen extravasation, and microgliosis within pvWMH with and without imaging evidence of periventricular infarction. Using postmortem neuroimaging of human brains (n = 20), we identified pvWMH with and without periventricular infarcts (PVI). We performed histological analysis of microvessel stenosis, perivascular spaces, microgliosis, and immunohistochemistry against fibrinogen as a measure of serum protein extravasation. Herein, we report distinctions between pvWMH with and without periventricular infarcts based on associations with microvessel stenosis, enlarged perivascular spaces, and fibrinogen IHC. Microvessel stenosis was significantly associated with PVI and with cellular deposition of fibrinogen in the white matter. The presence of fibrinogen was associated with PVI and increased number of microglia. These findings suggest that neuroimaging-based detection of infarction within pvWMH may help distinguish more severe lesions, associated with underlying microvascular disease and BBB dysfunction, from milder pvWMH that are a highly frequent finding on MRI

Neuroinflammation and cognitive plasticity following experimental stroke

Stroke is one of the leading causes of morbidity and mortality in Canada and only relatively few individuals avail of pharmacological treatment. Consequently, most stroke patients are left with permanent disabilities. Post-stroke rehabilitation is beneficial but is often incomplete. Animal models of stroke have helped in our understanding of the mechanisms involved in the recovery of sensorimotor function but little attention has been paid to cognitive impairments, which are common following stroke. -- Importantly, patients with cognitive problems are less likely to be reintegrated into society and benefit less well from rehabilitation. Animal models of ischemia have not demonstrated the lasting cognitive impairments that are apparent in human stroke. In the second chapter of this thesis I describe a cognitive assay that detected long-term (~9 mo) alterations in learning, working and reference memory function following global ischemia. Further, I identified a sustained neuroinflammatory state confined to area CA1 at a protracted time point of 270 days post-ischemia, a time when neuroinflammation is typically thought to have subsided. -- In the third chapter I assessed the impact of increased neuroinflammation caused by systemic inflammation on ischemic outcome. Systemic inflammation 24-hours post-ischemia significantly increased neuroinflammation at 3 days post-ischemia as indicated by increases in microglia/macrophages and infiltrating neutrophils. This resulted in significant increases in functional deficits and infarct volumes assessed 30 days post-ischemia. These results confirm for the first time, that systemic inflammation at such a delayed time point, similar to what occurs in a clinical setting, has a profound impact on ischemic outcome. -- The fourth chapter attempted to develop a post-stroke intervention to enhance cognitive function. A combination of 2 hours of physical activity (wheel running) and 2 hours of cognitive activity (Hebb-Williams maze exposure) significantly improved working memory in normal rats compared with either physical or cognitive activity alone, independent of significant changes in neuronal BDNF or pCREB levels. These results are the first to suggest that cognitive training in rats, when combined with only 2 hours of wheel running, can significantly improve working memory function, a finding that may be useful in developing cognitive rehabilitation strategies following stroke in humans

Contribution of physical fitness, cerebrovascular reserve and cognitive stimulation to cognitive function in postmenopausal women

Studies of the effects of physical fitness on cognition suggest that exercise can improve cognitive abilities in healthy older adults, as well as delay the onset of age-related cognitive decline. The mechanisms for the positive benefit of exercise and how these effects interact with other variables known to influence cognitive function (e.g., involvement in cognitive activities) are less well understood. The current study examined the associations between the physical fitness, cerebrovascular blood flow regulation and involvement in cognitive activities with neuropsychological function in healthy postmenopausal women. Methods: Forty-two healthy women between the ages of 55 and 90 were recruited. Physical fitness (V˙ o2max), cerebrovascular reserve (cerebral blood flow during rest and response to an increase in end-tidal (i.e., arterial) PCO2), and cognitive activity (self-reported number and hours of involvement in cognitive activities) were assessed. The association of these variables with neuropsychological performance was examined through linear regression. Results: Physical fitness, cerebrovascular reserve and total number of cognitive activities (but not total hours) were independent predictors of cognitive function, particularly measures of overall cognitive performance, attention and executive function. In addition, prediction of neuropsychological performance was better with multiple variables than each alone. Conclusions: Cognitive function in older adults is associated with multiple factors, including physical fitness, cerebrovascular health and cognitive stimulation. Interestingly, cognitive stimulation effects appear related more to the diversity of activities, rather than the duration of activity. Further examination of these relationships is ongoing in a prospective cohort study