Neuroscience
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Progranulin (PGRN) is known to play a role in the pathogenesis of neurodegenerative diseases. Recently, it has been demonstrated that patients with the homozygous mutation in the GRN gene present with neuronal ceroid lipofuscinosis, and there is growing evidence that PGRN is related to lysosomal function. In the present study, we investigated the possible role of PGRN in the lysosomes of activated microglia in the cerebral cortex after traumatic brain injury (TBI). ⋯ S6K1 phosphorylation in KO mice was significantly lower than that in WT mice. In addition, the number of nissl-positive and fluoro-jade B-positive cells around the injury was significantly decreased and increased, respectively, in KO as compared with WT mice. These results suggest that PGRN localized in the lysosome is involved in the activation of mTORC1, and its deficiency leads to increased TFEB nuclear translocation with a resultant increase in lysosomal biogenesis in activated microglia and exacerbated neuronal damage in the cerebral cortex after TBI.
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Randomized Controlled Trial
Long-term TENS treatment decreases cortical motor representation in multiple sclerosis.
This study investigated the effects of a long-term transcutaneous electrical nerve stimulation (TENS) treatment on cortical motor representation in patients with multiple sclerosis (MS). In this double-blind crossover design, patients received either TENS or sham stimulation for 3 weeks (1h per day) on the median nerve region of the most impaired hand, followed by the other stimulation condition after a washout period of 6 months. ⋯ Our results revealed that 3 weeks of daily stimulation with TENS significantly decreased the cortical motor representation of the stimulated muscle in MS patients. Although the mechanisms underlying this decrease remain unclear, our findings indicate that TENS has the ability to induce long-term reorganization in the motor cortex of MS patients.
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Randomized Controlled Trial
Acute caffeine administration impact on working memory-related brain activation and functional connectivity in the elderly: a BOLD and perfusion MRI study.
In young individuals, caffeine-mediated blockade of adenosine receptors and vasoconstriction has direct repercussions on task-related activations, changes in functional connectivity, as well as global vascular effects. To date, no study has explored the effect of caffeine on brain activation patterns during highly demanding cognitive tasks in the elderly. This prospective, placebo-controlled crossover design comprises 24 healthy elderly individuals (mean age 68.8 ± 4.0 years, 17 females) performing a 2-back working memory (WM) task in functional magnetic resonance imaging (fMRI). ⋯ The inverse comparison of placebo versus caffeine had no significant difference. Activation strength of the task-relevant-network component correlated with response accuracy for caffeine yet not for placebo, indicating a selective cognitive effect of caffeine. The present findings suggest that acute caffeine intake enhances WM-related brain activation as well as functional connectivity of blood oxygen level-dependent fMRI in elderly individuals.
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The cytoarchitecturally-homogeneous appearance of the globus pallidus, subthalamic nucleus and substantia nigra has long been said to imply a high degree of afferent convergence and sharing of inputs by nearby neurons. Moreover, axon collaterals of neurons in the external segment of the globus pallidus and the substantia nigra pars reticulata arborize locally and make inhibitory synapses on other cells of the same type. These features suggest that the connectivity of the basal ganglia may impose spike-time correlations among the cells, and it has been puzzling that experimental studies have failed to demonstrate such correlations. ⋯ The patterns of spike-timing among such neurons depend on the ionic mechanism of pacemaking, the level of background uncorrelated cellular and synaptic noise, and the firing rates of the neurons, as well as the properties of their synaptic connections. Application of these concepts to the basal ganglia circuitry suggests that the connectivity and physiology of these nuclei may be configured to prevent the establishment of permanent spike-timing relationships between neurons. The development of highly synchronous oscillatory patterns of activity in Parkinson's disease may result from the loss of pacemaking by some basal ganglia neurons, and accompanying breakdown of the mechanisms responsible for active decorrelation.
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Substantial epidemiological evidence shows an increased risk for developing Alzheimer's disease (AD) in people with diabetes. Yet the underlying molecular mechanisms still remain to be elucidated. This article reviews the current studies on common pathological processes of Alzheimer's disease and diabetes with particular focus on potential mechanisms through which diabetes affects the initiation and progression of Alzheimer's disease. Impairment of insulin signaling, inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, APOEε4 and cholesterol appear to be important mediators and are likely to act synergistically in promoting AD pathology.