No abstract

Cognitive impairment is a key clinical feature of ischemic leukoaraiosis (ILA); however, the underlying neurobiological mechanism is still unclear. ILA has been associated with widespread gray and white matter (WM) damage mainly located in cortical-cortical and cortico-subcortical pathways. A total of 36 patients with ILA (Fazekas rating score ≥2) and 31 healthy controls (HCs) underwent comprehensive neuropsychological assessments (covering four cognitive domains, i.e., information processing speed, episodic memory, executive and visuospatial function) and resting-state functional MRI scans. Graph theory-based analyses were employed to explore the topological organization of the brain connectome in ILA patients, and we further sought to explore the associations of connectome-based metrics and neuropsychological performances. An efficient small-world architecture in the functional brain connectome was observed in the ILA and control groups. Moreover, compared with the HCs, the ILA patients showed increased path length and decreased network efficiency (i.e., global and local efficiency) in their functional brain networks. Further network-based statistic (NBS) analysis revealed a functional-disconnected network in ILA, which is comprised of functional connections linking different brain modules (i.e., default mode, frontoparietal, ventral attention and limbic systems) and connections within single modules (i.e., ventral attention and limbic systems). Intriguingly, the abnormal network metrics correlated with cognitive deficits in ILA patients. Therefore, our findings provide further evidence to support the concept that ILA pathologies could disrupt brain connections, impairing network functioning, and cognition via a "disconnection syndrome."

Both hypercholesterolemia and aging are related to cognitive decline or Alzheimer’s disease. However, their interactive influence on the neurodegenerative progress remains unclear. To address this issue, 6-month-old and 16-month-old female mice were fed a 3% cholesterol diet for 8 weeks, followed by hippocampus-related functional, pathological, biochemical and molecular analyses. The high cholesterol diet did not exacerbate age-dependent cognitive decline and hippocampal neuronal death, and even greatly mitigated decreases of synaptophysin and growth associated protein 43 expression in the hippocampus of aged mice. Compared with young controls, aged mice fed normal diet showed mild activation of hippocampal microglia with increased expression of CD68, a marker of the microglial M1 phenotype, and decreased expression of CD206, a marker of the microglial M2 phenotype. More interestingly, the high cholesterol diet not only improved NLRP3 inflammasome activation and IL-1β expression, but also increased levels of anti-inflammatory cytokines IL-4 and IL-6 in the hippocampus of old mice, suggesting playing pro- and anti-neuroinflammatory effects. In addition, the cholesterol rich diet resulted in a defect of the blood-brain barrier of aged hippocampus, as revealed by increased brain albumin content. These results have revealed both harmful and protective effects of high cholesterol diet on aged brain, which helps us to understand that hypercholesterolemia in the aged population is not associated with dementia and cognitive impairment.

Background. Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods. To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results. Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-β and NMDAR2-α subtypes as well as their downstream signaling proteins β-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of β-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-β association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions. These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine’s lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.