When patients transition from PD-NCI to PD-MCI, there appears to be an increase in functional connectivity in the PCC, suggesting an expansion of the cortical network. Another new network (a compensatory prefrontal cortical-cerebellar loop) later develops during the transition from PD-MCI to PDD.

Cerebral ischemia/reperfusion (I/R) injury leads to brain vascular dysfunction, which is characterized by endothelial cell injury or death. Long noncoding (lnc) RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is reportedly associated with endothelial cell functions and dysfunctions. In the present study, the role of MALAT1 in I/R-induced cerebral vascular endothelial cell apoptosis was explored using oxygen-glucose deprivation and reoxygenation (OGD-R) as an in vitro I/R injury model. Primary human brain microvascular endothelial cells were cultured under OGD-R, and the expression levels of MALAT1 and cell apoptosis were measured at 6, 9, 12, 24 and 36 h post-reoxygenation. The expression levels of MALAT1 and the apoptotic rate of cells exposed to OGD-R exhibited contrasting trends following reoxygenation. Following OGD-R, lentiviral overexpression of MALAT1 increased phosphatidylinositol 3-kinase (PI3K) activities and the activation of Akt phosphorylation, and decreased cell apoptosis and caspase 3 activities, which were successfully abolished by treatment with a PI3K inhibitor, Wortmannin. Conversely, lentiviral knockdown of MALAT1 decreased PI3K activities and the activation of Akt phosphorylation, and increased cell apoptosis and caspase 3 activity. Overexpression and knockdown of MALAT1 exhibited no significant effects on OGD-R-induced reactive oxygen species (ROS) production. In conclusion, to the best of our knowledge, the present study was the first to suggest that lncRNA MALAT1 may protect human brain vascular endothelial cells from OGD-R-induced apoptosis via a PI3K-dependent mechanism. These findings suggest that MALAT1 may be a potential novel therapeutic target for cerebral I/R injury.

Radix Angelica Sinensis (RAS) has beneficial effects in patients suffering from cognitive impairment associated with chronic cerebral hypoperfusion. It has previously been demonstrated that RAS prevents the neurotoxic effects of β-amyloid (Aβ) in vitro, protects from injuries due to oxidative stress, inflammation and apoptosis and ameliorates scopolamine-induced amnesia in rats. Here, we studied the effects of RAS on cognitive improvement and neurogenic enhancement and examined the possible underlying mechanisms in a rat model with permanent bilateral common carotid artery occlusion, which serves as a model of chronic cerebral hypoperfusion-related neurodegenerative diseases. RAS enhances adult neurogenesis in the hippocampus following chronic cerebral hypoperfusion and improves the cognitive decline associated with hypoperfusion. Long-term ablation of adult hippocampal neurogenesis through cranial irradiation abolishes the protective effects of RAS on cognition. Furthermore, administration of RAS restores the decrease of brain-derived neurotrophic factor (BDNF) expression, the phosphorylation of cAMP-responsive element binding protein (CREB) and the glutamic acid decarboxylase 65 (GAD65) staining intensity in rats with chronic cerebral hypoperfusion. The present study supports the hypothesis that adult neurogenesis is required for RAS to facilitate recovery from the cognitive impairment induced by chronic cerebral hypoperfusion, while neurogenic enhancement secondary to RAS treatment may be due to increased BDNF and phosphorylated cAMP-responsive element binding protein (p-CREB) levels and increased γ-aminobutyric acid (GABA) expression. Based on the possible mechanisms suggested by the present study, this well-known traditional medicine may represent a candidate therapeutic agent for the treatment of dementia associated with vascular injury.

Environment enrichment (EE) has been demonstrated to improve the cognitive impairment that is induced by chronic cerebral hypoperfusion (CCH), but the underlying mechanism has not yet been elucidated. This study aimed to investigate the role of endogenous neuroprotection in EE-induced cognitive improvement in rats with CCH. Permanent bilateral common carotid artery occlusions (2-vessel occlusions (2VOs)) were performed to induce CCH in male adult Wistar rats. Four weeks after the surgeries, the rats were exposed to enriched environments for 4 weeks (6 h/day). Subsequently, we assessed the effects of EE on cognitive function, brain histone acetylation levels, neuroprotection-related transcription factors (i.e., cAMP response element-binding protein (CREB), phospho-CREB (p-CREB), hypoxia-inducible factor 1 (HIF-1) α, and nuclear regulatory factor 2 (Nrf2)), and oxidative stress and histological changes in the brain. After 2VO, the rats exposed to the EE treatment exhibited increased acetylation of histone 4 and increased p-CREB and Nrf2 protein levels in the brain. HIF-1α levels were increased after 2VO and reduced after EE treatment. The oxidative damage, histopathological changes in the brain, and spatial learning and memory impairments induced by 2VO were subsequently restored after EE treatment. These data indicate that EE promotes the acetylation of histone 4, regulates some neuroprotection-related transcription factors, attenuates oxidative damage, and protects against the histopathological damage to the brain induced by CCH. Together, the effects of EE in CCH rats might contribute to the recovery of spatial learning and memory.

The hypoxia-inducible factor (HIF)-mediated signaling pathway is an adaptive and protective mechanism that is triggered by hypoxia, ischemia, and other pathophysiological conditions. The expression of HIF-1α and downstream genes, some of which are pro-apoptotic whereas others are pro-survival, is up-regulated in ischemic stroke. Interestingly, however, the effects of HIF-1α activation are different in the early and late stages of acute cerebral ischemia, and these differences may depend on the duration and severity of hypoxia. Therefore, in the present study, we investigated the effect of HIF-1α activation in chronic cerebral hypoperfusion, which plays an important role in the development of dementia. Permanent bilateral common carotid artery occlusion (2VO) was used to induce chronic global cerebral hypoperfusion in rats. The expression of HIF-1α protein and the transcription of downstream genes were measured at different time points, including 0 h, 12 h, 24 h, 3 days, 7 days, 14 days, 28 days, 42 days, and 56 days after 2VO. HIF-1α increased as early as 12 h after the occlusion and remained high for at least 56 days. Interestingly, mRNA levels of both pro-apoptotic (Bcl-2/adenovirus EIB 19 kDa-interacting protein 3, NADPH oxidase activator 1, and NIP3-like protein X) and pro-survival (vascular endothelial growth factor, glucose transporter-1) genes were up-regulated at the early stage after 2VO, followed by a gradual decline to baseline/control levels. Thus, HIF-1α increased consistently during chronic cerebral hypoperfusion, whereas both pro-apoptotic and pro-survival downstream genes were up-regulated only early after 2VO. This mismatch in gene expression may contribute to the lack of a protective effect of highly expressed HIF-1α during the chronic stage of cerebral hypoperfusion.

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Background: Microglia plays an indispensable role in the pathological process of sleep deprivation (SD). Here, the potential role of microglial CX3C-chemokine receptor 1 (CX3CR1) in modulating the cognition decline during SD was evaluated in terms of microglial neuroinflammation and synaptic pruning. In this study, we aimed to investigat whether the interference in the microglial function by the CX3CR1 knockout affects the CNS's response to SD. Methods: Middle-aged wild-type (WT) C57BL/6 and CX3CR1 −/− mice were either subjected to SD or allowed normal sleep (S) for 8 h to mimic the pathophysiological changes of middle-aged people after staying up all night. After which, behavioral and histological tests were used to explore their different changes. Results: CX3CR1 deficiency prevented SD-induced cognitive impairments, unlike WT groups. Compared with the CX3CR1 −/− S group, the CX3CR1 −/− SD mice reported a markedly decreased microglia and cellular oncogene fos density in the dentate gyrus (DG), decreased expression of pro-inflammatory cytokines, and decreased microglial phagocytosis-related factors, whereas increased levels of anti-inflammatory cytokines in the hippocampus and a significant increase in the density of spines of the DG were also noted. Conclusions: These findings suggest that CX3CR1 deficiency leads to different cerebral behaviors and responses to SD. The inflammation-attenuating activity and the related modification of synaptic pruning are possible mechanism candidates, which indicate CX3CR1 as a candidate therapeutic target for the prevention of the sleep loss-induced cognitive impairments.

Aphasia shows high incidence in stroke patients and seriously impairs language comprehension, verbal communication, and social activities. Therefore, screening aphasic patients during the acute phase of stroke is crucial for language recovery and rehabilitation. The present study developed a Chinese version of the Language Screening Test (CLAST) and validated it in post-stroke patients. The CLAST was adapted from the Language Screening Test developed by Constance et al to incorporate Chinese cultural and linguistic specificities, and administered to 207 acute stroke patients and 89 stabilized aphasic or non-aphasic patients. Based on the Western Aphasia Battery (WAB) test, its reliability and validity were assessed. A cut-off for the CLAST in Chinese patients was determined by ROC curve analysis. The CLAST comprised 5 subtests and 15 items, including 2 subscores, namely expression (8 points, assessing naming, repetition, and automatic speech) and receptive (7 points maximum, evaluating picture recognition, and verbal instructions) indexes. Analysis of the alternate-form reliability of the questionnaire showed a retest correlation coefficient of 0.945 ( P < .001). Intraclass correlation coefficients of three rating teams were >0.98 ( P < .001). Internal consistency analysis showed a Cronbach's alpha coefficient of 0.909 ( P < .001). The non-aphasia group showed higher scores than the aphasia group (14.2 ± 1.3 vs 10.6 ± 3.8) ( P < .01). The questionnaire showed good construct validity by factor analysis. ROC curve analysis showed high sensitivity and specificity for the CLAST, with a cut-off of 13.5. The CLAST is suitable for Chinese post-stroke patients during the acute phase, with high reliability, validity, sensitivity, and specificity.