Cerebral Perfusion Characteristics and Dynamic Brain Structural Changes in Stroke-Prone Renovascular Hypertensive Rats: A Preclinical Model for Cerebral Small Vessel Disease.

Hypertension is a leading cause of cerebral small vessel disease (CSVD) and vascular dementia in elderly individuals. We aimed to assess cerebral perfusion and dynamic changes in brain structure in stroke-prone renovascular hypertensive rats (RHRSPs) with different durations of hypertension and to investigate whether they have pathophysiological features similar to those of humans with CSVD. The RHRSP model was established using the two-kidney, two-clip (2k2c) method, and the Morris water maze (MWM) test, MRI, immunohistochemistry, and biochemical analysis were performed at multiple time points for up to six months following the 2k2c operation. Systolic blood pressure was significantly greater in the RHRSP group than in the sham-operated group at week 4 post-surgery and continued to increase over time, leading to cognitive decline by week 20. Arterial spin labeling revealed cerebral hypoperfusion in the RHRSP group at 8 weeks, accompanied by vascular remodeling and decreased vessel density. Diffusion tensor imaging and Luxol fast blue staining indicated that white matter disintegration and demyelination gradually progressed in the corpus callosum and that myelin basic protein levels decreased. Eight weeks after surgery, blood-brain barrier (BBB) leakage into the corpus callosum was observed. The albumin leakage area was negatively correlated with the myelin sheath area (r=-0.88, p<0.001). RNA-seq analysis revealed downregulation of most angiogenic genes and upregulation of antiangiogenic genes in the corpus callosum of RHRSPs 24 weeks after surgery. RHRSPs developed cerebral hypoperfusion, BBB disruption, spontaneous white matter damage, and cognitive impairment as the duration of hypertension increased. RHRSPs share behavioral and neuropathological characteristics with CSVD patients, making them suitable animal models for preclinical trials related to CSVD.

Discontinuity of deep medullary veins in SWI is associated with deep white matter hyperintensity volume and cognitive impairment in cerebral small vessel disease.

BACKGROUND: Discontinuation of the deep medullary veins (DMVs) may be an early imaging marker for identifying cognitive impairment caused by cerebral small vessel disease (CSVD). However, this method lacks mechanistic exploration. We aimed to investigate whether the DMV score is related to CSVD imaging markers and cognitive impairment in patients with CSVD. METHODS: This retrospective study included patients with CSVD who completed DMV score and cognition (e.g., MMSE, MoCA) assessments, and underwent MRI scanning (T2-FLAIR for white matter hyperintensities (WMH) volume, T1-weighted MRI for brain parenchymal fractions (BPF) analysis, and SWI for assessment of DMV score). The CSVD imaging markers were quantitatively assessed using the AccuBrain® system. We assessed the diagnostic value of neuroimaging biomarkers for detecting CSVD-related cognitive impairment. In addition, we explored the relationship between the DMV score, CSVD imaging markers, and cognition using mediation analysis. RESULTS: Ninety-four patients with CSVD were divided into a cognitive impairment group (n = 39) and a non-cognitive impairment group (n = 55). Higher DMV scores, larger WMH volumes, and smaller BPF were observed in the cognitive impairment group than those in the non-cognitive impairment group. Receiver operating characteristics (ROC) analysis revealed that the discovery value of the integration of patient age, BPF, whole WMH volume, and DMV score for cognitive impairment was 0.742, with a sensitivity and specificity of 79.5 % and 61.5 %, respectively. Mediation analysis showed mediation by WMH and BPF in the relationship between DMV score and cognitive impairment (all P < 0.05). LIMITATIONS: This study did not evaluate the DMV score in subregions according to DMV anatomy. CONCLUSIONS: The DMV score is significantly associated with cognitive impairment in patients with CSVD, and this association is mediated through WMH and BPF.

Efficacy and safety of agomelatine versus SSRIs/SNRIs for post-stroke depression: a systematic review and meta-analysis of randomized controlled trials.

Agomelatine is effective in the treatment of depression, but its effect for post-stroke depression (PSD) remains unclear. This study was conducted to compare the efficacy and safety of agomelatine versus SSRIs/SNRIs in treating PSD. We systematically searched Embase, PubMed, Cochrane Library, WanFang Data, China National Knowledge Infrastructure, and Cqvip databases for double-blind randomized controlled studies comparing the efficacy and safety of agomelatine versus SSRIs/SNRIs for PSD until December 2022. The primary efficacy endpoint was the Hamilton Depression Rating Scale (HAMD) score, and the primary safety endpoint was the incidence of overall adverse reactions. Nine studies comprising 857 patients with PSD were included. After 6-12 weeks of treatment, the HAMD score ( P  = 0.16) and the overall response rates ( P  = 0.20) in the agomelatine group were comparable to that in the SSRIs/SNRIs group. Participants treated with agomelatine achieved higher Barthel Index scores compared with the SSRIs/SNRIs group ( P  = 0.02). There was a significantly lower incidence of overall adverse reactions ( P  = 0.008) and neurological adverse reactions ( P  < 0.0001) in the agomelatine group. The efficacy of agomelatine for treating PSD is probably comparable to that of SSRIs/SNRIs, and it may improve stroke outcomes with better safety.

Enhanced angiogenesis in the thalamus induced by a novel TSPO ligand ameliorates cognitive deficits after focal cortical infarction.

Neuronal loss in the ipsilateral thalamus after focal cortical infarction participates in post-stroke cognitive deficits, and enhanced angiogenesis in the thalamus is expected to reduce neuronal damage. We hypothesize that novel translocator protein (TSPO) ligand, 2-Cl-MGV-1, can promote angiogenesis, attenuate neuronal loss in the thalamus, and ameliorate post-stroke cognitive deficits. Cortical infarction was induced by distal middle cerebral artery occlusion (dMCAO) in stroke-prone renovascular hypertensive rats. 2-Cl-MGV-1 or dimethyl sulfoxide was administered 24 h after dMCAO and then for 6 or 13 days. Spatial learning and memory were assessed using the Morris water maze. Neuronal loss, TSPO expression, angiogenesis, and intrinsic pathway were determined by immunofluorescence and immunoblotting 7 and 14 days after dMCAO. Cortical infarction caused post-stroke cognitive deficits and secondary neuronal loss with gliosis in the ipsilateral thalamus within 14 days of dMCAO. Increased angiogenesis and elevated expression of vascular TSPO were detected in the ipsilateral thalamus, and treatment with 2-Cl-MGV-1 enhanced angiogenesis by stimulating the PI3K-AKT-mTOR pathway. The effects of 2-Cl-MGV-1 on angiogenesis coincided with reduced neuronal loss in the thalamus and contributed to improvements in post-stroke cognitive deficits. Our findings suggest that 2-Cl-MGV-1 stimulates angiogenesis, ameliorates neuronal loss in the thalamus, and improves post-stroke cognitive deficits.

Apathy is associated with striatal atrophy and cognitive impairment in cerebral small vessel disease.

BACKGROUND: Apathy has been considered a common neuropsychiatric symptom and an important contributor to cognitive impairment in cerebral small vessel disease (SVD). However, the mechanism leading to apathy in SVD and the process whereby apathy promotes cognitive impairments remain largely unknown. We aimed to explore the relationship between apathy, cognition, and structural changes of deep grey matter (DGM) in SVD patients. METHODS: Participants were screened for SVD, completed assessments of apathy cognition, underwent magnetic resonance imaging (MRI) scanning, and then stratified into apathy and non-apathy groups. We used region of interest (ROI)-based, voxel-based volume, and vertex-based shape analyses to compare DGM structures between study groups. Using linear regression analysis, we examined the association between apathy, structural changes, and cognition, followed by a mediation analysis of these factors. RESULTS: A total of sixty-four SVD participants were included, with thirty in the apathy group and thirty-four in the non-apathy group. Intergroup comparison showed significantly lower volumes in bilateral caudate, right putamen, and pallidum and smaller vertex-based shapes in the right caudate and pallidum in participants with apathy compared to those without apathy. Apathy was associated with the striatal atrophy (i.e., lower volumes and smaller shape) and independently contributed to cognitive impairments in SVD. However, the above structural differences did not mediate the association between apathy and cognitive impairments. CONCLUSION: These results highlight the important role of striatal atrophy in apathy in SVD and call for additional studies to explore the relationship between apathy, cognition, and DGM.

Association between periodic limb movements during sleep and neuroimaging features of cerebral small vessel disease: A preliminary cross-sectional study.

Evidence on the relationship between periodic limb movements during sleep (PLMS) and cerebral small vessel disease is lacking. This study aimed to assess the association between the PLMS index and the neuroimaging features of cerebral small vessel disease on magnetic resonance imaging. Consecutive patients diagnosed with cerebral small vessel disease were enrolled. Data on the clinical characteristics, polysomnography, and brain magnetic resonance imaging were collected. The Accubrain software was used to calculate automatically the volume of white matter hyperintensities, the number of lacunar infarctions, and cerebral microbleeds. The severity of white matter hyperintensities, enlarged basal ganglia perivascular spaces, and the total cerebral small vessel disease scores were also rated visually using semiquantitative scales. The severity of PLMS was measured using the PLMS index, and the patients were divided into two groups using an established cut-off value of ≥15 per hour. Logistic regression was used to examine the association between PLMS and the neuroimaging features of cerebral small vessel disease. In total, 37 patients were included in the final analyses. The mean age was 66.49 ± 11.31 years, and 73.0% were males. The mean PLMS index was 19.30 ± 10.18. In univariate analyses, it was found that patients with cerebral small vessel disease with a PLMS index ≥15 had increased enlarged basal ganglia perivascular spaces (OR 6.136, 95%CI 1.101-34.214) and increased total cerebral small vessel disease scores (OR 6.0, 95%CI 1.253-28.742). Only the association between the PLMS index and the total cerebral small vessel disease burden score remained statistically significant after adjusting for age, sex, and the presence of moderate to severe obstructive sleep apnea syndrome. In conclusion, an elevated PLMS index is likely to be associated with a greater cerebral small vessel disease burden. PLMS might be a novel potential marker of cerebral small vessel disease.

Stent-Assisted Angioplasty in Spontaneous Bilateral Extracranial Internal Carotid Artery Dissection.

Internal carotid artery dissection (ICAD) results from a tear in the intima or rupture of the vasa vasorum with bleeding within the media resulting in separation of the vessel wall layers and a false lumen. It may cause arterial stenosis, occlusion, or dissecting pseudoaneurysm. Currently, the treatment of ICAD is controversial, including drug therapy and endovascular stent implantation. Simultaneous spontaneous dissection of bilateral carotid artery is rarely reported. We reported a 39-year-old-man with bilateral ICAD. Although the long-term durability of endovascular stent remains to be determined, for ICAD failed with active drug treatment and combined with hemodynamic impairment, early endovascular stent should be considered.

Intermittent Theta Burst Stimulation Improves the Spatial Cognitive Function of Rats with Chronic Hypertension-induced Cerebral Small Vessel Disease.

We investigated whether intermittent theta burst stimulation (iTBS) can improve the spatial cognitive function of rats with hypertension-induced cerebral small vessel disease. To prove our hypothesis, stroke-prone renovascular hypertensive rats (RHRSPs) were treated with iTBS beginning at postoperative week 22. The Morris water maze was performed to assess spatial cognitive function. The expression of the N-methyl-d-aspartate receptor (NMDAR) subunits NR1, NR2A and NR2B, calcium/calmodulin-dependent protein kinase IIα (CaMKIIα), p-CaMKIIα and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1 (GluR1) in the hippocampus were evaluated by western blot analysis. The distribution of GluR1, glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule-1 (IBa-1) in the CA1 and CA3 regions and dentate gyrus (DG) of the hippocampus were evaluated by immunofluorescence analysis. Treatment with iTBS significantly improved the spatial cognitive function of RHRSPs, increased the expression of NR2B, p-CaMKIIα and GluR1 in the hippocampus, and decreased the proliferation of astrocytes and microglia. Our results showed that iTBS treatment had a beneficial effect on the cognitive impairments induced by cerebral small vessel disease, potentially through the activation of the NR2B-CaMKII pathway, an increase in GluR1 expression and the suppression of astrocyte and microglial activation.