Dissociable Contributions of Thalamic-Subregions to Cognitive Impairment in Small Vessel Disease.

BACKGROUND: Structural network damage is a potentially important mechanism by which cerebral small vessel disease (SVD) can cause cognitive impairment. As a central hub of the structural network, the role of thalamus in SVD-related cognitive impairments remains unclear. We aimed to determine the associations between the structural alterations of thalamic subregions and cognitive impairments in SVD. METHODS: In this cross-sectional study, 205 SVD participants without thalamic lacunes from the third follow-up (2020) of the prospective RUN DMC study (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort), which was initiated in 2006, Nijmegen, were included. Cognitive functions included processing speed, executive function, and memory. Probabilistic tractography was performed from thalamus to 6 cortical regions, followed by connectivity-based thalamic segmentation to assess each thalamic subregion volume and connectivity (measured by mean diffusivity [MD] of the connecting white matter tracts) with the cortex. Least absolute shrinkage and selection operator regression analysis was conducted to identify the volumes or connectivity of the total thalamus and 6 thalamic subregions that have the strongest association with cognitive performance. Linear regression and mediation analyses were performed to test the association of least absolute shrinkage and selection operator-selected thalamic subregion volume or MD with cognitive performance, while adjusting for age and education. RESULTS: We found that higher MD of the thalamic-motor tract was associated with worse processing speed (ß=-0.27; P<0.001), higher MD of the thalamic-frontal tract was associated with worse executive function (ß=-0.24; P=0.001), and memory (ß=-0.28; P<0.001), respectively. The mediation analysis showed that MD of thalamocortical tracts mediated the association between corresponding thalamic subregion volumes and the cognitive performances in 3 domains. CONCLUSIONS: Our results suggest that the structural alterations of thalamus are linked to cognitive impairment in SVD, largely depending on the damage pattern of the white matter tracts connecting specific thalamic subregions and cortical regions.

Meta-analysis of the efficacy of acupuncture in the treatment of the vascular cognitive impairment associated with cerebral small vessel disease.

OBJECTIVE: To systematically evaluate the efficacy and safety of acupuncture in the treatment of the vascular cognitive impairment (VCI) associated with cerebral small vessel disease (CSVD-VCI) and to provide a theoretical basis for clinical acupuncture treatment for CSVD-VCI. METHOD: Various databases, including China National Knowledge Infrastructure, Wanfang Data, Chinese Science and Technology Journal Database, Chinese BioMedical Literature Service System, PubMed, the Cochrane Library, and EBSCOhost, were searched for randomized controlled trials (RCTs) related to acupuncture treatment for CSVD-VCI. The quality of the included trials was evaluated, and a meta-analysis was conducted using the Review Manager 5.4 software. RESULTS: Ten articles on RCTs were included, involving 761 patients, i.e., 381 in the acupuncture group and 380 in the control group. The meta-analysis results indicated that the use of acupuncture alone and acupuncture alongside other therapies for CSVD-VCI could improve the overall clinical response rate [odds ratio = 3.51, 95% confidence interval (CI) = (2.05, 6.00), P < 0.00001], increase the patients' Montreal Cognitive Assessment scores [mean difference (MD) = 3.33, 95%CI (2.98, 3.68), P < 0.00001], Mini-Mental State Examination scores [MD = 2.78, 95%CI (2.51, 3.06), P < 0.00001], and activities of daily living scores [MD = 6.30, 95%CI (4.22, 8.37), P < 0.00001], and shorten the latency of auditory evoked potential P300 [MD = -14.67, 95%CI (-19.54, -9.80), P < 0.00001]. CONCLUSION: Acupuncture alone and acupuncture alongside other therapies are superior to non-acupuncture-based therapies in the treatment of CSVD-VCI. However, due to the small number of relevant available articles and their general low quality, this conclusion may be biased. More clinical RCTs with a larger sample size and higher quality are needed to support this theory.

Evaluation of eight-style Tai chi on cognitive function in patients with cognitive impairment of cerebral small vessel disease: study protocol for a randomised controlled trial.

INTRODUCTION: Cerebral small vessel disease (CSVD) is a critical factor that causes cognitive decline and progresses to vascular dementia and acute cerebrovascular events. Tai chi has been proven to improve nerve plasticity formation and directly improve cognitive function compared with other sports therapy, which has shown its unique advantages. However, more medical evidence needs to be collected in order to verify that Tai chi exercises can improve cognitive impairment due to CSVD. The main purposes of this study are to investigate the effect of Tai chi exercise on neuropsychological outcomes of patients with cognitive impairment related to CSVD and to explore its mechanism of action with neuroimaging, including functional MRI (fMRI) and event-related potential (P300). METHODS AND ANALYSIS: The design of this study is a randomised controlled trial with two parallel groups in a 1:1 allocation ratio with allocation concealment and assessor blinding. A total of 106 participants will be enrolled and randomised to the 24-week Tai chi exercise intervention group and 24-week health education control group. Global cognitive function and the specific domains of cognition (memory, processing speed, executive function, attention and verbal learning and memory) will be assessed at baseline and 12 and 24 weeks after randomisation. At the same time, fMRI and P300 will be measured the structure and function of brain regions related to cognitive function at baseline and 24 weeks after randomisation. Recruitment is currently ongoing (recruitment began on 9 November 2020). The approximate completion date for recruitment is in April 2021, and we anticipate to complete the study by December 2021. ETHICS AND DISSEMINATION: Ethics approval was given by the Medical Ethics Committee of the Affiliated People's Hospital of Fujian University of Traditional Chinese Medicine (approval number: 2019-058-04). The findings will be disseminated through peer-reviewed publications and at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2000033176; Pre-results.

Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy.

Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aß deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss.

Chinese herbal medicine for vascular cognitive impairment in cerebral small vessel disease: A protocol for systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Cerebral small vessel disease (CSVD) is the most common etiology of vascular cognitive impairment (VCI). VCI in CSVD (CSVD-VCI) shows a progressive course with multiple stages and is also associated with dysfunctions such as gait, emotional and behavioral, and urinary disturbances, which seriously affect the life quality of elderly people. In mainland China, Chinese herbal medicine (CHM) is clinically used for CSVD-VCI and presenting positive efficacy, but the evidence revealed in relevant clinical trials has not been systematically evaluated. The purpose of this study is to assess the current evidence available for the clinical efficacy and safety of CHM for CSVD-VCI. METHODS: A literature search of published RCTs up to April 30, 2020, has been conducted in the following 7 electronic databases: PubMed, Embase, the Cochrane Library, Chinese National Knowledge Infrastructure Database (CNKI), Chinese Science and Technology Journals Database (VIP), Wanfang Database, and Chinese Biomedical Literature Service System (SinoMed). For unpublished studies, 2 clinical trial online registration websites will be searched: ClinicalTrials.gov and Chinese Clinical Trial Registry (ChiCTR). Only randomized controlled trials (RCTs) using CHM in the treatment of patients with CSVD-VCI, which compares CHM with no treatment, placebo, or other conventional treatments, will be included in this systematic review. Primary outcomes will be set as acknowledged scales measuring cognitive function. Secondary outcomes will involve activities of daily living, behavioral, and psychological symptoms, global performance of dementia, neurological function, biological markers of endothelial dysfunction, the clinical effective rate, and adverse events. After screening studies and extracting data, the Cochrane Collaborations tool for assessing risk of bias will be applied to assess the methodological quality of included RCTs. Review Manager Version 5.3 software will be used for data synthesis and statistical analysis. Subgroup analyses, sensitivity analyses, and meta-regression will be conducted to detect potential sources of heterogeneity. The funnel plot and Eggers test will be developed to evaluate publication bias, if available. We will perform the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to appraise the quality of evidence. RESULTS: Evidence exhibited in this systematic review will provide practical references in the field of CHM treating CSVD-VCI. Moreover, our detailed appraisals of methodological deficiencies of relevant RCTs will offer helpful advice for researchers who are designing trials of CHMs in the treatment of CSVD-VCI. CONCLUSION: The conclusion about the clinical efficacy and safety of CHM for CSVD-VCI will be provided for clinical plans, decisions, and policy developments in the full version of this systematic review. SYSTEMATIC REVIEW REGISTRATION: INPLASY202080120.

Epimedium flavonoids improve cognitive impairment and white matter lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/NRG1/PI3K pathway in rats.

Chronic cerebral hypoperfusion is a common cause of cerebral small vascular disease (CSVD). White matter (WM) lesions are the typical pathological manifestation of CSVD and contribute to cognitive decline. Epimedium flavonoids (EF) are the main component in Epimedium brevicornu Maxim., which is commonly used in traditional Chinese medicine. The purpose of this study was to investigate the effects of EF on cognitive impairment and the underlying mechanisms in a CSVD rat model induced with chronic cerebral hypoperfusion. The model was established by permanent bilateral common carotid artery occlusion (2VO) in rats. EF (50, 100, and 200 mg/kg) was intragastrically administered once a day for 12 weeks starting 2 weeks after 2VO surgery. The learning and memory capacity of the rats were measured using the Morris water maze and step-through tests. WM lesions were observed by MRI-diffusion tensor imaging, transmission electron microscopy, and LFB staining. Oligodendrocytes were detected by immunohistochemistry. Western blotting assay was used to determine the level of protein expression. The results showed that EF significantly improved learning and memory impairment, alleviated WM nerve fiber injuries and demyelination, and increased the number of mature oligodendrocytes in the corpus callosum, subcortical WM, and periventricular WM in 2VO rats. Mechanistically, EF reduced the expression of Lingo-1 and ROCK2 and increased the levels of phosphorylated (p-) Fyn, brain-derived neurotrophic factor (BDNF), TrkB, neuregulin-1 (NRG-1), p-ErbB4, PI3K p85 and p110α, p-Akt, and p-CREB in the corpus callosum of 2VO rats. These results suggest that EF may improve cognitive impairment and WM lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/TrkB, NRG-1/ErbB4, and the downstream PI3K/Akt/CREB pathways in WM. Thus, EF can be used as a potential neuroprotective agent in CSVD therapy.

Association of nimodipine and choline alphoscerate in the treatment of cognitive impairment in patients with cerebral small vessel disease: study protocol for a randomized placebo-controlled trial-the CONIVaD trial.

BACKGROUND: Vascular cognitive impairment (VCI) is an extremely disabling condition that includes post-stroke dementia and VCI caused by cerebral small vessel disease (SVD). Currently, there is no approved treatment for this condition. Drugs active on the cholinergic pathway have been tested in VCI patients showing positive but limited efficacy. The calcium-antagonist nimodipine also showed some moderate positive effects in VCI patients. AIMS: CONIVaD (choline alphoscerate and nimodipine in vascular dementia) is a pilot, single-center, double-blinded, randomized trial aimed to assess whether the association of choline alphoscerate and nimodipine is more effective than nimodipine alone in reducing cognitive decline in patients with SVD and mild-to-moderate cognitive impairment. METHODS: All patients are evaluated at baseline and after 12 months with: (1) clinical, daily functions, quality of life, and mood assessment and (2) extensive neuropsychological evaluation. After the baseline evaluation, patients are randomly assigned to one of the two arms of treatment: (1) nimodipine 90 mg/die t.i.d plus placebo b.i.d and (2) nimodipine 90 mg t.i.d plus choline alphoscerate 1200 mg/die b.i.d. for a total of 12 months. The primary endpoint is cognitive decline, expressed as the loss of at least two points on the Montreal Cognitive Assessment at 12 months. Secondary endpoints include safety and tolerability, functional, quality of life, and neuropsychological measures. DISCUSSION: CONIVaD study is the first randomized controlled trial to examine the cognitive efficacy of combined choline alphoscerate-nimodipine treatment in VCI patients. Results of this pilot study will serve as a methodological basis for other clinical controlled, multicentric, double-blinded, and randomized trials. TRIAL REGISTRATION: Clinical Trial NCT03228498. Registered 25 July 2017.

Functional brain connectome and its relation to mild cognitive impairment in cerebral small vessel disease patients with thalamus lacunes: A cross-sectional study.

To investigate the functional connectome alterations in cerebral small-vessel disease (CSVD) patients with thalamus lacunes and its relation to cognitive impairment.This case-control study was approved by the local research ethics committee, and all participants provided informed consent. There were 14 CSVD patients with thalamus lacunes (CSVDw.), 27 without (CSVDwo.), and 34 healthy controls (HC) recruited matched for age, sex, and education to undergo a 3T resting-state functional MR examination. The whole-brain functional connectome was constructed by thresholding the Pearson correlation matrices of 90 brain regions, and the topologic properties were analyzed by using graph theory approaches. Networks were compared between CSVD patients and HC, and associations between network measures and cognitive function were tested.Compared with HC, the functional connectome in CSVDw. patients showed abnormalities at the global level and at the nodal level (P < .05, false discovery rate corrected). The network-based statistics method identified a significantly altered network consisting 6 nodes and 13 connections. Among all the 13 connections, only two connections had significant correlation with episodic memory (EM) and processing speed (PS) respectively (P < .05). The CSVDwo. patients showed no significant network alterations relative to controls (P > .05).The configurations of brain functional connectome in CSVDw. patients were perturbed but not obvious for those without, and correlated with the mild cognitive impairment, especially for EM and PS. This study suggested that lacunes on thalamus played a vital role in mediating the neural functional changes of CSVD patients.

Acute bithalamic infarct manifesting as sleep-like coma: A diagnostic challenge.

Bilateral thalamic infarction (BTI) typically presents as a sleep-like coma (SLC) without localizing signs, posing a diagnostic challenge that may lead the treating physician to search for toxic or metabolic causes and delay treatment. We review our experience with BTI of different etiologies, and emphasize the critical role of timely imaging, diagnosis, and management in a series of 12 patients with a presentation of SLC and acute BTI who were managed in our Medical Centers from 2006-2015. In 11/12, urgent head CT scans showed normal brain tissue, while diffusion-weighted (DWI) MRI revealed symmetric bilateral thalamic hyperintense lesions with variable degrees of brainstem involvement. In 1/12, CT scans revealed a contralateral subacute stroke from a thalamic infarct 1month earlier with a unilateral hyperintense lesion on DWI-MRI. From clinical and imaging findings (DWI-MRI, CT angiography and venography), etiology was attributed to embolic causes (cardio-embolism, artery-to-artery mechanism), small vessel disease, or deep sinus vein thrombosis secondary to dural arteriovenous (AV) fistula. Three patients had good outcomes after prompt diagnosis and optimal treatment in <3hours (intravenous tissue plasminogen activator in two patients cardio-embolic etiology and neuro-endovascular repair in one patient with venous infarction due to a dural AV fistula). The diagnosis was made beyond the therapeutic window in seven patients, who were left with significant neurological sequelae. Higher awareness of BTI presenting as SLC is warranted. Optimal patient management includes urgent DWI-MRI. In cases of BTI, further imaging workup is indicated to provide a comprehensive assessment for etiology. Early diagnosis and prompt, targeted intervention are crucial.

Thalamic fractional anisotropy predicts accrual of cerebral white matter damage in older subjects with small-vessel disease.

White matter hyperintensities (WMHs) and lacunes are magnetic resonance imaging hallmarks of cerebral small-vessel disease, which increase the risk of stroke, cognitive, and mobility impairment. Although most studies of cerebral small-vessel disease have focused on white matter abnormalities, the gray matter (GM) is also affected, as evidenced by frequently observed lacunes in subcortical GM. Diffusion tensor imaging (DTI) is sensitive to subtle neurodegenerative changes in deep GM structures. We explored the relationship between baseline DTI characteristics of the thalamus, caudate, and putamen, and the volume and subsequent accrual of WMHs over a 4-year period in 56 community-dwelling older (⩾75 years) individuals. Baseline thalamic fractional anisotropy (FA) was an independent predictor of WMH accrual. WMH accrual also correlated with baseline lacune count and baseline WMH volume, the latter showing the strongest predictive power, explaining 27.3% of the variance. The addition of baseline thalamic FA in multivariate modeling increased this value by 70%, which explains 46.5% of the variance in WMH accrual rate. Thalamic FA might serve as a novel predictor of cerebral small-vessel disease progression in clinical settings and trials. Furthermore, our findings point to the possibility of a causal relationship between thalamic damage and the accrual of WMHs.