Enhancing cognitive performance prediction by white matter hyperintensity connectivity assessment.

White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks. We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

Memory deficit in patients with cerebral small vessel disease: evidence from eye tracking technology.

Cerebral small vessel disease is the one of the most prevalent causes of vascular cognitive impairment. We aimed to find objective and process-based indicators related to memory function to assist in the detection of memory impairment in patients with cerebral small vessel disease. Thirty-nine cerebral small vessel disease patients and 22 healthy controls were invited to complete neurological examinations, neuropsychological assessments, and eye tracking tasks. Eye tracking indicators were recorded and analyzed in combination with imaging features. The cerebral small vessel disease patients scored lower on traditional memory task and performed worse on eye tracking memory task performance compared to the healthy controls. The cerebral small vessel disease patients exhibited longer visit duration and more visit count within areas of interest and targets and decreased percentage value of total visit duration on target images to total visit duration on areas of interest during decoding stage among all levels. Our results demonstrated the cerebral small vessel disease patients performed worse in memory scale and eye tracking memory task, potentially due to their heightened attentional allocation to nontarget images during the retrieval stage. The eye tracking memory task could provide process-based indicators to be a beneficial complement to memory assessment and new insights into mechanism of memory impairment in cerebral small vessel disease patients.

Shared Proteins and Pathways of Cardiovascular and Cognitive Diseases: Relation to Vascular Cognitive Impairment.

One of the primary goals of systems medicine is the detection of putative proteins and pathways involved in disease progression and pathological phenotypes. Vascular cognitive impairment (VCI) is a heterogeneous condition manifesting as cognitive impairment resulting from vascular factors. The precise mechanisms underlying this relationship remain unclear, which poses challenges for experimental research. Here, we applied computational approaches like systems biology to unveil and select relevant proteins and pathways related to VCI by studying the crosstalk between cardiovascular and cognitive diseases. In addition, we specifically included signals related to oxidative stress, a common etiologic factor tightly linked to aging, a major determinant of VCI. Our results show that pathways associated with oxidative stress are quite relevant, as most of the prioritized vascular cognitive genes and proteins were enriched in these pathways. Our analysis provided a short list of proteins that could be contributing to VCI: DOLK, TSC1, ATP1A1, MAPK14, YWHAZ, CREB3, HSPB1, PRDX6, and LMNA. Moreover, our experimental results suggest a high implication of glycative stress, generating oxidative processes and post-translational protein modifications through advanced glycation end-products (AGEs). We propose that these products interact with their specific receptors (RAGE) and Notch signaling to contribute to the etiology of VCI.

Inhibiting CSF1R alleviates cerebrovascular white matter disease and cognitive impairment.

White matter abnormalities, related to poor cerebral perfusion, are a core feature of small vessel cerebrovascular disease, and critical determinants of vascular cognitive impairment and dementia. Despite this importance there is a lack of treatment options. Proliferation of microglia producing an expanded, reactive population and associated neuroinflammatory alterations have been implicated in the onset and progression of cerebrovascular white matter disease, in patients and in animal models, suggesting that targeting microglial proliferation may exert protection. Colony-stimulating factor-1 receptor (CSF1R) is a key regulator of microglial proliferation. We found that the expression of CSF1R/Csf1r and other markers indicative of increased microglial abundance are significantly elevated in damaged white matter in human cerebrovascular disease and in a clinically relevant mouse model of chronic cerebral hypoperfusion and vascular cognitive impairment. Using the mouse model, we investigated long-term pharmacological CSF1R inhibition, via GW2580, and demonstrated that the expansion of microglial numbers in chronic hypoperfused white matter is prevented. Transcriptomic analysis of hypoperfused white matter tissue showed enrichment of microglial and inflammatory gene sets, including phagocytic genes that were the predominant expression modules modified by CSF1R inhibition. Further, CSF1R inhibition attenuated hypoperfusion-induced white matter pathology and rescued spatial learning impairments and to a lesser extent cognitive flexibility. Overall, this work suggests that inhibition of CSF1R and microglial proliferation mediates protection against chronic cerebrovascular white matter pathology and cognitive deficits. Our study nominates CSF1R as a target for the treatment of vascular cognitive disorders with broader implications for treatment of other chronic white matter diseases.

Botch improves cognitive impairment after cerebral ischemia associated with microglia-induced A1-type astrocyte activation.

Vascular cognitive impairment (VCI) is a clinical syndrome that arises from cerebrovascular issues and associated risk factors, resulting in difficulties in at least one area of cognitive function. VCI has emerged as the second most prevalent type of dementia following Alzheimer's disease, yet there is no effective clinical treatment. Botch, an endogenous Notch1 antagonist, demonstrates neuroprotective effects by inhibiting neuroinflammatory responses mediated through the Notch pathway. While its role in stroke-induced neuroinflammation is well-established, its involvement in VCI remains largely unexplored. This study investigates the role and potential mechanisms of Botch in a rat model of cognitive impairment caused by bilateral common carotid artery occlusion (BCCAO). Firstly, we observed that Botch levels were down-regulated in BCCAO rats, which correlated with increased release of inflammatory cytokines and neuronal damage. Microglia in BCCAO rats released interleukin-1α (IL-1α), tumor necrosis factor-α (TNF-α), and complement component 1q (C1q), leading to the activation of neurotoxic C3+ A1 reactive astrocytes. Then, the down-regulation of Botch exacerbated microglia-mediated inflammation, activated C3+ A1 astrocytes, worsened neuronal damage, and led to a decline in cognitive function. Conversely, the re-expression of Botch alleviated C3+ astrocyte activation, inhibited neuronal damage, and improved mental function. In conclusion, Botch plays a crucial role in inhibiting neuroinflammation induced by type A1 reactive astrocytes. It achieves this by blocking the activation of microglia triggered by the Notch pathway. Ultimately, it inhibits neuronal damage to play a neuroprotective role. These findings suggest that Botch may represent a novel potential target for treating VCI.

Association between Blood Pressure and Post-Stroke Cognitive Impairment: A Meta-Analysis.

Background: Post-stroke cognitive impairment (PSCI) represents a serious post-stroke complication with poor cognitive consequences. A vascular consequence after a stroke is that the occurrence and progression of PSCI may be closely related to blood pressure (BP). Thus, we systematically reviewed and performed a meta-analysis of the literature to examine the correlations between BP and PSCI. Methods: We systematically queried databases, including PubMed, the Cochrane Library, Embase, and Scopus, and conducted meta-analyses on studies reporting odds ratios (ORs) related to the association between BP and PSCI. Two authors autonomously assessed all titles, abstracts, and full texts and extracted data following the Meta-Analysis of Observational Studies in Epidemiology guidelines. The quality of the studies was evaluated using the modified Newcastle-Ottawa scale. Results: Meta-analyses incorporated 12 articles comprising a cumulative participant cohort of 21,732 individuals. The quality assessment indicated good in five studies, fair in one study, and poor in six. Through meta-analyses, we found that hypertension, systolic or diastolic BP (SBP or DBP) was significantly associated with PSCI (OR 1.53, 95% confidence interval (CI), 1.18-1.99; p = 0.001, I 2 = 66%; OR 1.13, 95% CI, 1.05-1.23; p = 0.002, I 2 = 52%; OR 1.38, 95% CI, 1.11-1.72; p = 0.004, I 2 = 90%, respectively). In the subgroup analysis, SBP < 120 mmHg, 120-139 mmHg, 140-159 mmHg, 160-179 mmHg, and DBP ≥ 100 mmHg highly predicted the occurrence of PSCI (OR 1.15, p = 0.0003; OR 1.26, p = 0.010; OR 1.15, p = 0.05; OR 1.02, p = 0.009; OR 1.96, p < 0.00001, respectively). However, the predictive effect of BP for PSCI declines when SBP ≥ 180 mmHg and DBP ≤ 99 mmHg (p > 0.05). Statistical heterogeneity was moderate to high, and publication bias was detected in SBP for PSCI. Conclusions: Considering the multifactorial etiology of PSCI, it is difficult to conclude that BP is an independent risk factor for PSCI. Given the restricted inclusion of studies, caution is advised when interpreting the findings from this meta-analysis. Subsequent investigations with substantial sample sizes are essential to exploring BP as a prospective target for addressing PSCI. Trial Registration Number: CRD42023437783 from PROSPERO.

Altered Callosal Morphology and Connectivity in Asymptomatic Carotid Stenosis.

BACKGROUND: Carotid stenosis, even in the clinically asymptomatic stage, causes cognitive impairment, silent lesions, and hemispheric changes. The corpus callosum (CC) is crucial for hemispheric cortical integration and specialization. PURPOSE: To examine if CC morphology and connectivity relate to cognitive decline and lesion burden in asymptomatic carotid stenosis (ACS). STUDY TYPE: Retrospective, cross-sectional. POPULATION: 33 patients with unilaterally severe (70%) ACS and 28 demographically and comorbidity-matched controls. A publicly available healthy adult lifespan (ages between 18 and 80; n = 483) MRI dataset was also included. FIELD STRENGTH/SEQUENCE: A 3.0 T; T1 MPRAGE and diffusion weighted gradient echo-planar imaging sequences. ASSESSMENT: Structural MRI and multidomain cognitive data were obtained. Midsagittal CC area, circularity, thickness, integrity, and probabilistic tractography were calculated and correlated with cognitive tests and white matter hyperintensity. Fractional anisotropy, mean diffusivity (MD), and radial diffusivity were determined from DTI. STATISTICAL TESTS: Independent two-sample t-tests, χ2 tests, Mann-Whitney U, locally weighted scatterplot smoothing (LOWESS) curve fit, and Pearson correlation. A P value < 0.05 was considered statistically significant. RESULTS: Patients with ACS demonstrated significant reductions in callosal area, circularity, and thickness compared to controls. The callosal atrophy was significantly correlated with white matter hyperintensity size (r = -0.629, P < 0.001). Voxel-wise analysis of diffusion measures in the volumetric CC showed that ACS patients exhibited significantly lower fractional anisotropy and higher MD and radial diffusivity in the genu and splenium of the CC than controls. Further lifespan trajectory analysis showed that although the midsagittal callosal area, circularity, and thickness exhibited age-related decreases, the values in the ACS patients were significantly lower in all age groups. DATA CONCLUSION: Midsagittal callosal atrophy and connectivity reflect the load of silent lesions and the severity of cognitive decline, respectively, suggesting that CC degeneration has potential to serve as an early marker in ACS. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Associations of Intracranial Artery Length and Branch Number on Time-of-Flight MRA With Cognitive Impairment in Hypertensive Older Males.

BACKGROUND: Hypertension-induced impairment of the cerebral artery network contributes to cognitive impairment. Characterizing the structure and function of cerebral arteries may facilitate the understanding of hypertension-related pathological mechanisms and lead to the development of new indicators for cognitive impairment. PURPOSE: To investigate the associations between morphological features of the intracranial arteries distal to the circle of Willis on time-of-flight MRA (TOF-MRA) and cognitive performance in a hypertensive cohort. STUDY TYPE: Prospective observational study. POPULATION: 189 hypertensive older males (mean age 64.9 ± 7.2 years). FIELD STRENGTH/SEQUENCE: TOF-MRA sequence with a 3D spoiled gradient echo readout and arterial spin labeling perfusion imaging sequence with a 3D stack-of-spirals fast spin echo readout at 3T. ASSESSMENT: The intracranial arteries were segmented from TOF-MRA and the total length of distal arteries (TLoDA) and number of arterial branches (NoB) were calculated. The mean gray matter cerebral blood flow (GM-CBF) was extracted from arterial spin labeling perfusion imaging. The cognitive level was assessed with short-term and long-term delay-recall auditory verbal learning test (AVLT) scores, and with montreal cognitive assessment. STATISTICAL TESTS: Univariable and multivariable linear regression were used to analyze the associations between TLoDA, NoB, GM-CBF and the cognitive assessment scores, with P < 0.05 indicating significance. RESULTS: TLoDA (r = 0.314) and NoB (r = 0.346) were significantly correlated with GM-CBF. Multivariable linear regression analyses showed that TLoDA and NoB, but not GM-CBF (P = 0.272 and 0.141), were significantly associated with short-term and long-term delay-recall AVLT scores. These associations remained significant after adjusting for GM-CBF. DATA CONCLUSION: The TLoDA and NoB of distal intracranial arteries on TOF-MRA are significantly associated with cognitive impairment in hypertensive subjects. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Cognitive Outcome after Acute Spontaneous Intracerebral Hemorrhage: Analysis of the iDEF Randomized Trial.

INTRODUCTION: The impact of intracerebral hemorrhage (ICH) on cognition and the determinants of cognitive recovery early after ICH remain elusive. In this post hoc analysis of the intracerebral hemorrhage deferoxamine (iDEF) trial, we examined the trajectories of cognitive impairment and the determinants of early cognitive recovery after ICH. METHODS: We examined baseline factors associated with a 90-day cognitive outcome and constructed generalized linear mixed models to examine the trajectory of cognitive function over time among iDEF participants. Cognition was measured by the Montreal Cognitive Assessment (MoCA) scores on days 7, 30, and 90. RESULTS: 291 were available for analysis under the trial's modified intention-to-treat definition (38% female, mean age 60.3 ± 12.0 years, median NIHSS 13, IQR 8-18). The median baseline ICH volume was 12.9 IQR (6.4-26.0) mL; 59 (20%) of the ICH cases were lobar, 120 (41%) had intraventricular extension. There was an overall significant increase in total MOCA score with time (p < 0.0001). Total MOCA score increased by an estimated 3.9 points (95% CI: 3.1, 4.7) between the day 7 and day 30 assessments and by an additional 2.9 points (95% CI: 2.2, 3.6) between the day 30 and day 90 assessments. Despite the overall improvement, 134 of 205 (65%) patients with an available 90-day MoCA score remained cognitively impaired with a score <26 on day 90. Older age, higher NIHSS score, baseline ICH volume, intraventricular hemorrhage, and perihematoma edema had an adjusted negative impact on cognitive recovery. CONCLUSIONS: Although ICH survivors exhibit significant improvement of cognitive status over the first 3 months, cognitive performance remains impaired in the majority of patients. Among factors independently associated with worse cognitive recovery, higher baseline ICH, intraventricular blood and perihematomal edema volumes, are potential therapeutic targets that merit further exploration.

The associations between peripheral inflammatory and lipid parameters, white matter hyperintensity, and cognitive function in patients with non-disabling ischemic cerebrovascular events.

BACKGROUND: The global prevalence of VCI has increased steadily in recent years, but diagnostic biomarkers for VCI in patients with non-disabling ischemic cerebrovascular incidents (NICE) remain indefinite. The primary objective of this research was to investigate the relationship between peripheral serological markers, white matter damage, and cognitive function in individuals with NICE. METHODS: We collected clinical data, demographic information, and medical history from 257 patients with NICE. Using the MoCA upon admission, patients were categorized into either normal cognitive function (NCF) or VCI groups. Furthermore, they were classified as having mild white matter hyperintensity (mWMH) or severe WMH based on Fazekas scores. We then compared the levels of serological markers between the cognitive function groups and the WMH groups. RESULTS: Among 257 patients with NICE, 165 were male and 92 were female. Lymphocyte count (OR = 0.448, P < 0.001) and LDL-C/HDL-C (OR = 0.725, P = 0.028) were protective factors for cognitive function in patients with NICE. The sWMH group had a higher age and inflammation markers but a lower MoCA score, and lymphocyte count than the mWMH group. In the mWMH group, lymphocyte count (AUC = 0.765, P < 0.001) and LDL-C/HDL-C (AUC = 0.740, P < 0.001) had an acceptable diagnostic value for the diagnosis of VCI. In the sWMH group, no significant differences were found in serological markers between the NCF and VCI groups. CONCLUSION: Lymphocyte count, LDL-C/HDL-C were independent protective factors for cognitive function in patients with NICE; they can be used as potential biological markers to distinguish VCI in patients with NICE and are applicable to subgroups of patients with mWMH.

Neurofilament Light Chain as a Biomarker of Global Cognition in Individuals With Possible Vascular Mild Cognitive Impairment.

BACKGROUND: Neurofilament Light Chain (NfL) is a biomarker of axonal injury elevated in mild cognitive impairment (MCI) and Alzheimer's disease dementia. Blood NfL also inversely correlates with cognitive performance in those conditions. However, few studies have assessed NfL as a biomarker of global cognition in individuals demonstrating mild cognitive deficits who are at risk for vascular-related cognitive decline. OBJECTIVE: To assess the relationship between blood NfL and global cognition in individuals with possible vascular MCI (vMCI) throughout cardiac rehabilitation (CR). Additionally, NfL levels were compared to age/sex-matched cognitively unimpaired (CU) controls. METHOD: Participants with coronary artery disease (vMCI or CU) were recruited at entry to a 24-week CR program. Global cognition was measured using the Montreal Cognitive Assessment (MoCA) and plasma NfL level (pg/ml) was quantified using a highly sensitive enzyme-linked immunosorbent assay. RESULTS: Higher plasma NfL was correlated with worse MoCA scores at baseline (ß = -.352, P = .029) in 43 individuals with vMCI after adjusting for age, sex, and education. An increase in NfL was associated with worse global cognition (b[SE] = -4.81[2.06], P = .023) over time, however baseline NfL did not predict a decline in global cognition. NfL levels did not differ between the vMCI (n = 39) and CU (n = 39) groups (F(1, 76) = 1.37, P = .245). CONCLUSION: Plasma NfL correlates with global cognition at baseline in individuals with vMCI, and is associated with decline in global cognition during CR. Our findings increase understanding of NfL and neurobiological mechanisms associated with cognitive decline in vMCI.

Association between the incident hypertension duration and cognitive performance in older adults: data from the NHANES 2011-2014.

BACKGROUND: Established evidences have demonstrated that hypertension was associated with the cognitive impairment. But the associations between the duration of hypertension exposure and cognitive performance are still inconclusive. OBJECTIVES: The objective of this study was to assess the association between the duration of hypertension diagnosis and cognitive performance in older adults by the National Health and Nutrition Examination Survey (2011-2014). METHODS: To evaluate the relationship between the hypertension duration and cognitive performance, we conducted the logistic regression analysis. Furthermore, we also performed the Restricted cubic spline (RCS) analysis to assess the nonlinear relationship between the duration of exposure to hypertension and cognitive performance. RESULTS: Initially, total 19,931 participants were included in this study, and 2928 individuals were enrolled. With the increase of hypertension duration, more risk of cognitive impairment was observed in the Digit Symbol Substitution test (DSST) (OR = 1.012, 1.006-1.019), and a similar trend was observed in Animal Fluency test (AFT) (OR = 1.009,1.003-1.016). The RCS results showed that the hypertension duration pattern was linear associated with the risk of cognitive impairment in DDST (P for non-linearity = 0.758). Meanwhile, subgroups analysis of midlife hypertension, we revealed that linear association with the risk of cognitive impairment in DSST (P for non-linearity = 0.391) and CERAD (P for non-linearity = 0.849) among hypertension diagnose < 55 years populations. CONCLUSION: Collectively, our finding indicates that longer duration of exposure to hypertension worsens the cognition performance, especially for middle-aged hypertension.

Cerebrovascular reactivity MRI as a biomarker for cerebral small vessel disease-related cognitive decline: Multi-site validation in the MarkVCID Consortium.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

Lower cerebral blood flow predicts cognitive decline in patients with vascular cognitive impairment.

INTRODUCTION: Chronic cerebral hypoperfusion is one of the assumed pathophysiological mechanisms underlying vascular cognitive impairment (VCI). We investigated the association between baseline cerebral blood flow (CBF) and cognitive decline after 2 years in patients with VCI and reference participants. METHODS: One hundred eighty-one participants (mean age 66.3 ± 7.4 years, 43.6% women) underwent arterial spin labeling (ASL) magnetic resonance imaging (MRI) and neuropsychological assessment at baseline and at 2-year follow-up. We determined the association between baseline global and lobar CBF and cognitive decline with multivariable regression analysis. RESULTS: Lower global CBF at baseline was associated with more global cognitive decline in VCI and reference participants. This association was most profound in the domain of attention/psychomotor speed. Lower temporal and frontal CBF at baseline were associated with more cognitive decline in memory. DISCUSSION: Our study supports the role of hypoperfusion in the pathophysiological and clinical progression of VCI. HIGHLIGHTS: Impaired cerebral blood flow (CBF) at baseline is associated with faster cognitive decline in VCI and normal aging. Our results suggest that low CBF precedes and contributes to the development of vascular cognitive impairment. CBF determined by ASL might be used as a biomarker to monitor disease progression or treatment responses in VCI.

Angiotensin II-mediated hippocampal hypoperfusion and vascular dysfunction contribute to vascular cognitive impairment in aged hypertensive rats.

INTRODUCTION: Chronic hypertension increases the risk of vascular cognitive impairment (VCI) by ∼60%; however, how hypertension affects the vasculature of the hippocampus remains unclear but could contribute to VCI. METHODS: Memory, hippocampal perfusion, and hippocampal arteriole (HA) function were investigated in male Wistar rats or spontaneously hypertensive rats (SHR) in early (4 to 5 months old), mid (8 to 9 months old), or late adulthood (14 to 15 months old). SHR in late adulthood were chronically treated with captopril (angiotensin converting enzyme inhibitor) or apocynin (antioxidant) to investigate the mechanisms by which hypertension contributes to VCI. RESULTS: Impaired memory in SHR in late adulthood was associated with HA endothelial dysfunction, hyperconstriction, and ∼50% reduction in hippocampal blood flow. Captopril, but not apocynin, improved HA function, restored perfusion, and rescued memory function in aged SHR. DISCUSSION: Hippocampal vascular dysfunction contributes to hypertension-induced memory decline through angiotensin II signaling, highlighting the therapeutic potential of HAs in protecting neurocognitive health later in life. HIGHLIGHTS: Vascular dysfunction in the hippocampus contributes to vascular cognitive impairment. Memory declines with age during chronic hypertension. Angiotensin II causes endothelial dysfunction in the hippocampus in hypertension. Angiotensin II-mediated hippocampal arteriole dysfunction reduces blood flow. Vascular dysfunction in the hippocampus impairs perfusion and memory function.

MINocyclinE to Reduce inflammation and blood-brain barrier leakage in small Vessel diseAse (MINERVA): A phase II, randomized, double-blind, placebo-controlled experimental medicine trial.

INTRODUCTION: Cerebral small vessel disease (SVD) is a common cause of stroke/vascular dementia with few effective treatments. Neuroinflammation and increased blood-brain barrier (BBB) permeability may influence pathogenesis. In rodent models, minocycline reduced inflammation/BBB permeability. We determined whether minocycline had a similar effect in patients with SVD. METHODS: MINERVA was a single-center, phase II, randomized, double-blind, placebo-controlled trial. Forty-four participants with moderate-to-severe SVD took minocycline or placebo for 3 months. Co-primary outcomes were microglial signal (determined using 11C-PK11195 positron emission tomography) and BBB permeability (using dynamic contrast-enhanced MRI). RESULTS: Forty-four participants were recruited between September 2019 and June 2022. Minocycline had no effect on 11C-PK11195 binding (relative risk [RR] 1.01, 95% confidence interval [CI] 0.98-1.04), or BBB permeability (RR 0.97, 95% CI 0.91-1.03). Serum inflammatory markers were not affected. DISCUSSION: 11C-PK11195 binding and increased BBB permeability are present in SVD; minocycline did not reduce either process. Whether these pathophysiological mechanisms are disease-causing remains unclear. INTERNATIONAL CLINICAL TRIALS REGISTRY PORTAL IDENTIFIER: ISRCTN15483452 HIGHLIGHTS: We found focal areas of increased microglial signal and increased blood-brain barrier permeability in patients with small vessel disease. Minocycline treatment was not associated with a change in these processes measured using advanced neuroimaging. Blood-brain barrier permeability was dynamic but MRI-derived measurements correlated well with CSF/serum albumin ratio. Advanced neuroimaging is a feasible outcome measure for mechanistic clinical trials.

Electroacupuncture improves vascular cognitive impairment no dementia: A Randomized Clinical Trial.

BACKGROUND: Electroacupuncture (EA) could represent a clinically effective treatment strategy for patients with vascular cognitive impairment no dementia (VCIND). This randomized trial aims to explore the underlying mechanism of EA in VCIND patients through cognitive function assessment and neuroimaging assessment. METHODS: 140 eligible patients with VCIND were recruited and randomly divided into EA group (n = 70) and Control group (n = 70). The Montreal Cognitive Assessment (MoCA), and the Auditory Verbal Learning Test (AVLT), the Stroop color-naming task (STROOP), and the resting-state functional magnetic resonance imaging assessment. The EA group received treatment for 30 min/day, 5 times/week, for 8 weeks. RESULTS: EA intervention could increase the MoCA score and improve the neutral and consistency response of the STROOP test in VCIND patients (P < 0.05). fMRI functional connectivity analysis showed that, after EA, the default mode network (DMN) function of the posterior cingulate gyrus, left middle frontal gyrus, left anterior cingulate gyrus, left and right superior temporal gyrus, right insula, left precentral gyrus and other brain regions were significantly higher than that in the control group. The functional connectivity between the posterior cingulate gyrus-left middle frontal gyrus and the posterior cingulate gyrus-right superior temporal gyrus was positively correlated with cognitive function (P < 0.05). Gray Matter Volume increased in VCIND after EA(P < 0.05). CONCLUSIONS: EA can increase the functional connectivity between posterior cingulate gyrus-other gyri in VCIND patients. The functional connectivity is positively correlated with cognitive function.

[Correlations between serum BDNF, IL-18 and hs-CRP levels in patients with acute cerebral infarction and vascular cognitive impairment].

OBJECTIVE: To explore the correlations between serum levels of brain-derived neurotrophic factor (BDNF), interleukin-18 (IL-18) and hypersensitivity C-reactive protein (hs-CRP) in patients with acute cerebral infarction and vascular cognitive impairment (VCI), and to provide some clinical bases for early prevention of VCI. METHODS: A total of 160 patients with acute cerebral infarction admitted in Department of Neurology of Jincheng People' s Hospital from May 2019 to April 2020 were enrolled in this study and were devided into three groups according to whether or not combined with cognitive impairment, including no cognitive impairment group (NCI, 57 cases), vascular cognitive impairment no dementia group (VCIND, 56 cases) and vascular dementia group (VaD, 47 cases). The cognitive function of all the patients were evaluated by Montreal cognitive assessment (MoCA). The National Institute of Health stroke scale (NIHSS) was used to assess the degree of neurological deficit (mild-, moderate-, severe-neurologic deficit group). The infarct size was calculated by Pullicino' s method (small-, middle-, large-infarct group). The levels of serum BDNF and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA), and serum levels of hs-CRP were measured by immunoturbidimetry during the acute phase (0-7 d), recovery period (15-30 d) and 6 months after cerebral infarction. The effects of varying degrees of neurological deficits and different size of infarction on BDNF, IL-18 and hs-CRP were observed. The levels of serum BDNF, IL-18 and hs-CRP in the patients of the three groups with acute, convalescent and six-month cerebral infarction were compared, and their correlations with VCI were analyzed. RESULTS: Serum BDNF level and MoCA scores in mild-neurologic deficit group and small-infarct group were significantly higher than those in moderate- and severe-deficit group, middle- and large-infarct group, respectively (P < 0.05). Their levels of IL-18 and hs-CRP were significantly lower than those in moderate- and severe-deficit group, middle- and large-infarct group, respectively (P < 0.05). The levels of serum BDNF in NCI group, VCIND group and VaD group during the acute phase, convalescence and 6 months after cerebral infarction were in a significant decline, and the differences during the acute phase and recovery period were statistically significant (P < 0.05). The levels of IL-18 and hs-CRP during the acute phase, recovery period and 6 months after cerebral infarction showed a significant increasing trend with significance (P < 0.05). Correlation analysis revealed that the levels of BDNF was positively correlated with MoCA scores but negatively correlated with the severity of cognitive impairment while the expression levels of IL-18 and hs-CRP were negatively correlated with MoCA scores but positively correlated with the severity of cognitive impairment. CONCLUSION: Serum BDNF, IL-18 and hs-CRP are involved in the pathological process of occurrence and development of VCI in the patients with acute cerebral infarction. BDNF has a protective effect on VCI while IL-18 and hs-CRP cause severe cognitive impairment. The levels of serum BDNF、IL-18 and hs-CRP in the patients with acute ischemic cerebral infarction are closely related to the severity of cognitive impairment and can be used as biomarkers of early diagnosis of VCI.

[Application Progress of Resting-State Functional Magnetic Resonance Imaging in Study of Default Mode Network in Patients with Vascular Cognitive Impairment].

Vascular cognitive impairment（VCI） is a group of syndromes ranging from mild cognitive impairment to dementia caused by cerebrovascular disease, due to the lack of sensitivity and specific biomarkers, it is difficult to identify and diagnose early. Abnormal connectivity is observed in brain regions of patients with vascular cognitive disorders, locates mainly in the default mode network（DMN）, and changes in their abnormal functional connectivity correlated with the degree of patients' cognitive impairment. Resting-state functional magnetic resonance imaging(rs-fMRI) is a commonly used method to detect the internal activity of the brain at resting state. The use of various rs-fMRI to study abnormal changes in the DMN in patients with VCI is useful to further investigate the pathogenesis of VCI and provide an objective basis for imaging. This article mainly reviews the application of rs-fMRI in the DMN in patients with VCI, bringing new perspectives for the correct diagnosis and assessment of VCI.

The Combination of Citicoline and Nicotinamide Mononucleotide Induces Neurite Outgrowth and Mitigates Vascular Cognitive Impairment via SIRT1/CREB Pathway.

Vascular dementia (VD) is characterized with vascular cognitive impairment (VCI), which currently has few effective therapies in clinic. Neuronal damage and white matter injury are involved in the pathogenesis of VCI. Citicoline has been demonstrated to exhibit neuroprotection and neurorepair to improve cognition in cerebrovascular diseases. Nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin (SIRT) signaling pathway constitutes a strong intrinsic defense system against various stresses including neuroinflammation in VCI. Our hypothesis is that the combined use of citicoline and the precursor of NAD+, nicotinamide mononucleotide (NMN), could enhance action on cognitive function in VCI. We investigated the synergistic effect of these two drugs in the rat model of VCI by bilateral common carotid artery occlusion (BCCAO). Citicoline significantly enhanced neurite outgrowth in Neuro-2a cells, and the combination of citicoline and NMN remarkably induced neurite outgrowth in Neuro-2a cells and primary cortical neuronal cells with an optimal proportion of 4:1. In the rat model of BCCAO, when two drugs in combination of 160 mg/kg citicoline and 40 mg/kg NMN, this combination administrated at 7 days post-BCCAO significantly improved the cognitive impairment in BCCAO rats compared with vehicle group by the analysis of the Morris water maze and the novel object recognition test. This combination also decreased microglial activation and neuroinflammation, and protected white matter integrity indicated by the increased myelin basic protein (MBP) expression through activation of SIRT1/TORC1/CREB signaling pathway. Our results suggest that the combination of citicoline and NMN has a synergistic effect for the treatment of VD associated with VCI.