Vascular Cognitive Impairment And Dementia Research Articles

A review of SaiLuoTong (MLC-SLT) development in vascular cognitive impairment and dementia

The dementia epidemic, attributed to aging populations, represents a growing socio-economic burden. It is estimated that in 2019 about 55 million people worldwide were living with dementia. With many possible causes of dementia and the possibility of mixed dementia combining Alzheimer’s disease (AD) and vascular dementia the question is whether diagnostic uncertainty exists or whether diagnostic constructs based on single etiologies are incorrect. Vascular Cognitive Impairment and Dementia (VCID) designates the extent of cognitive dysfunctions from the most benign state to that of dementia, of vascular origin. We reviewed epidemiological, pathophysiological and clinical data on VCID with a focus on VaD, as well as key data on the development of a new therapeutic solution, SaiLuoTong (MLC-SLT). From documentary research executed on different web sources (PubMed, Clintrials.gov, Z-library and Google), our initial selection for the short review of VCID and VaD was based on keywords contained in each paragraph subtitles of this article with exclusion of publications in a language other than English or published before 2010. For the review of SaiLuoTong development, there was just the language exclusion criterion. Sorted by relevance and publication date, 47 references were selected from 140 shortlisted for review. With new evidence-based classification systems, vascular cognitive impairment was proposed as umbrella term covering all forms of cognitive deficits related to vascular causes. The scope of application expanded with the VCID which includes VaD and mixed pathologies. No drugs are approved for the treatment of VaD by major Western regulatory agencies, while some traditional Chinese medicines are registered in China. VCID treatment should have a dual focus: managing the underlying cerebrovascular disease and dementia symptoms. This is the objective set for the development of the MLC-SLT, the essential data of which are reviewed in detail. To strengthen VCID and VaD research, consensus groups should attempt to consolidate scattered local research initiatives into coordinated international programs. In two VaD clinical trials, MLC-SLT improved cognitive symptoms and activities of daily living, with good safety and potential disease-modifying effect. In a placebo-controlled study in 325 patients with mild to moderate VaD and randomized according to a delayed-start design, MLC-SLT demonstrated significant improvement in memory tests and performance in executive function tasks, expanding its place in the management of VCID. At week 26, changes in VADAS-cog scores (SD) from baseline were 23.25 (0.45) for MLC-SLT 180 mg bid), 23.05 (0.45) for MLC-SLT 120 mg bid (both p < 0.0001), and 20.57 (0.45) for placebo (p = 0.15). At week 52, differences between both groups MLC-SLT and placebo were 2.67 and 2.48, respectively (p < 0.0001), without significant difference between MLC-SLT groups.

Atherosclerotic burden and cerebral small vessel disease: exploring the link through microvascular aging and cerebral microhemorrhages.

Cerebral microhemorrhages (CMHs, also known as cerebral microbleeds) are a critical but frequently underestimated aspect of cerebral small vessel disease (CSVD), bearing substantial clinical consequences. Detectable through sensitive neuroimaging techniques, CMHs reveal an extensive pathological landscape. They are prevalent in the aging population, with multiple CMHs often being observed in a given individual. CMHs are closely associated with accelerated cognitive decline and are increasingly recognized as key contributors to the pathogenesis of vascular cognitive impairment and dementia (VCID) and Alzheimer's disease (AD). This review paper delves into the hypothesis that atherosclerosis, a prevalent age-related large vessel disease, extends its pathological influence into the cerebral microcirculation, thereby contributing to the development and progression of CSVD, with a specific focus on CMHs. We explore the concept of vascular aging as a continuum, bridging macrovascular pathologies like atherosclerosis with microvascular abnormalities characteristic of CSVD. We posit that the same risk factors precipitating accelerated aging in large vessels (i.e., atherogenesis), primarily through oxidative stress and inflammatory pathways, similarly instigate accelerated microvascular aging. Accelerated microvascular aging leads to increased microvascular fragility, which in turn predisposes to the formation of CMHs. The presence of hypertension and amyloid pathology further intensifies this process. We comprehensively overview the current body of evidence supporting this interconnected vascular hypothesis. Our review includes an examination of epidemiological data, which provides insights into the prevalence and impact of CMHs in the context of atherosclerosis and CSVD. Furthermore, we explore the shared mechanisms between large vessel aging, atherogenesis, microvascular aging, and CSVD, particularly focusing on how these intertwined processes contribute to the genesis of CMHs. By highlighting the role of vascular aging in the pathophysiology of CMHs, this review seeks to enhance the understanding of CSVD and its links to systemic vascular disorders. Our aim is to provide insights that could inform future therapeutic approaches and research directions in the realm of neurovascular health.

The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID).

Vascular cognitive impairment and dementia (VCID) represents a broad spectrum of cognitive decline secondary to cerebral vascular aging and injury. It is the second most common type of dementia, and the prevalence continues to increase. Nuclear factor erythroid 2-related factor 2 (NRF2) is enriched in the cerebral vasculature and has diverse roles in metabolic balance, mitochondrial stabilization, redox balance, and anti-inflammation. In this review, we first briefly introduce cerebrovascular aging in VCID and the NRF2 pathway. We then extensively discuss the effects of NRF2 activation in cerebrovascular components such as endothelial cells, vascular smooth muscle cells, pericytes, and perivascular macrophages. Finally, we summarize the clinical potential of NRF2 activators in VCID.

CO2 cerebrovascular reactivity measured with CBF-MRI in older individuals: Association with cognition, physical function, amyloid, and tau proteins.

Vascular pathology is the second leading cause of cognitive impairment and represents a major contributing factor in mixed dementia. However, biomarkers for vascular cognitive impairment and dementia (VCID) are under-developed. Here we aimed to investigate the potential role of CO2 Cerebrovascular Reactivity (CVR) measured with phase-contrast quantitative flow MRI in cognitive impairment and dementia. Forty-five (69 ± 7 years) impaired (37 mild-cognitive-impairment and 8 mild-dementia by syndromic diagnosis) and 22 cognitively-healthy-control (HC) participants were recruited and scanned on a 3 T MRI. Biomarkers of AD pathology were measured in cerebrospinal fluid. We found that CBF-CVR was lower (p = 0.027) in the impaired (mean±SE, 3.70 ± 0.15%/mmHg) relative to HC (4.28 ± 0.21%/mmHg). After adjusting for AD pathological markers (Aβ42/40, total tau, and Aβ42/p-tau181), higher CBF-CVR was associated with better cognitive performance, including Montreal Cognitive Assessment, MoCA (p = 0.001), composite cognitive score (p = 0.047), and language (p = 0.004). Higher CBF-CVR was also associated with better physical function, including gait-speed (p = 0.006) and time for five chair-stands (p = 0.049). CBF-CVR was additionally related to the Clinical-Dementia-Rating, CDR, including global CDR (p = 0.026) and CDR Sum-of-Boxes (p = 0.015). CBF-CVR was inversely associated with hemoglobin A1C level (p = 0.017). In summary, CBF-CVR measured with phase-contrast MRI shows associations with cognitive performance, physical function, and disease-severity, independent of AD pathological markers.

IGF1R deficiency in vascular smooth muscle cells impairs myogenic autoregulation and cognition in mice.

Cerebrovascular pathologies contribute to cognitive decline during aging, leading to vascular cognitive impairment and dementia (VCID). Levels of circulating insulin-like growth factor 1 (IGF-1), a vasoprotective hormone, decrease during aging. Decreased circulating IGF-1 in animal models leads to the development of VCID-like symptoms, but the cellular mechanisms underlying IGF-1-deficiency associated pathologies in the aged cerebrovasculature remain poorly understood. Here, we test the hypothesis that vascular smooth muscle cells (VSMCs) play an integral part in mediating the vasoprotective effects of IGF-1. We used a hypertension-based model of cerebrovascular dysfunction in mice with VSMC-specific IGF-1 receptor (Igf1r) deficiency and evaluated the development of cerebrovascular pathologies and cognitive dysfunction. VSMC-specific Igf1r deficiency led to impaired cerebral myogenic autoregulation, independent of blood pressure changes, which was also associated with impaired spatial learning and memory function as measured by radial arm water maze and impaired motor learning measured by rotarod. In contrast, VSMC-specific IGF-1 receptor knockdown did not lead to cerebral microvascular rarefaction. These studies suggest that VSMCs are key targets for IGF-1 in the context of cerebrovascular health, playing a role in vessel stability alongside other cells in the neurovascular unit, and that VSMC dysfunction in aging likely contributes to VCID.

Proteome Profiling of Brain Vessels in a Mouse Model of Cerebrovascular Pathology.

Cerebrovascular pathology that involves altered protein levels (or signaling) of the transforming growth factor beta (TGFβ) family has been associated with various forms of age-related dementias, including Alzheimer disease (AD) and vascular cognitive impairment and dementia (VCID). Transgenic mice overexpressing TGFβ1 in the brain (TGF mice) recapitulate VCID-associated cerebrovascular pathology and develop cognitive deficits in old age or when submitted to comorbid cardiovascular risk factors for dementia. We characterized the cerebrovascular proteome of TGF mice using mass spectrometry (MS)-based quantitative proteomics. Cerebral arteries were surgically removed from 6-month-old-TGF and wild-type mice, and proteins were extracted and analyzed by gel-free nanoLC-MS/MS. We identified 3602 proteins in brain vessels, with 20 demonstrating significantly altered levels in TGF mice. For total and/or differentially expressed proteins (p ≤ 0.01, ≥ 2-fold change), using multiple databases, we (a) performed protein characterization, (b) demonstrated the presence of their RNA transcripts in both mouse and human cerebrovascular cells, and (c) demonstrated that several of these proteins were present in human extracellular vesicles (EVs) circulating in blood. Finally, using human plasma, we demonstrated the presence of several of these proteins in plasma and plasma EVs. Dysregulated proteins point to perturbed brain vessel vasomotricity, remodeling, and inflammation. Given that blood-isolated EVs are novel, attractive, and a minimally invasive biomarker discovery platform for age-related dementias, several proteins identified in this study can potentially serve as VCID markers in humans.

Modern trial outcome measures increase trial participation and recruitment of representative peoples

AbstractBackgroundClinical trials have been one size fits all, despite evidence that dementia ensues from a combination of pathologies with effects from environment, sex/gender, race/ethnicity and other factors influencing disease course. Cardiovascular diseases and cancer have measures (imaging and molecular biomarkers) that aid in capturing targetable biology. These biomarkers are used for risk stratification, precise diagnostic classification, in addition to inclusion as outcomes in trials. Clinical trials for brain degenerative disorders would benefit from a similar precision approaches.MethodWe performed proteomics analyses on banked plasma samples from longitudinal observational studies of vascular cognitive impairment and dementia (VCID) and a clinical trial (SPRINT‐MIND) targeting hypertension, a major VCID risk factor. Using multi‐modal analytical approaches we combined molecular measures with imaging and clinical outcomes to identify promising molecular markers for risk stratification for VCID clinical trials and maximizing benefit of interventions for VCID.ResultProteins related to angiogenesis as well as innate immune activation were found to be dysregulated in cases versus controls. With multivariate analyses, components with high loading from proteins involved in these multi‐cellular phenotypes were associated with cognitive outcomes. Using network analyses, key molecular nodes were validated via orthogonal methods.ConclusionA simple molecular panel with key proteins involved in dysregulated molecular networks mediating the effect of vascular disease on cognition could be developed and used for risk stratification in clinical trials of VCID. Greater precision in clinical trials would ensure higher benefit at lower cost, at all levels.

Cross vendor test‐retest validation of diffusion tensor analysis along the perivascular space (DTI‐ALPS) method for evaluating glymphatic system function in vascular cognitive impairment and dementia (VCID)

AbstractBackgroundGlymphatic system (GS) is a recently discovered brain‐wide perivascular fluid transport system in the cerebral nervous system (CNS)(Benveniste H et al., 2019) The impairment of glymphatic transport has been demonstrated to be associated with several neurological diseases, in particular the vascular cognitive impairment and dementia (VCID)(Tang J et al., 2022). The diffusion tensor analysis along the perivascular space (DTI‐ALPS) was proposed to non‐invasively evaluate the GS clearance dysfunction which has been used to investigate the GS in various pathologies(Taoka T et al., 2017, Hsu JL et al., 2022). However, studies on the cross‐vendor and test‐retest reliability of DTI‐ALPS method are lacking. The current study aimed to perform cross‐vendor, inter‐rater and test‐retest validations of DTI‐ALPS method by using a cohort from the MarkVCID consortium.MethodFifty participants’ DTI data from the MarkVCID consortium (consists of 7 sites) were included in this study: 15 participants were scanned on four MRI scanners; 35 participants underwent two MR scans within 14 days. The DTI data were acquired used a single shell, b = 1000s/mm2, 40‐direction with a voxel size of 2.02.02.0mm3 and six b = 0 s/mm2 on 3T MR scanners from seven sites, including two Siemens systems, one Philips system and one GE system. Two pipelines by using DSI studio and FSL software were developed for data processing and ALPS index calculation (Figure 1). The mean ALPS (mALPS) index was obtained by the average of bilateral ALPS index and was used for testing the inter‐rater, cross‐vendor and test‐retest reliability. The association between mALPS index and Montreal Cognitive assessment (MoCA) scores were evaluated using a general linear model with age and gender as covariate.ResultThe Bland‐Altman plot and scatterplot illustrated the validation results of the mALPS index analyzed using DSI studio and FSL pipelines (Figure 2). The mALPS index demonstrated favorable inter‐scanner reproducibility (ICC = 0.77 to 0.95, P< 0.001), inter‐rater reliability (ICC = 0.96 to 1, P< 0.001) and test‐retest repeatability (ICC = 0.89 to 0.95, P< 0.001). A significantly positive correlation was observed between mALPS index and MoCA scores (r = 0.502, P< 0.01) (Figure 3).ConclusionThe mALPS index offers a robust potential biomarker for evaluating GS clearance function in VCID.

DPP4 Valorphin Activate NR4As Pathway and OPA1 That Protect from CoQ10 Deficiency, OPA1 Dysfunctions and WMH

Deficiencies in Threonine (Thr), Tryptophan hydroxylase (Tph), Glutamate (Glu), Glutamine (Gln), and Leucine can result from increased polarizability in mTORC1 and its subunits. These deficiencies may lead to disorders in OPA1 repair, which can be a primary cause of Coenzyme Q10 (CoQ10) deficiency disease. CoQ10 is crucial for maintaining the inner mitochondrial membrane and is necessary for the synthesis of the glucocorticoid receptor (GCR). Mitochondrial damage or dysfunction can lead to the accumulation of pro-inflammatory molecules, which may cause mutations in subunits and proteins. Reduced levels of Tryptophan, Glycine (Gly), and Arginine (Arg) can result in decreased Proline synthesis, subsequently reducing tRNA levels. This, in turn, can impair mitochondrial OPA1 repair and function due to decreased GTPase activity. The reduced function of GTPase can lead to decreased IL-17 synthesis and the accumulation of pro-inflammatory molecules, resulting in a reduction in serotonin production, as well as decreased production of GCbeta, oxytocin, and Nrf2. These changes can lead to a decrease in the proliferation of megakaryocytes and, consequently, reduced hematopoiesis, which is associated with white matter hyperintensity. Opioid receptors play a role in producing powerful analgesia, contributing to the function of immune cells, and modulating acquired immune responses, including the function of lymphocytes. Tryptophan, Leucine, and Tyrosine kinases are crucial for activating mitochondrial OPA1 repairs, which are essential for CoQ10 synthesis. Tryptophan (TGG) is necessary for activating Proline, which is essential for both OPA1 function and tRNA production. Additionally, it plays a role in IL17 synthesis and the activation of the NR4As pathway, which includes the activation of GCs-beta, oxytocin, and Nrf2 production, respectively. Cytotoxic edema can result from uncontrolled or uncompensated cation influx, primarily sodium (Na+). This edema occurs due to high levels of potassium (K) and sodium (Na) binding toxicity, leading to coagulation and reduced ATPase and GTPase activity. It starts with a decrease in CoQ10 synthesis and an increase in Plasma Glial Fibrillary Acidic Protein (GFAP), resulting in decreased mineralocorticoid. Increased sodium and potassium binding, associated with decreased anions binding in biological molecules, can be due to reduced GTPase and OPA1 function. This reduction in anions function is the result of a primary Coenzyme Q10 (CoQ10) deficiency, leading to elevated GFAP levels in cognitively normal older adults at risk of Alzheimer's disease. Primary Coenzyme Q10 (CoQ10) deficiency is typically associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypoxia, late-onset multiple-system atrophy-like symptoms, dystonia, spasticity, seizures, and intellectual disability. Autoimmune diseases and skin inflammatory disorders can start due to increased cation binding toxicity, which reduces ATPase and GTPase function, characterized by a deficiency in proper GTPase production, leading to a reduction in mitochondrial OPA1 function and a deficiency in GCs-beta synthesis via the NR4As pathway. GFAP is an important neuroinflammation biomarker, and an increase in its levels may indicate OPA1 dysfunction, a decrease in CoQ10, neuroinflammation, and a reduction in the NR4As pathway. The increase in GFAP during acute ischemic stroke can be initiated by increased cation binding to anions, leading to enhanced energy stability and decreased tRNA production, which is proline-dependent. This decrease in tRNAs and GTPase activity can result in a decrease in IL17 production, increased inflammation, decreased blood flow to the brain, and reduced oxygen supply to the brain, ultimately contributing to neuronal damage. A decrease in hemorphin (valorphin) reflects reduced lymphocyte function and a loss of cholinecontaining phospholipids (CCPLs). Valorphin contains Tyrosine, which is essential for kinases production, required for choline kinases synthesis, and crucial for activating tRNAs, serotonin, oxytocin, and Nrf2 via the NR4As pathway, all of which are essential for lymphocyte function and antiinflammatory growth. Nrf2 dysfunction, connected to NR4As and oxytocin dysfunction, plays a significant role in the pathogenesis of vascular cognitive impairment and dementia (VCID).

Multi-Site Cross-Site Inter-Rater and Test-Retest Reliability and Construct Validity of the MarkVCID White Matter Hyperintensity Growth and Regression Protocol.

White matter hyperintensities (WMH) that occur in the setting of vascular cognitive impairment and dementia (VCID) may be dynamic increasing or decreasing volumes or stable over time. Quantifying such changes may prove useful as a biomarker for clinical trials designed to address vascular cognitive-impairment and dementia and Alzheimer's Disease. Conducting multi-site cross-site inter-rater and test-retest reliability of the MarkVCID white matter hyperintensity growth and regression protocol. The NINDS-supported MarkVCID Consortium evaluated a neuroimaging biomarker developed to track WMH change. Test-retest and cross-site inter-rater reliability of the protocol were assessed. Cognitive test scores were analyzed in relation to WMH changes to explore its construct validity. ICC values for test-retest reliability of WMH growth and regression were 0.969 and 0.937 respectively, while for cross-site inter-rater ICC values for WMH growth and regression were 0.995 and 0.990 respectively. Word list long-delay free-recall was negatively associated with WMH growth (p < 0.028) but was not associated with WMH regression. The present data demonstrate robust ICC validity of a WMH growth/regression protocol over a one-year period as measured by cross-site inter-rater and test-retest reliability. These data suggest that this approach may serve an important role in clinical trials of disease-modifying agents for VCID that may preferentially affect WMH growth, stability, or regression.

A novel needle mouse model of vascular cognitive impairment and dementia.

Bilateral common carotid artery (CCA) stenosis (BCAS) is a useful model to mimic vascular cognitive impairment and dementia (VCID). However, current BCAS models have the disadvantages of high cost and incompatibility with MRI scanning due to metal implantation. We have established a new low-cost VCID model that better mimics human VCID and is compatible with live-animal MRI. The right and the left CCAs were temporarily ligated to 32 and 34 gauge needles with three ligations, respectively. After needle removal, CCA blood flow, cerebral blood flow, white matter injury (WMI) and cognitive function were measured. In male mice, needle removal led to ∼49.8% and ∼28.2% blood flow recovery in the right and left CCA, respectively. This model caused persistent and long-term cerebral hypoperfusion in both hemispheres (more severe in the left hemisphere), and WMI and cognitive dysfunction in about 90% of mice, which is more reliable compared to other models. Importantly, these pathological changes and cognitive impairments lasted for up to 24 weeks after surgery. The survival rate over 24 weeks was 81.6%. Female mice showed similar cognitive dysfunction, but a higher survival rate (91.6%) and relatively milder white matter injury. A novel, low-cost VCID model compatible with live-animal MRI with long-term outcomes was established.Significance StatementBCAS is an animal model mimicking carotid artery stenosis to study VCID. However, current BCAS models cost high cost and is incompatibility with MRI scanning due to metal implantation. We established a new asymmetric BCAS model by ligating the common carotid artery to various needle gauges followed by an immediate needle removal. Needle removal led to moderate stenosis in the right CCA and severe stenosis in the left CCA. This needle model replicates the hallmarks of VCID well in about 90% of mice, which is more reliable compared to other models, has ultra-low cost, and is compatible with MRI scanning in live animals. It will provide a new valuable tool and offer new insights for VCID research.

Neuroprotection from protein misfolding in cerebral hypoperfusion concurrent with metabolic syndrome. A translational perspective.

Based on clinical and experimental evidence, metabolic syndrome (MetS) and type 2 diabetes (T2D) are considered risk factors for chronic cerebral hypoperfusion (CCH) and neurodegeneration. Scientific evidence suggests that protein misfolding is a potential mechanism that explains how CCH can lead to either Alzheimer's disease (AD) or vascular cognitive impairment and dementia (VCID). Over the last decade, there has been a significant increase in the number of experimental studies regarding this issue. Using several animal paradigms and different markers of CCH, scientists have discussed the extent to which MetSor T2D causes a decrease in cerebral blood flow (CBF). In addition, different models of CCH have explored how long-term reductions in oxygen and energy supply can trigger AD or VCID via protein misfolding and aggregation. Research that combines two or three animal models could broaden knowledge of the links between these pathological conditions. Recent experimental studies suggest novel neuroprotective properties of protein-remodeling factors. In this review, we present a summarized updated revision of preclinical findings, discussing clinical implications and proposing new experimental approaches from a translational perspective. We are confident that research studies, both clinical and experimental, may find new diagnostic and therapeutic tools to prevent neurodegeneration associated with MetS, diabetes, and any other chronic non-communicable disease (NCD) associated with diet and lifestyle risk factors.

Defective hippocampal neurogenesis underlies cognitive impairment by carotid stenosis-induced cerebral hypoperfusion in mice.

Chronic cerebral hypoperfusion due to carotid artery stenosis is a major cause of vascular cognitive impairment and dementia (VCID). Bilateral carotid artery stenosis (BCAS) in rodents is a well-established model of VCID where most studies have focused on white matter pathology and subsequent cognitive deficit. Therefore, our aim was to study the implication of adult hippocampal neurogenesis in hypoperfusion-induced VCID in mice, and its relationship with cognitive hippocampal deficits. Mice were subjected to BCAS; 1 and 3 months later, hippocampal memory and neurogenesis/cell death were assessed, respectively, by the novel object location (NOL) and spontaneous alternation performance (SAP) tests and by immunohistology. Hypoperfusion was assessed by arterial spin labeling-magnetic resonance imaging (ASL-MRI). Hypoperfused mice displayed spatial memory deficits with decreased NOL recognition index. Along with the cognitive deficit, a reduced number of newborn neurons and their aberrant morphology indicated a remarkable impairment of the hippocampal neurogenesis. Both increased cell death in the subgranular zone (SGZ) and reduced neuroblast proliferation rate may account for newborn neurons number reduction. Our data demonstrate quantitative and qualitative impairment of adult hippocampal neurogenesis disturbances associated with cerebral hypoperfusion-cognitive deficits in mice. These findings pave the way for novel diagnostic and therapeutic targets for VCID.

Clustering patients with vascular cognitive impairment using quantitative magnetic resonance imaging data and a finite mixture model

AbstractBackgroundBlood‐brain barrier (BBB) leakage is a marker of vascular cognitive impairment and dementia (VCID). The advance of in vivo imaging enabled us to quantify the degree of BBB transfer rates in VCID patients. However, a consensus has not been reached on the role of BBB in the differential diagnosis of VCI subtypes. The objective of this work was to use neuroinflammatory and in vivo imaging data on BBB health to identify clusters of VCID patients with distinct underlying pathologies.MethodPatients included were on average 61 (SD = 15.94, M/F = 27/34) years old. The MRI data were collected by using a 1.5 Tesla Siemens Sonata scanner. Pixel‐by‐pixel BBB transfer rate (Ki) was calculated using Patlak compartmental analysis on dynamic contrast‐enhanced T1 maps. The mean BBB transfer rate was calculated for the brain section above the ventricular zone (sampled by six consecutive slices). MR Spectroscopy was used to investigate N‐Acetylaspartate (NAA), Creatine (Cr), and Choline (Cho) levels. Moreover, Active MMP3 data were used in patients clustering. Thirty‐eight patients enrolled in the study have all data for three entities; NAA, mean Ki, and active MMP3 used for clustering. A multi‐parametric model‐based classification method was used to blindly classify VCID data based on Ki, NAA, and active MMPs.ResultBBB leakage increased by age, which is more pronounced in patients diagnosed with cognitive impairment when compared with 17 controls, r2 = 0.060, P = 0.021. Statistical classifiers identified three clusters in VCID patients. Identified VCID clusters are similar to the distinction that was made on this VCID cohort based on the clinical scores and psychological entities that we have published earlier.ConclusionThe results suggest that a statistical combination of imaging and inflammatory attributes renders a tool to blindly separate VCID patients into distinct groups that may have different underlying pathology.

Lifestyle and pharmacological interventions in South America: Potential barriers for recruitment, implementation, and effectiveness

AbstractBackgroundThe study of vascular cognitive impairment and dementia (VCID) risk factors must be reproduced in every community so that disparities may be addressed. In South America, diverse levels of education, mixed ethnicity, genetic and cultural heterogeneity, and the burden of cerebrovascular risk are important features to be investigated for proper interventions.MethodsObservational and interventional VCID studies from South America will be discussed so that issues concerning potential barriers for participant recruitment and research effectiveness may be addressed.ResultsFew South American institutions have studied risk factors for VCID. Older people suffer the effects of restrictions to female education that occurred a century ago. Cross‐sectional studies demonstrated that APOE‐ε4 carrier status predisposes to physical inactivity and has smaller effects over dementia onset than in studies from the Northern Hemisphere, possibly due to ethnical disparities, while the burden of combined cerebrovascular risk factors (and smoking in particular) in this regard is high. Foreigners living in Brazil had later dementia onset, unexplained by common genetic variants. While prevalent in almost half of the older population, and associated with earlier dementia onset particularly in women, depression could be a risk factor or a prodromal symptom. Late life prospective studies verified that cerebrovascular risk factors such as arterial hypertension, hypercholesterolemia and a higher coronary heart disease risk, or increased creatinine clearance for women only, may be neuroprotective against cognitive and functional decline, probably due to enhanced cerebral perfusion. Lifetime sanitary conditions and increasing late life body mass index may protect against frailty, while education is neuroprotective for women and APOE‐ε4 carriers (though associated with faster cognitive decline in some cohorts). Longitudinal pharmacogenetic studies demonstrated that potential benefits of cerebrovascular metabolism modulators such as angiotensin‐converting enzyme inhibitors and lipophilic statins depend upon epistatic interactions among specific genetic variants. Caregiver awareness of the need to control cerebrovascular risk is beneficial for patients.ConclusionsGenomic effects of cognitive reserve, cerebral perfusion, and hormonal changes interact on mechanisms of neurodegeneration. Adherence to lifestyle and pharmacological interventions in South America is highly dependent upon proper funding, public support, harmonization efforts, institutional expertise and leadership, and caregiver education. (Supported by FAPESP grant #2015/10109‐5)

Renal function affects circulating levels of neurofilament light chain: MarkVCID‐CHARGE

AbstractBackgroundPlasma NfL is a promising fluid biomarker for risk stratification and quantifying the extent of neuronal injury in conditions such as vascular cognitive impairment and dementia (VCID) and Alzheimer’s dementia. However, systemic factors such as kidney function can affect circulating levels and this requires further investigation to ensure appropriate use as a biomarker.MethodWe examined the cross‐sectional association between plasma NfL levels and renal function among adult participants from four community‐based studies in the MarkVCID‐Cohorts for Heart and Aging Research in Genomic Epidemiology consortium who were free from stroke, multiple sclerosis, dementia, and renal failure. Estimated glomerular filtration rate (eGFR, mL/min/1.73m2) was calculated using the CKD‐EPI equation and categorized using Kidney Disease: Improving Global Outcomes (KDIGO) classification. Plasma NfL was measured using single molecule array technology. Multivariable linear regression models were used to investigate the linear relationship between eGFR and NfL, overall and stratified by KDIGO category. Study level estimates were combined in meta‐analysis. Models were adjusted for age, sex, sub‐cohort, hypertension, diabetes, body mass index, smoking, and race. Factors affecting eGFR can also cause MRI brain injury, hence we examined whether any apparent increase in NfL levels in persons with a lower eGFR merely reflected greater brain injury by performing a sensitivity analysis in a subsample with brain MRI, additionally adjusting in a single model for brain volume, white matter hyperintensities, and free water.ResultIn meta‐analysis (n = 5,954), lower eGFR was associated with higher plasma NfL (β = ‐0.0073, standard error[SE] = 0.0021, P = 0.0006). This relationship persisted within categories of reduced renal function, eGFR 60‐74 (mild), 45‐59 (moderate), and 15‐44 (severe) (P‐values&lt;0.0001), but was not evident with normal eGFR ≥90 (P = 0.3) or mildly decreased eGFR 75‐89 (P = 0.2). Further adjustment for white matter hyperintensities, brain volume, and free water among a subgroup with brain MRI (n = 2192) did not change the associations of eGFR and NfL (β = ‐0.0065,SE = 0.0025, P = 0.0091).ConclusionReduced renal function is associated with higher circulating NfL, even at an eGFR range (60‐74) considered normal in clinical practice. Adjusting for renal function may improve the accuracy of plasma NfL as a biomarker for risk stratification or for assessment of neuronal injury in conditions such as VCID.

Metformin attenuates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion.

Vascular cognitive impairment and dementia (VCID) is a series of cognitive dysfunction associated with cerebrovascular diseases and currently lacks effective treatments. The white matter, which is essential for neuronal information processing and integration, is nourished by a network of capillaries and is vulnerable to chronic hypoperfusion. Here, we show that metformin, a widely used drug for the treatment of type 2 diabetes, alleviates the white matter damage and improves cognitive impairment in a mouse model of VCID established by bilateral carotid artery stenosis (BCAS)-induced chronic hypoperfusion. Mechanistically, metformin restores the dysfunctions of oligodendrocyte precursor cells (OPCs) under hypoxia. Metformin up-regulates prolyl hydroxylases 2 via activating the AMP-activated protein kinase pathway, leading to hypoxia-inducible factor-1α (HIF-1α) degradation in OPCs. These findings suggest that metformin may have a promising therapeutic role in alleviating cognitive abnormalities by ameliorating white matter damage of VCID.

LRP1 in vascular mural cells modulates cerebrovascular integrity and function in the presence of APOE4.

Cerebrovasculature is critical in maintaining brain homeostasis; its dysregulation often leads to vascular cognitive impairment and dementia (VCID) during aging. VCID is the second most prevalent cause of dementia in the elderly, after Alzheimer's disease (AD), with frequent cooccurrence of VCID and AD. While multiple factors are involved in the pathogenesis of AD and VCID, APOE4 increases the risk for both diseases. A major apolipoprotein E (apoE) receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in vascular mural cells (pericytes and smooth muscle cells). Here, we investigated how deficiency of vascular mural cell LRP1 affects the cerebrovascular system and cognitive performance using vascular mural cell-specific Lrp1-KO mice (smLrp1-/-) in a human APOE3 or APOE4 background. We found that spatial memory was impaired in the 13- to 16-month-old APOE4 smLrp1-/- mice but not in the APOE3 smLrp1-/- mice, compared with their respective littermate control mice. These disruptions in the APOE4 smLrp1-/- mice were accompanied with excess paravascular glial activation and reduced cerebrovascular collagen IV. In addition, blood-brain barrier (BBB) integrity was disrupted in the APOE4 smLrp1-/- mice. Together, our results suggest that vascular mural cell LRP1 modulates cerebrovasculature integrity and function in an APOE genotype-dependent manner.

Vascular Effects on Cerebrovascular Permeability and Neurodegeneration.

Neurons and glial cells in the brain are protected by the blood brain barrier (BBB). The local regulation of blood flow is determined by neurons and signal conducting cells called astrocytes. Although alterations in neurons and glial cells affect the function of neurons, the majority of effects are coming from other cells and organs of the body. Although it seems obvious that effects beginning in brain vasculature would play an important role in the development of various neuroinflammatory and neurodegenerative pathologies, significant interest has only been directed to the possible mechanisms involved in the development of vascular cognitive impairment and dementia (VCID) for the last decade. Presently, the National Institute of Neurological Disorders and Stroke applies considerable attention toward research related to VCID and vascular impairments during Alzheimer's disease. Thus, any changes in cerebral vessels, such as in blood flow, thrombogenesis, permeability, or others, which affect the proper vasculo-neuronal connection and interaction and result in neuronal degeneration that leads to memory decline should be considered as a subject of investigation under the VCID category. Out of several vascular effects that can trigger neurodegeneration, changes in cerebrovascular permeability seem to result in the most devastating effects. The present review emphasizes the importance of changes in the BBB and possible mechanisms primarily involving fibrinogen in the development and/or progression of neuroinflammatory and neurodegenerative diseases resulting in memory decline.

Exercise Improves Cerebral Blood Flow and Functional Outcomes in an Experimental Mouse Model of Vascular Cognitive Impairment and Dementia (VCID).

Vascular cognitive impairment and dementia (VCID) are a growing threat to public health without any known treatment. The bilateral common carotid artery stenosis (BCAS) mouse model is valid for VCID. Previously, we have reported that remote ischemic postconditioning (RIPostC) during chronic cerebral hypoperfusion (CCH) induced by BCAS increases cerebral blood flow (CBF), improves cognitive function, and reduces white matter damage. We hypothesized that physical exercise (EXR) would augment CBF during CCH and prevent cognitive impairment in the BCAS model. BCAS was performed in C57/B6 mice of both sexes to establish CCH. One week after the BCAS surgery, mice were randomized to treadmill exercise once daily or no EXR for four weeks. CBF was monitored with an LSCI pre-, post, and 4weeks post-BCAS. Cognitive testing was performed for post-BCAS after exercise training, and brain tissue was harvested for histopathology and biochemical test. BCAS led to chronic hypoperfusion resulting in impaired cognitive function and other functional outcomes. Histological examination revealed that BCAS caused changes in neuronal morphology and cell death in the cortex and hippocampus. Immunoblotting showed that BCAS was associated with a significant downregulate of AMPK and pAMPK and NOS3 and pNOS3. BCAS also decreased red blood cell (RBC) deformability. EXR therapy increased and sustained improved CBF and cognitive function, muscular strength, reduced cell death, and loss of white matter. EXR is effective in the BCAS model, improving CBF and cognitive function, reducing white matter damage, improving RBC deformability, and increasing RBC NOS3 and AMPK. The mechanisms by which EXR improves CBF and attenuates tissue damage need further investigation.