Form Of Vascular Cognitive Impairment Research Articles

Reshaping the path of vascular cognitive impairment with progressive resistance training: A 12‐Month Randomized Trial

AbstractBackgroundSubcortical ischaemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Importantly, SIVCI is considered the most treatable form of cognitive impairment, due to its modifiable risk factors such as hypertension and diabetes mellitus. Exercise training is a promising intervention to delay the progression of SIVCI, as it actively targets these cardiometabolic risk factors. Despite the demonstrated benefits of resistance training on cognitive function and emerging evidence suggesting resistance training may reduce the progression of white matter hyperintensities, research on SIVCI has predominantly focused on the use of aerobic exercise. Thus, we examined the efficacy of a 12‐month, twice‐weekly progressive resistance training (RT) program on cognitive function in older adults with SIVCI.MethodWe conducted a 12‐month single‐blinded, randomized controlled trial with 91 adults with SIVCI who were randomly allocated to: 1) progressive RT; or 2) balance and tone exercises (BAT; control). Study eligibility included: 1) age 55 years and older; 2) neuroimaging evidence of cerebral small vessel disease at study entry; 3) mild cognitive impairment, as indicated by Montreal Cognitive Assessment scores < 26/30; and 4) the absence of dementia. Measurements occurred at baseline, 6 months, and 12 months. The primary outcome for cognitive function was the Alzheimer’s Disease Assessment Scale‐Cognitive‐Plus (ADAS‐Cog 13 with additional cognitive tests). Gait speed over 4 meters was also assessed as impaired mobility is common among those with SIVCI.ResultForty‐five participants were randomized to the RT group and 46 to the BAT group. Mean baseline age was 74.6 years (SD = 5.7 years), 66% of participants were female, and the median Fazekas score was 1. After adjusting for baseline, participants in the RT group had significantly better ADAS‐Cog Plus performance at 12 months vs. BAT (estimated mean difference [RT – BAT]:‐0.20; 95% CI:[‐0.39, ‐0.01]; p = 0.039). In addition, participants in RT had significantly faster gait speed at 12 months vs. BAT (estimated mean difference: ‐0.08 m/s; 95% CI: [‐0.16, 0.00]; p = 0.047).ConclusionThe prevalence and burden of SIVCI will only increase due to the world’s aging population. Our results suggest progressive resistance training should be considered in the management and treatment of individuals with SIVCI.

Willis Lecture: Biomarkers for Inflammatory White Matter Injury in Binswanger Disease Provide Pathways to Precision Medicine.

Binswanger disease is the small vessel form of vascular cognitive impairment and dementia. Deposition of Alzheimer disease proteins can begin in midlife and progress slowly, whereas aging of the vasculature also can begin in midlife, continuing to progress into old age, making mixed dementia the most common type of dementia. Biomarkers facilitate the early diagnosis of dementias. It is possible to diagnose mixed dementia before autopsy with biomarkers for vascular disease derived from diffusor tensor images on magnetic resonance imaging and Alzheimer disease proteins, Aβ (amyloid β), and phosphorylated tau, in cerebrospinal fluid or in brain with positron emission tomography. The presence of vascular disease accelerates cognitive decline. Both misfolded proteins and vascular disease promote inflammation, which can be detected in cerebrospinal fluid by the presence of MMPs (matrix metalloproteinases), angiogenic growth factors, and cytokines. MMPs disrupt the blood-brain barrier and break down myelin, producing Binswanger disease's 2 main pathological features. Advances in detecting biomarkers in plasma will provide early detection of dementia and aided by machine learning and artificial intelligence, will enhance diagnosis and form the basis for early treatments.

Global Cardiovascular Risk Profile and Cerebrovascular Abnormalities in Presymptomatic Individuals with CADASIL or Autosomal Dominant Alzheimer's Disease.

Cardiovascular risk factors increase the risk of developing dementia, including Alzheimer's disease and vascular dementia. Studying individuals with autosomal dominant mutations leading to the early onset of dementia, this study examines the effect of the global cardiovascular risk profile on early cognitive and neuroimaging features of Alzheimer's disease and vascular dementia. We studied 85 non-demented and stroke-free individuals, including 20 subjects with Presenilin1 (PSEN1) E280A mutation leading to the early onset of autosomal dominant Alzheimer's disease (ADAD), 20 subjects with NOTCH3 mutations leading to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and to the early onset of vascular dementia, and 45 non-affected family members (non-carriers). All subjects underwent clinical and neuropsychological evaluations and an MRI. The global cardiovascular risk profile was estimated using the office-based Framingham Cardiovascular Risk Profile (FCRP) score. In individuals with CADASIL, a higher FCRP score was associated with a reduced hippocampal volume (B = -0.06, p < 0.05) and an increased severity of cerebral microbleeds (B = 0.13, p < 0.001), lacunes (B = 0.30, p < 0.001), and perivascular space enlargement in the basal ganglia (B = 0.50, p < 0.05). There was no significant association between the FCRP score and neuroimaging measures in ADAD or non-carrier subjects. While the FCRP score was related to performance in executive function in non-carrier subjects (B = 0.06, p < 0.05), it was not significantly associated with cognitive performance in individuals with CADASIL or ADAD. Our results suggest that individuals with CADASIL and other forms of vascular cognitive impairment might particularly benefit from early interventions aimed at controlling cardiovascular risks.

Reshaping the path of vascular cognitive impairment with resistance training: a study protocol for a randomized controlled trial

BackgroundSubcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Importantly, SIVCI is considered the most treatable form of cognitive impairment in older adults, due to its modifiable risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia. Exercise training is a promising intervention to delay the progression of SIVCI, as it actively targets these cardiometabolic risk factors. Despite the demonstrated benefits of resistance training on cognitive function and emerging evidence suggesting resistance training may reduce the progression of white matter hyperintensities (WMHs), research on SIVCI has predominantly focused on the use of aerobic exercise. Thus, the primary aim of this proof-of-concept randomized controlled trial is to investigate the efficacy of a 12-month, twice-weekly progressive resistance training program on cognitive function and WMH progression in adults with SIVCI. We will also assess the efficiency of the intervention.MethodsEighty-eight community-dwelling adults, aged > 55 years, with SIVCI from metropolitan Vancouver will be recruited to participate in this study. SIVCI will be determined by the presence of cognitive impairment (Montreal Cognitive Assessment < 26) and cerebral small vessel disease using computed tomography or magnetic resonance imaging. Participants will be randomly allocated to a twice-weekly exercise program of (1) progressive resistance training or (2) balance and tone training (i.e., active control). The primary outcomes are cognitive function measured by the Alzheimer’s Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-13 with additional cognitive tests) and WMH progression.DiscussionThe burden of SIVCI is immense, and to our knowledge, this will be the first study to quantify the effect of progressive resistance training on cognitive function and WMH progression among adults with SIVCI. Slowing the rate of cognitive decline and WMH progression could preserve functional independence and quality of life. This could lead to reduced health care costs and avoidance of early institutional care.Trial registrationClinicalTrials.gov NCT02669394. Registered on February 1, 2016

Vascular Cognitive Impairment.

This article provides an overview of vascular cognitive impairment; discusses its epidemiology, subtypes, and associations with other neurodegenerative diseases; and reviews the diagnostic evaluation and management of these disorders. Cerebrovascular disease is a common cause of dementia and frequently coexists with neurodegenerative causes. The heterogeneity of mechanisms leading to vascular cognitive impairment makes developing unifying clinical and research criteria difficult. Recognizing the neuroimaging hallmarks of different forms of vascular cognitive impairment can allow for individualized treatment and management. In individuals with mild vascular cognitive impairment, aerobic exercise appears to be a promising treatment but requires further investigation. Vascular cognitive impairment can be caused by several mechanisms. While treating vascular risk factors is rational to prevent worsening of cognitive impairment, well-designed studies are needed to demonstrate efficacy.

Binswanger's disease: biomarkers in the inflammatory form of vascular cognitive impairment and dementia.

Vascular cognitive impairment and dementia (VCID) is a major public health concern because of the increased incidence of vascular disease in the aging population and the impact of vascular disease on Alzheimer's disease. VCID is a heterogeneous group of diseases for which there are no proven treatments. Biomarkers can be used to select more homogeneous populations. Small vessel disease is the most prevalent form of VCID and is the optimal form for treatment trials because there is a progressive course with characteristic pathological changes. Subcortical ischemic vascular disease of the Binswanger type (SIVD-BD) has a characteristic set of features that can be used both to identify patients and to follow treatment. SIVD-BD patients have clinical, neuropsychological, cerebrospinal fluid (CSF) and imaging features that can be used as biomarkers. No one feature is diagnostic, but a multimodal approach defines the SIVD-BD spectrum disorder. The most important features are large white matter lesions with axonal damage, blood-brain barrier disruption as shown by magnetic resonance imaging and CSF, and neuropsychological evidence of executive dysfunction. We have used these features to create a Binswanger Disease Scale and a probability of SIVD-BD, using a machine-learning algorithm. The patients discussed in this review are derived from published studies. Biomarkers not only aid in early diagnosis before the disease process has progressed too far for treatment, but also can indicate response to treatment. Refining the use of biomarkers will allow dementia treatment to enter the era of precision medicine. This article is part of the Special Issue "Vascular Dementia".

Chronic administration of isocarbophos induces vascular cognitive impairment in rats.

Vascular dementia, being the most severe form of vascular cognitive impairment (VCI), is caused by cerebrovascular disease. Whether organophosphorus causes VCI remains unknown. Isocarbophos (0.5 mg/kg per 2 days) was intragastrically administrated to rats for 16 weeks. The structure and function of cerebral arteries were assayed. The learning and memory were evaluated by serial tests of step‐down, step‐through and morris water maze. Long‐term administration of isocarbophos reduced the hippocampal acetylcholinesterase (AChE) activity and acetylcholine (ACh) content but did not alter the plasma AChE activity, and significantly damaged the functions of learning and memory. Moreover, isocarbophos remarkably induced endothelial dysfunction in the middle cerebral artery and the expressions of ICAM‐1 and VCAM‐1 in the posterior cerebral artery. Morphological analysis by light microscopy and electron microscopy indicated disruptions of the hippocampus and vascular wall in the cerebral arteries from isocarbophos‐treated rats. Treatment of isocarbophos injured primary neuronal and astroglial cells isolated from rats. Correlation analysis demonstrated that there was a high correlation between vascular function of cerebral artery and hippocampal AChE activity or ACh content in rats. In conclusion, chronic administration of isocarbophos induces impairments of memory and learning, which is possibly related to cerebral vascular dysfunction.

Abstract T P417: Remote Ischemic Post Conditioning (RIPostC) Is Effective In A Mouse Model Of Vascular Cognitive Impairment

Background and Purpose: The mouse bilateral common carotid artery stenosis (BCAS) model is regarded as the best animal model for vascular cognitive impairment (VCI). RIPostC is a simple and safe therapy that others and we found protective in ischemic stroke. Other than risk factor control, there are no established treatments for VCI. However observational studies suggest exercise may be effective in patients with leukoaraiosis and cognitive impairment, the major form of VCI. Since RIPostC and exercise share some common mechanisms of action, we hypothesized that RIPostC would be effective in the mouse BCAS model and in VCI. Methods: Adult C57BL/6J male mice of (10-weeks) were subjected to either Sham for BCAS or BCAS surgery using micro coils twined around common carotid arteries. We randomized BCAS mice to daily RIPostC or sham procedure for RIPostC beginning 7 days post-BCAS for 2 weeks until day 21. Cerebral blood flow (CBF) was measured by laser speckle contrast imager. All mice underwent blinded testing for cognitive functions using novel object recognition (NOR). Histopathological examination and beta amyloid contents were investigated in the brain at day 30 post-BCAS. Statistical significance was determined at p &lt;0.05. Results: At 1 hour, CBF was decreased significantly in all animals subjected to BCAS. RIPostC improved CBF in comparison to sham-operated group for RIPostC at day 14 and 28 post-VCI (p&lt;0.05). BCAS impaired the discrimination index of mice in the NOR test but this was improved in the BCAS group treated with RIPostC (p&lt;.05). Histopathological studies revealed that BCAS caused frequent vacuolization, cell death, microglial activation, loss in white matter (WM) and increased accumulation of beta amyloid. This was all attenuated significantly with RIPostC. Conclusions: RIPostC improves CBF, cognition and reduces cell death, WM damage and beta amyloid accumulation in the mouse BCAS model. Chronic RIPostC-therapy might be an effective treatment for VCI and in patients with leukoaraiosis and cognitive impairment Key words: RIPostC, VCI, white matter, beta-amyloid

Abstract 2749: Amyloid-beta (1-42) is Reduced in CSF in Vascular Cognitive Impairment

Introduction: Vascular cognitive impairment (VCI) and Alzheimer’s disease (AD) have a high degree of overlap in a number of large autopsy series. However, few studies have examined the overlap during life. VCI is a heterogeneous disorder due to large and small vessel vascular disease (SVD). Biomarkers of inflammation are present in the SVD, which is a progressive form of VCI that is characterized by MRI findings of lacunar strokes and white matter hyperintensities (WMHs), executive dysfunction, focal neurological findings, apathy, urinary problems and gait imbalance. Recently, we showed an association between a reduced matrix metalloproteinase-2 (MMP-2) CSF index and disruption of the blood-brain barrier (BBB) in SVD. We hypothesized that patients with both VCI and AD would show CSF and MRI biomarkers for both diseases. Patients and Methods: Patients (N=60) with VCI underwent neurological and neuropsychological testing. MRI was done with FLAIR, proton magnetic resonance spectroscopy (1H-MRS) to measure ischemia with N-acetylaspartate (NAA), and dynamic contrast-enhanced MRI (DCEMRI) to measure BBB transfer constants (K i ). CSF (N=37) was obtained by lumbar puncture for measurements of albumin index, MMP-2 and MMP-9 indexes, ABeta 1-42, total-tau (T-Tau) and hyperphosphorylated-tau (P-Tau). Results: BD patients had large WMHs, while large vessel (multi-infarct and single strategic stroke) patients had small WMHs. NAA was used as a biomarker of lesion size due to ischemic damage in the white matter. ROC plots showed that a NAA cut-point of 12 separated patients with large WMHs (low NAA) from small WMHs (p&lt;0.0001). K i transfer constants above 0.0018 (ROC; p&lt;0.0001) and MMP-2 below 0.0099 (ROC; p&lt;0.0001) were considered abnormal. SVD patients had reduced ABeta 1-42 compared to control CSF. P-Tau was unaffected. Abnormal values for K i and MMP-2 index were present in both large and small vessel disease patients. Conclusions: Our results show that SVD patients have significantly reduced levels of ABeta 1-42 in CSF, suggesting impairment in amyloid metabolism associated with vascular disease. These findings conform to the autopsy findings and suggest that multimodal biomarkers may provide information during life about the presence of both AD and VCI.

Matrix Metalloproteinases Are Associated With Increased Blood–Brain Barrier Opening in Vascular Cognitive Impairment

Subcortical ischemic vascular disease (SIVD) is a major form of vascular cognitive impairment (VCI) due to small vessel disease. Matrix metalloproteinases (MMPs) are neutral proteases that disrupt the blood-brain barrier and degrade myelin basic protein under conditions of neuroinflammation. Brain tissues and cerebrospinal fluid (CSF) of patients with VCI have increased levels of MMPs. We hypothesized that patients with SIVD have increased MMPs in the CSF, which are associated with increased CSF albumin. We studied 60 patients with suspected VCI. Twenty-five were classified as SIVD, whereas other groups included mixed Alzheimer disease and VCI, multiple strokes, and leukoaraiosis when white matter lesions were present and the diagnosis of VCI was uncertain. MMP-2 and MMP-9 in CSF and plasma were measured by gel zymography and indexed to CSF and plasma albumin. MMP-3 activity was measured by fluorescent assay. We found reduced MMP-2 index (P<0.001) in the CSF for the full group of patients (SIVD, multiple strokes, mixed Alzheimer disease and VCI, and leukoaraiosis) compared with control subjects, whose CSF was obtained during spinal anesthesia. MMP-3 activity was increased in VCI compared with control subjects (P<0.01). In SIVD, MMP-2 index showed a negative correlation with albumin index, which was absent with the MMP-9 index. Combining MMP-2 index and MMP-3 activity separated the patients with SIVD from the control subjects with high specificity (P<0.0005). Our results support the hypothesis that MMPs are associated with increased CSF albumin and suggest that they may contribute to the pathophysiology of SIVD.

Dementia and Stroke: The Present and Future Epidemic

Stroke and dementia are closely associated, whether in the form of vascular cognitive impairment or Alzheimer's disease. Alzheimer's disease and stroke share very similar risk factor profiles and may be prevented with similar modification programs. We are dealing with a present and future epidemic that will fundamentally affect health care provision in all high-income countries. At least 35 million people worldwide currently have dementia. Dementia prevalence is predicted to double every 20-years: an expected 66 million in 2030, 115 million in 2050. The burden of these diseases is considerable when taken with the annual 15 million people worldwide who will suffer stroke. There remains a disconnection between the nodes and modes of practice of stroke neurologists and cognitive physicians. As members of a broad medical community, we need to be aggressively managing vascular risk factors, as well as developing techniques to address the divide between the acute stroke patient of today and the dementia referral of tomorrow.

Inflammation and White Matter Damage in Vascular Cognitive Impairment

Vascular cognitive impairment is a term used to describe a heterogeneous group of diseases, including large vessel disease with strategic single and multiple strokes and small vessel disease with progressive damage to the deep white matter. Identification of patients with the progressive form of vascular cognitive impairment, referred to by some investigators as Binswanger disease, is important for treatment trials. Pathologically, Binswanger disease is associated with small vessel disease, extensive regions of demyelination, inflammatory cells around damaged blood vessels, and lacunar infarcts. Clinically, patients with Binswanger disease have impairments of gait and balance, focal neurological findings, and executive dysfunction on neuropsychological tests. White matter changes on MRI are thought to be due to hypoxic episodes related to hypoperfusion of the vulnerable deep white matter secondary to hypertension, diabetes, and other vessel diseases. Disruption of the blood-brain barrier suggests an inflammatory response. Matrix metalloproteinases are present in the brain of patients with vascular cognitive impairment and can be measured in the cerebrospinal fluid of some patients. Preliminary studies with quantification of the blood-brain barrier, using the multiple time graphical method (Patlak plots), supports disruption of the blood-brain barrier. Because no single clinical feature or diagnostic test is sufficient to identify patients with the small vessel form of vascular cognitive impairment, we propose that a multimodal approach will be needed to select patients for treatment trials.

Vascular dementia.

Vascular dementia (VaD) is a term used to describe a particular constellation of cognitive and functional impairment, and is now generally seen as a subset of the larger syndrome of vascular cognitive impairment (VCI). The latter is seen as cognitive impairment in the face of cerebrovascular disease. VCI can be classified clinically by whether patients meet criteria for dementia, and whether the syndrome is distinct or overlaps with primary neurodegenerative diseases, such as Alzheimer's disease. This clinical classification can be further classified by neuroimaging, with subgroups that show cortical infarction, subcortical infarction and white matter changes, each alone or in combination. Understood in this way, VCI is likely the most common form of cognitive impairment in the population. Attempts to treat VaD had varying degrees of success, but it now appears that many forms of VCI might be preventable, especially with good control of vascular risk factors in middle age.

Vascular Cognitive Impairment

Abstract: The term vascular cognitive impairment (VCI) is now employed to capture the spectrum of illness and disability arising from impaired cognitive function of vascular origin. As such, it supplants the more narrowly focussed terms “Vascular dementia (VaD)” and “multi‐infarct dementia”. It is meant to include both those whose cognitive impairment is different from that assumed by the usual criteria for dementia. Traditionally, dementia criteria have been modelled on AD, a disorder with more characteristic neuropathological and clinical disease expression than is seen in VaD, which can occur in many forms. VCI is common, and is associated with many adverse outcomes, including worse cognition, institutionalization, and death.One form of VCI is coincident AD and VaD, a category which, although it has been comparatively neglected, may be amongst the most common forms of dementia. Another common form of VCI has a predilection for subcortical ischemic lesions, and for a clinical presentation which reflects frontal and subcortical involvement.At present, there is no specific treatment for VCI, although several agents appear to offer the hope of both treatment and prevention. Further research on the clinical, pathological and mechanistic underpinnings of this important syndrome is needed. For a long time, VaD has been recognized as the second most common cause of dementia.1,2) More recently, however, the concept of cognitive impairment in relation to cerebrovascular disease has been expanded. This paper will review the notion of “vascular cognitive impairment” (VCI) as it relates to clinical practice, and to our understanding of disease mechanisms in dementia and related disorders. It will propose that while the expanded concept has merit, within it are to be found distinct subgroups, including some of particular importance as targets for clinical trials of therapeutic and even preventive interventions.

Prevalence and outcomes of vascular cognitive impairment. Vascular Cognitive Impairment Investigators of the Canadian Study of Health and Aging.

To assess the importance of vascular cognitive impairment and its three subgroups (cognitive impairment, no dementia; vascular dementia; and AD with a vascular component) to the prevalence and burden of cognitive impairment in elderly people. Vascular lesions may produce a spectrum of cognitive changes. Omitting elderly patients whose cognitive impairment falls short of dementia (vascular cognitive impairment, no dementia) may give a falsely low indication of the prevalence and burden of disease. To test this proposition, we compared the rates of adverse outcomes for patients with no cognitive impairment, vascular cognitive impairment (and its subgroups), and probable AD. The Canadian Study of Health and Aging is a prospective cohort study of 10,253 randomly selected community-dwelling and institution-dwelling respondents aged 65 years or older. In the community, all participants (n = 9,008) were screened for cognitive impairment; those who screened positive and a sample of those who screened negative received a clinical assessment (n = 1,659). All patients living in institutions received a clinical assessment (n = 1,255). Participants were reassessed 5 years after the original survey. Vascular cognitive impairment without dementia was the most prevalent form of vascular cognitive impairment among those aged 65 to 84 years. Rates of institutionalization and mortality for those with vascular cognitive impairment were significantly higher than those of people who had no cognitive impairment, and the mortality rate for patients with vascular cognitive impairment was similar to that of patients with AD. Failure to consider vascular cognitive impairment without dementia underestimates the prevalence of impairment and the risk for adverse outcomes associated with vascular cognitive impairment.