Special Issue "Vascular Cognitive Impairment and Dementia Focused on Subcortical Small Vessel Disease"

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Clinical Neuroscience".

Deadline for manuscript submissions: 30 November 2019.

Special Issue Editors

Guest Editor
Prof. Dr. Anders Wallin Website E-Mail
Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Interests: the challenge of cognitive medicine; observational studies in patients seeking help for memory complaints, Alzheimer’s disease; vascular cognitive impairment; cerebral small vessel disease; white matter changes, cerebrospinal fluid markers; magnetic resonance imaging; assessment of cognitive impairment
Guest Editor
Prof. Dr. Gustavo C. Roman Website E-Mail
Methodist Neurological Institute, Houston, TX, USA
Interests: Neurology; Neuroepidemiology; Alzheimer disease; Vascular Dementia; Sleep disorders; Normal-pressure Hydrocephalus; Tropical neurology

Special Issue Information

Dear Colleagues,

The most important research advance in the field of vascular cognitive impairment and dementia in the last decade has been the scientific demonstration that age-related white matter involvement is a sign of subcortical small-vessel disease (SSVD) that leads to cognitive failure and impaired functional capacity. The advances comprise increased knowledge of the symptom profile of the disorder, the relationship between white matter involvement and reduced cerebral blood flow using MRI, the deviations of cerebrospinal fluid markers reflecting subcortical degeneration, inflammation and extracellular matrix breakdown, the potential importance of deep vein collagenosis, the clinical and pathological criteria, and the associations between SSVD and normal pressure hydrocephalus. Although several of the new findings need to be tested in new studies, they already now imply that focusing on SSVD using various approaches is a promising way of addressing the great challenge of preventing and treating age-related cognitive impairment. Future studies investigating the relationships between sporadic SSVD and genetic factors are needed as well as research on various mechanisms of causation. The intriguing issues of the relationship between SSVD and Alzheimer’s disease (AD) on one hand and stroke on the other need also to be clarified. These goals aim primarily at finding targets for intervention in patients with SSVD early in the course of the disease but may also have positive consequences for the treatment of AD and stroke.

The upcoming issue will highlight the most recent advances in clinical presentation, diagnostic markers, pathogenetic pathways, co-morbid conditions and therapeutic options of SSVD.

Prof. Dr. Anders Wallin
Prof. Dr. Gustavo C. Roman
Guest Editors

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Keywords

  • cerebral small vessel disease
  • age-related white matter changes
  • cognitive impairment
  • disability
  • clinical trials

Published Papers (8 papers)

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Research

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Open AccessArticle
Cerebral Vascular Reactivity in Frail Older Adults with Vascular Cognitive Impairment
Brain Sci. 2019, 9(9), 214; https://doi.org/10.3390/brainsci9090214 - 24 Aug 2019
Abstract
Background: Frailty, a state of increased vulnerability, could play a role in the progression of vascular dementia. We aim to describe the changes in cerebrovascular reactivity of older adults with frailty and vascular-type mild cognitive impairment (MCIv). Methods: This was a [...] Read more.
Background: Frailty, a state of increased vulnerability, could play a role in the progression of vascular dementia. We aim to describe the changes in cerebrovascular reactivity of older adults with frailty and vascular-type mild cognitive impairment (MCIv). Methods: This was a cross-sectional study. A comprehensive geriatric assessment, neuropsychological evaluation, and transcranial Doppler ultrasound (TCD) was performed on 180 participants who were allocated into four groups: healthy (n = 74), frail (n = 40), MCIv (n = 35), and mixed (frail + MCIv) (n = 31). ANOVA and Kruskal–Wallis tests were used for the analysis of continuous variables with and without normal distribution. Multinomial logistic regression was constructed to identify associated covariates. Results: Subjects in the mixed group, compared to healthy group, were older (75.0 ± 5.9 vs 70.3 ± 5.9 years; p < 0.001), showed lower education (9.3 ± 6.4 vs 12.2 ± 4.0 years; p = 0.054), greater frequency of diabetes (42% vs 12%; p = 0.005), worse cognitive performance (z = −0.81 ± 0.94), and reduced left medial-cerebral artery cerebrovascular reactivity (0.43 ± 0.42 cm/s). The mixed group was associated with age (odds ratio (OR) 1.16, 95% Confidence Interval (CI) = 1.06–1.27; p < 0.001), diabetes (OR 6.28, 1.81–21.84; p = 0.004), and Geriatric Depression Scale (GDS) score (OR 1.34, 95% CI = 1.09–1.67; p = 0.007). Conclusions: Frailty among older adults was associated with worse cognitive performance, diabetes, and decreased cerebral blood flow. Full article
Open AccessArticle
A Multimodal Approach to Stratification of Patients with Dementia: Selection of Mixed Dementia Patients Prior to Autopsy
Brain Sci. 2019, 9(8), 187; https://doi.org/10.3390/brainsci9080187 - 01 Aug 2019
Abstract
Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID) are major causes of dementia, and when combined lead to accelerated cognitive loss. We hypothesized that biomarkers of neurodegeneration and neuroinflammation could be used to stratify patients into diagnostic groups. Diagnosis of AD [...] Read more.
Alzheimer’s disease (AD) and vascular cognitive impairment and dementia (VCID) are major causes of dementia, and when combined lead to accelerated cognitive loss. We hypothesized that biomarkers of neurodegeneration and neuroinflammation could be used to stratify patients into diagnostic groups. Diagnosis of AD can be made biologically with detection of amyloid and tau proteins in the cerebrospinal fluid (CSF) and vascular disease can be identified with diffusion tensor imaging (DTI). We recruited patients with cognitive complaints and made an initial clinical diagnosis. After one year of follow-up we made a biological diagnosis based on the use of biomarkers obtained from DTI, CSF AD, and inflammatory proteins, and neuropsychological testing. Patients with AD had primarily findings of neurodegeneration (CSF showing increased tau and reduced amyloid), while patients with neuroinflammation had abnormal DTI mean diffusion (MD) in the white matter. Using the biological biomarkers resulted in many of the clinically diagnosed AD patients moving into mixed dementia (MX). Biomarkers of inflammation tended to be higher in the MX than in either the AD or VCID, suggesting dual pathology leads to increased inflammation, which could explain accelerated cognitive decline in that group. Full article
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Open AccessArticle
Stability of Estimated Premorbid Cognitive Ability over Time after Minor Stroke and Its Relationship with Post-Stroke Cognitive Ability
Brain Sci. 2019, 9(5), 117; https://doi.org/10.3390/brainsci9050117 - 22 May 2019
Abstract
Considering premorbid or “peak” adult intelligence (IQ) is important when examining post-stroke cognition. The stability of estimated premorbid IQ and its relationship to current cognitive ability in stroke is unknown. We investigated changes in estimated premorbid IQ and current cognitive ability up to [...] Read more.
Considering premorbid or “peak” adult intelligence (IQ) is important when examining post-stroke cognition. The stability of estimated premorbid IQ and its relationship to current cognitive ability in stroke is unknown. We investigated changes in estimated premorbid IQ and current cognitive ability up to three years post-stroke. Minor stroke patients (NIHSS < 8) were assessed at one to three months, one and three years’ post-stroke. The National Adult Reading Test (NART) and Addenbrooke’s Cognitive Examination-Revised (ACE-R) were used to estimate premorbid IQ (NART IQ) and current cognitive ability respectively at each time-point. Baseline demographics, vascular and stroke characteristics were included. Of the 264 patients recruited (mean age 66), 158 (60%), 151 (57%), and 153 (58%) completed cognitive testing at each time-point respectively. NART IQ initially increased (mean difference (MD) = 1.32, 95% CI = 0.54 to 2.13, p < 0.001) before decreasing (MD = −4.269, 95% CI = −5.12 to −3.41, p < 0.001). ACE-R scores initially remained stable (MD = 0.29, 95% CI = −0.49 to 1.07, p > 0.05) before decreasing (MD = −1.05, 95% CI = −2.08 to −0.01, p < 0.05). Adjusting for baseline variables did not change the relationship between NART IQ and ACE-R with time. Increases in NART IQ were associated with more education. For ACE-R, older age was associated with declines, and higher NART IQ and more education was associated with increases. Across 3 years, we observed fluctuations in estimated premorbid IQ and minor changes in current cognitive ability. Future research should aim to identify variables associated with these changes. However, studies of post-stroke cognition should account for premorbid IQ. Full article
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Review

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Open AccessReview
Blood Pressure Gradients in the Brain: Their Importance to Understanding Pathogenesis of Cerebral Small Vessel Disease
Brain Sci. 2019, 9(2), 21; https://doi.org/10.3390/brainsci9020021 - 23 Jan 2019
Cited by 2
Abstract
The term “lacunar infarction” referred to small infarctions in the basal ganglia, internal capsule, thalamus, and brainstem, due to hypertensive small vessel disease. However, it has become common to refer to all small infarctions as lacunar. It is important to understand that true [...] Read more.
The term “lacunar infarction” referred to small infarctions in the basal ganglia, internal capsule, thalamus, and brainstem, due to hypertensive small vessel disease. However, it has become common to refer to all small infarctions as lacunar. It is important to understand that true lacunes occur in a phylogenetically ancient part of the brain, the “vascular centrencephalon”, where short straight arteries with few branches transmit high blood pressure straight through to end-arterioles. The cortex is supplied by long arteries with many branches, so there is a very large blood pressure gradient in the brain. When blood pressure in the brachial artery is 117/75 mmHg, the pressure in the lenticulostriate artery would be 113/73, and the pressure in small parietal arterioles would be only 59/38 mmHg. Recent studies have reported that patients with a pulse pressure >60 mmHg and diastolic pressure <60 mmHg have a doubling of coronary risk and a 5.85-fold increase in stroke risk. This means that new low systolic targets being proposed will probably decrease the incidence of true lacunes, but increase small subcortical infarctions in the hemispheres. The pathogenesis of small vessel disease should be interpreted in the light of these blood pressure gradients. Full article
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Other

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Open AccessPerspective
MTHFR Gene Mutations Correlate with White Matter Disease Burden and Predict Cerebrovascular Disease and Dementia
Brain Sci. 2019, 9(9), 211; https://doi.org/10.3390/brainsci9090211 - 22 Aug 2019
Abstract
The incidence of dementia is on the rise and expected to continue to increase in the foreseeable future. Two of the most common subtypes of dementia are Alzheimer’s subtype and vascular dementia. Hyperhomocysteinemia has been shown to serve as a risk factor for [...] Read more.
The incidence of dementia is on the rise and expected to continue to increase in the foreseeable future. Two of the most common subtypes of dementia are Alzheimer’s subtype and vascular dementia. Hyperhomocysteinemia has been shown to serve as a risk factor for dementia due to an associated blood–brain barrier dysfunction and subsequent small-vessel disease pathology. There are varying causes for hyperhomocysteinemia, including genetic and dietary, among others. We highlight the importance of identifying hyperhomocysteinemia as a potential etiologic and therapeutic target for the most common subtypes of dementia. Full article
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Open AccessPerspective
Brain White Matter: A Substrate for Resilience and a Substance for Subcortical Small Vessel Disease
Brain Sci. 2019, 9(8), 193; https://doi.org/10.3390/brainsci9080193 - 08 Aug 2019
Abstract
Age-related brain white matter disease is a form of small vessel disease (SVD) that may be associated with lacunar and other small subcortical infarcts, cerebral microbleeds, and perivascular spaces. This common form of cerebrovascular disease may manifest clinically as cognitive impairment of varying [...] Read more.
Age-related brain white matter disease is a form of small vessel disease (SVD) that may be associated with lacunar and other small subcortical infarcts, cerebral microbleeds, and perivascular spaces. This common form of cerebrovascular disease may manifest clinically as cognitive impairment of varying degrees and difficulty with mobility. Whereas some persons show cognitive decline and mobility failure when there are brain white matter hyperintensities (WMH) and acute stroke, others recover, and not everyone with brain white matter disease is disabled. Thus, repair or compensation of brain white matter may be possible, and furthermore, certain vascular risks, such as raised blood pressure, are targets for prevention of white matter disease or are administered to reduce the burden of such disease. Vascular risk modification may be useful, but alone may not be sufficient to prevent white matter disease progression. In this chapter, we specifically focus on WMH of vascular origin and explore white matter development, plasticity, and enduring processes of myelination across the health span in the context of experimental and human data, and compare and contrast resilient brain white matter propensity to a diseased white matter state. We conclude with thoughts on novel ways one might study white matter resilience, and predict future healthy cognitive and functional outcomes. Full article
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Open AccessCase Report
Mixed Small Vessel Disease in a Patient with Dementia with Lewy Bodies
Brain Sci. 2019, 9(7), 159; https://doi.org/10.3390/brainsci9070159 - 04 Jul 2019
Abstract
Background: Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid in small/medium size brain vessels, and may coexist with Alzheimer’s disease or dementia with Lewy bodies (DLB). We describe a patient with a clinical diagnosis of DLB and imaging/biochemical characteristics suggestive of [...] Read more.
Background: Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid in small/medium size brain vessels, and may coexist with Alzheimer’s disease or dementia with Lewy bodies (DLB). We describe a patient with a clinical diagnosis of DLB and imaging/biochemical characteristics suggestive of mixed small vessel disease (both CAA and non-amyloid microangiopathy). Methods: Clinical evaluation according to recent diagnostic criteria, magnetic resonance imaging, dopamine-transporter scan (DAT-scan) and cerebrospinal fluid (CSF) analysis for dementia biomarkers were all performed. Results: The patient is a 71-year-old male, fulfilling criteria for probable DLB, with a positive DAT-scan, but with multiple microbleeds in a cortical-subcortical location suggestive of CAA, some microbleeds in deep brain nuclei suggestive of non-amyloid microangiopathy and abnormal levels of only amyloid-beta (Aβ42) in CSF. Conclusion: Coexistent mixed vascular and neurodegenerative disorders are frequent in older subjects with dementia and each one of the underlying pathologies may contribute to, or modify the clinical presentation. Full article
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Open AccessCase Report
Sustained Opening of the Blood-Brain Barrier with Progressive Accumulation of White Matter Hyperintensities Following Ischemic Stroke
Brain Sci. 2019, 9(1), 16; https://doi.org/10.3390/brainsci9010016 - 21 Jan 2019
Abstract
Objective: To report a patient in whom an acute ischemic stroke precipitated chronic blood-brain barrier (BBB) disruption and expansion of vascular white matter hyperintensities (WMH) into regions of normal appearing white matter (NAWM) during the following year. Background: WMH are a common finding [...] Read more.
Objective: To report a patient in whom an acute ischemic stroke precipitated chronic blood-brain barrier (BBB) disruption and expansion of vascular white matter hyperintensities (WMH) into regions of normal appearing white matter (NAWM) during the following year. Background: WMH are a common finding in patients with vascular risk factors such as a history of stroke. The pathophysiology of WMH is not fully understood; however, there is growing evidence to suggest that the development of WMH may be preceded by the BBB disruption in the NAWM. Methods: We studied a patient enrolled in the National Institutes of Health Natural History of Stroke Study who was scanned with magnetic resonance imaging (MRI) after presenting to the emergency room with an acute stroke. After a treatment with IV tPA, she underwent further MRI scanning at 2 h, 24 h, 5 days, 30 days, 90 days, 6 months, and 1-year post stroke. BBB permeability images were generated from the perfusion weighted imaging (PWI) source images. MRIs from each time point were co-registered to track changes in BBB disruption and WMH over time. Results: An 84-year-old woman presented after acute onset right hemiparesis, right-sided numbness and aphasia with an initial NIHSS of 13. MRI showed diffusion restriction in the left frontal lobe and decreased blood flow on perfusion imaging. Fluid attenuated inversion recovery (FLAIR) imaging showed bilateral confluent WMH involving the deep white matter and periventricular regions. She was treated with IV tPA without complication and her NIHSS improved initially to 3 and ultimately to 0. Permeability maps identified multiple regions of chronic BBB disruption remote from the acute stroke, predominantly spanning the junction of WMH and NAWM. The severity of BBB disruption was greatest at 24 h after the stroke but persisted on subsequent MRI scans. Progression of WMH into NAWM over the year of observation was detected bilaterally but was most dramatic in the regions adjacent to the initial stroke. Conclusions: WMH-associated BBB disruption may be exacerbated by an acute stroke, even in the contralateral hemisphere, and can persist for months after the initial event. Transformation of NAWM to WMH may be evident in areas of BBB disruption within a year after the stroke. Further studies are needed to investigate the relationship between chronic BBB disruption and progressive WMH in patients with a history of cerebrovascular disease and the potential for acute stroke to trigger or exacerbate the process leading to the development of WMH. Full article
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