Extracellular matrix inflammation in vascular cognitive impairment and dementia

2017 ◽  
Vol 131 (6) ◽  
pp. 425-437 ◽  
Author(s):  
Gary A. Rosenberg
Keyword(s):  
Extracellular Matrix ◽  
Cognitive Impairment ◽  
Blood Vessel ◽  
Vascular Disease ◽  
Small Vessel Disease ◽  
Wide Spectrum ◽  
Neurovascular Unit ◽  
Vascular Cognitive Impairment ◽  
Small Vessel ◽  
Chronic Hypertension

Vascular cognitive impairment and dementia (VCID) include a wide spectrum of chronic manifestations of vascular disease related to large vessel strokes and small vessel disease (SVD). Lacunar strokes and white matter (WM) injury are consequences of SVD. The main vascular risk factor for SVD is brain hypoperfusion from cerebral blood vessel narrowing due to chronic hypertension. The hypoperfusion leads to activation and degeneration of astrocytes with the resulting fibrosis of the extracellular matrix (ECM). Elasticity is lost in fibrotic cerebral vessels, reducing the response of stiffened blood vessels in times of increased metabolic need. Intermittent hypoxia/ischaemia activates a molecular injury cascade, producing an incomplete infarction that is most damaging to the deep WM, which is a watershed region for cerebral blood flow. Neuroinflammation caused by hypoxia activates microglia/macrophages to release proteases and free radicals that perpetuate the damage over time to molecules in the ECM and the neurovascular unit (NVU). Matrix metalloproteinases (MMPs) secreted in an attempt to remodel the blood vessel wall have the undesired consequences of opening the blood–brain barrier (BBB) and attacking myelinated fibres. This dual effect of the MMPs causes vasogenic oedema in WM and vascular demyelination, which are the hallmarks of the subcortical ischaemic vascular disease (SIVD), which is the SVD form of VCID also called Binswanger's disease (BD). Unravelling the complex pathophysiology of the WM injury-related inflammation in the small vessel form of VCID could lead to novel therapeutic strategies to reduce damage to the ECM, preventing the progressive damage to the WM.

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

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Gary A Rosenberg ◽  
Jillian Prestopnik ◽  
Jeffrey Thompson ◽  
Charles Gasparovic ◽  
Branko N Huisa-Garate ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Vascular Disease ◽  
Small Vessel Disease ◽  
Executive Dysfunction ◽  
Vascular Cognitive Impairment ◽  
Small Vessel ◽  
Matrix Metalloproteinase 2 ◽  
Resonance Spectroscopy ◽  
Mri Findings

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<0.0001). K i transfer constants above 0.0018 (ROC; p<0.0001) and MMP-2 below 0.0099 (ROC; p<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.

scholarly journals Vascular cognitive impairment in small vessel disease: clinical and neuropsychological features of lacunar state and Binswanger's disease

2011 ◽  
Vol 40 (2) ◽  
pp. 175-180 ◽  
Author(s):  
C. Ramos-Estebanez ◽  
I. Moral-Arce ◽  
A. Gonzalez-Mandly ◽  
V. Dhagubatti ◽  
J. Gonzalez-Macias ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Small Vessel Disease ◽  
Vascular Cognitive Impairment ◽  
Small Vessel ◽  
Vessel Disease ◽  
Binswanger’S Disease ◽  
Binswanger's Disease

scholarly journals Executive dysfunction and altered cerebrovascular activity in a rodent model of vascular cognitive impairment

2018 ◽  
Vol 45 (S1) ◽  
pp. S4-S5
Author(s):  
K.D. Langdon ◽  
C. Cordova ◽  
S. Granter-Button ◽  
J. Boyd ◽  
J. Peeling ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Small Vessel Disease ◽  
Executive Dysfunction ◽  
Vascular Cognitive Impairment ◽  
Cerebral Hypoperfusion ◽  
Small Vessel ◽  
Sprague Dawley ◽  
Middle Aged ◽  
Metabolic Disturbances ◽  
Vessel Disease

Most basic science research has focused on overt stroke caused by blockage of major blood vessels. Less attention has been paid to small vessel disease giving rise to covert stroke that often leads to vascular cognitive impairment (VCI). One reason for this may be the relative lack of relevant animal models. This talk will describe a model of VCI induced in middle-aged Sprague-Dawley rats exposed to a diet high in saturated fats, salt and refined sugar (HFSS). In Experiment 1, rats fed HFSS and subjected to a small mediodorsal (MD) thalamic stroke with or without concomitant cerebral hypoperfusion experienced significant executive dysfunction. In Experiment 2, dietary influences on functional, physiological and anatomical parameters were assessed. We found significant hypertension, blockage of brain microvessels (2-photon microscopy) and white matter atrophy in HFSS diet animals. As in Experiment 1, profound, specific set-shifting executive dysfunction was noted following both small MD infarcts (0.332 mm3) and the HFSS diet. In summary, these data describe a middle-aged animal model of VCI that includes clinically-relevant metabolic disturbances and small vessel disease and as such may be helpful in developing new cognitive therapies.

scholarly journals Evaluating vascular cognitive impairment and dementia due to small‐vessel disease using plasma levels of PLGF and VEGF‐A

2020 ◽  
Vol 16 (S5) ◽  
Author(s):  
Zachary Winder ◽  
Tiffany Lee ◽  
David W Fardo ◽  
Qiang Cheng ◽  
Larry Goldstein ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Plasma Levels ◽  
Small Vessel Disease ◽  
Vascular Cognitive Impairment ◽  
Small Vessel ◽  
Vessel Disease

scholarly journals Blood and CSF biomarkers in brain subcortical ischemic vascular disease: Involved pathways and clinical applicability

2015 ◽  
Vol 36 (1) ◽  
pp. 55-71 ◽  
Author(s):  
A Vilar-Bergua ◽  
I Riba-Llena ◽  
C Nafría ◽  
A Bustamante ◽  
V Llombart ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Vascular Disease ◽  
Large Scale ◽  
Small Vessel Disease ◽  
Large Population ◽  
Vascular Cognitive Impairment ◽  
Population Based ◽  
Endothelial Damage ◽  
Csf Biomarkers ◽  
Lacunar Infarcts

Vascular dementia is the second most common type of dementia after Alzheimer’s disease (AD). Subcortical ischemic vascular disease refers to a form of vascular cognitive impairment characterized by the presence of diffuse white matter hyperintensities (WMHs) and multiple lacunar infarcts. These neuroimaging findings are mainly caused by cerebral small-vessel disease (cSVD) and relate to aging and cognitive impairment, but they can also be silent and highly prevalent in otherwise healthy individuals. We aimed to review studies on blood and cerebrospinal fluid (CSF) markers related to the presence of WMHs and lacunar infarcts that have been conducted in the past in large population-based studies and in high-risk selected patients (such as those with vascular risk factors, vascular cognitive impairment, or AD). Relevant associations with the presence and progression of cSVD have been described in the blood for markers related to inflammatory processes, endothelial damage and coagulation/fibrinolysis processes, etc. Also, different combinations of CSF markers might help to differentiate between etiologic types of dementia. In the future, to translate these findings into clinical practice and use biomarkers to early diagnosis and monitoring vascular cognitive impairment would require the replication of candidate markers in large-scale, multicenter, and prospectively designed studies.

scholarly journals Evaluation of Cerebral Blood Flow Measured by 3D PCASL as Biomarker of Vascular Cognitive Impairment and Dementia (VCID) in a Cohort of Elderly Latinx Subjects at Risk of Small Vessel Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Kay Jann ◽  
Xingfeng Shao ◽  
Samantha J. Ma ◽  
Steven Y. Cen ◽  
Lina D’Orazio ◽  
...  
Keyword(s):  
At Risk ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cognitive Impairment ◽  
White Matter ◽  
Small Vessel Disease ◽  
Vascular Cognitive Impairment ◽  
Small Vessel ◽  
Vessel Disease ◽  
Brain White Matter

Cerebral small vessel disease (cSVD) affects arterioles, capillaries, and venules and can lead to cognitive impairments and clinical symptomatology of vascular cognitive impairment and dementia (VCID). VCID symptoms are similar to Alzheimer’s disease (AD) but the neurophysiologic alterations are less well studied, resulting in no established biomarkers. The purpose of this study was to evaluate cerebral blood flow (CBF) measured by 3D pseudo-continuous arterial spin labeling (pCASL) as a potential biomarker of VCID in a cohort of elderly Latinx subjects at risk of cSVD. Forty-five elderly Latinx subjects (12 males, 69 ± 7 years) underwent repeated MRI scans ∼6 weeks apart. CBF was measured using 3D pCASL in the whole brain, white matter and 4 main vascular territories (leptomeningeal anterior, middle, and posterior cerebral artery (leptoACA, leptoMCA, leptoPCA), as well as MCA perforator). The test-retest repeatability of CBF was assessed by intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). Absolute and relative CBF was correlated with gross cognitive measures and domain specific assessment of executive and memory function, vascular risks, and Fazekas scores and volumes of white matter hyperintensity (WMH). Neurocognitive evaluations were performed using Montreal Cognitive Assessment (MoCA) and neuropsychological test battery in the Uniform Data Set v3 (UDS3). Good to excellent test-retest repeatability was achieved (ICC = 0.77–0.85, wsCV 3–9%) for CBF measurements in the whole brain, white matter, and 4 vascular territories. Relative CBF normalized by global mean CBF in the leptoMCA territory was positively correlated with the executive function composite score, while relative CBF in the leptoMCA and MCA perforator territory was positively correlated with MoCA scores, controlling for age, gender, years of education, and testing language. Relative CBF in WM was negatively correlated with WMH volume and MoCA scores, while relative leptoMCA CBF was positively correlated with WMH volume. Reliable 3D pCASL CBF measurements were achieved in the cohort of elderly Latinx subjects. Relative CBF in the leptomeningeal and perforator MCA territories were the most likely candidate biomarker of VCID. These findings need to be replicated in larger cohorts with greater variability of stages of cSVD.

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