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<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.

Download Full-text

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

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.47 ◽

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.

Download Full-text

Deep microbleeds and periventricular white matter disintegrity are independent predictors of attention/executive dysfunction in non-dementia patients with small vessel disease

International Psychogeriatrics ◽

10.1017/s1041610216002118 ◽

2016 ◽

Vol 29 (5) ◽

pp. 793-803 ◽

Cited By ~ 4

Author(s):

Wen-wei Cao ◽

Yao Wang ◽

Quan Dong ◽

Xue Chen ◽

Yan-sheng Li ◽

...

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

Diffusion Tensor ◽

Small Vessel Disease ◽

Early Stage ◽

Mean Diffusivity ◽

Executive Dysfunction ◽

Small Vessel ◽

Periventricular White Matter ◽

Vessel Disease

ABSTRACTBackground:Cerebral small vessel disease (SVD) is the common cause of cognitive decline in the old population. MRI can be used to clarify its mechanisms. However, the surrogate markers of MRI for early cognitive impairment in SVD remain uncertain to date. We investigated the cognitive impacts of cerebral microbleeds (CMBs), diffusion tensor imaging (DTI), and brain volumetric measurements in a cohort of post-stroke non-dementia SVD patients.Methods:Fifty five non-dementia SVD patients were consecutively recruited and categorized into two groups as no cognitive impairment (NCI) (n = 23) or vascular mild cognitive impairment (VaMCI) (n = 32). Detailed neuropsychological assessment and multimodal MRI were completed.Results:The two groups differed significantly on Z scores of all cognitive domains (all p < 0.01) except for the language. There were more patients with hypertension (p = 0.038) or depression (p = 0.019) in the VaMCI than those in the NCI group. Multiple regression analysis of cognition showed periventricular mean diffusivity (MD) (β = −0.457, p < 0.01) and deep CMBs numbers (β = −0.352, p < 0.01) as the predictors of attention/executive function, which explained 45.2% of the total variance. Periventricular MD was the independent predictor for either memory (β = −0.314, p < 0.05) or visuo-spatial function (β = −0.375, p < 0.01); however, only small proportion of variance could be accounted for (9.8% and 12.4%, respectively). Language was not found to be correlated with any of the MRI parameters. No correlation was found between brain atrophic indices and any of the cognitive measures.Conclusion:Arteriosclerotic CMBs and periventricular white matter disintegrity seem to be independent MRI surrogated markers in the early stage of cognitive impairment in SVD.

Download Full-text

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

Frontiers in Neuroscience ◽

10.3389/fnins.2021.627627 ◽

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.

Download Full-text

Extracellular matrix inflammation in vascular cognitive impairment and dementia

Clinical Science ◽

10.1042/cs20160604 ◽

2017 ◽

Vol 131 (6) ◽

pp. 425-437 ◽

Cited By ~ 56

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.

Download Full-text

Vascular cognitive impairment in the mouse reshapes visual, spatial network functional connectivity

10.1101/2020.11.04.366294 ◽

2020 ◽

Author(s):

Gerard R Hall ◽

Philipp Boehm-Sturm ◽

Ulrich Dirnagl ◽

Carsten Finke ◽

Marco Foddis ◽

...

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

Small Vessel Disease ◽

Vascular Cognitive Impairment ◽

Network Activity ◽

Small Vessel ◽

Vessel Disease ◽

Visual Spatial ◽

Structural Connectome ◽

Global Efficiency

AbstractConnectome analysis of neuroimaging data is a rapidly expanding field to identify disease specific biomarkers. Structural diffusion MRI connectivity has been useful in individuals with radiological features of small vessel disease, such as white matter hyperintensities. Global efficiency, a network metric calculated from the structural connectome, is an excellent predictor of cognitive decline. To dissect the biological underpinning of these changes, animal models are required. We tested whether the structural connectome is altered in a mouse model of vascular cognitive impairment. White matter damage was more pronounced by 6 compared to 3 months. Global efficiency remained intact, but the visual association cortex exhibited increased structural connectivity with other brain regions. Exploratory resting state functional MRI connectivity analysis revealed diminished default mode network activity in the model compared to shams. Further perturbations were observed in a primarily cortical hub and the retrosplenial and visual cortices, and the hippocampus were the most affected nodes. Behavioural deficits were observed in the cued water maze, supporting the suggestion that the visual and spatial memory networks are affected. We demonstrate specific circuitry is rendered vulnerable to vascular stress in the mouse, and the model will be useful to examine pathophysiological mechanisms of small vessel disease.Graphical abstract

Download Full-text

Executive dysfunction and blockage of brain microvessels in a rat model of vascular cognitive impairment

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17739219 ◽

2017 ◽

Vol 38 (10) ◽

pp. 1727-1740 ◽

Cited By ~ 4

Author(s):

Kristopher D Langdon ◽

Chris A Cordova ◽

Shirley Granter-Button ◽

Jamie D Boyd ◽

James Peeling ◽

...

Keyword(s):

Cognitive Impairment ◽

Small Vessel Disease ◽

Control Diet ◽

Executive Dysfunction ◽

Vascular Cognitive Impairment ◽

Small Vessel ◽

Middle Aged ◽

Vessel Disease ◽

Brain Microvessels ◽

Bilateral Carotid

Most research focuses on overt stroke caused by blockage of major blood vessels. Less attention has been paid to small vessel disease which gives 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. Herein, we 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 were fed HFSS and subjected to a small mediodorsal (MD) thalamic stroke with or without concomitant permanent bilateral carotid artery occlusion. MD lesions produce significant executive dysfunction in an attention set-shift task ( p = 0.012). In Experiment 2, rats were exposed to either HFSS or control diet and functional effects assessed. We found significant hypertension ( p = 0.013), blockage of brain microvessels ( p = 0.018) and white matter atrophy ( p = 0.039) in HFSS diet animals. As in Experiment 1, profound, specific set-shifting executive dysfunction was noted ( p = 0.003) 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.

Download Full-text

Biomarkers identify the Binswanger type of vascular cognitive impairment

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x18762655 ◽

2018 ◽

Vol 39 (8) ◽

pp. 1602-1612 ◽

Cited By ~ 7

Author(s):

Erik Barry Erhardt ◽

John C Pesko ◽

Jillian Prestopnik ◽

Jeffrey Thompson ◽

Arvind Caprihan ◽

...

Keyword(s):

Cognitive Impairment ◽

Magnetic Resonance ◽

Vascular Disease ◽

Neuropsychological Testing ◽

Vascular Cognitive Impairment ◽

Matrix Metalloproteinase 2 ◽

Resonance Spectroscopy ◽

Classification Methods ◽

Csf Analysis

Binswanger’s disease is a form of subcortical ischemic vascular disease (SIVD-BD) with extensive white matter changes. To test the hypothesis that biomarkers could improve classification of SIVD-BD, we recruited 62 vascular cognitive impairment and dementia (VCID) patients. Multimodal biomarkers were collected at entry into the study based on clinical and neuropsychological testing, multimodal magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. The patients’ diagnoses were confirmed by long-term follow-up, and they formed a “training set” to test classification methods, including (1) subcortical ischemic vascular disease score (SIVDS), (2) exploratory factor analysis (EFA), (3) logistic regression (LR), and (4) random forest (RF). A subsequently recruited cohort of 43 VCID patients with provisional diagnoses were used as a “test” set to calculate the probability of SIVD-BD based on biomarkers obtained at entry. We found that N-acetylaspartate (NAA) on proton magnetic resonance spectroscopy (1H-MRS) was the best variable for classification, followed by matrix metalloproteinase-2 in CSF and blood–brain barrier permeability on MRI. Both LR and RF performed better in diagnosing SIVD-BD than either EFA or SIVDS. Two-year follow-up of provisional diagnosis patients confirmed the accuracy of statistically derived classifications. We propose that biomarker-based classification methods could diagnose SIVD-BD patients earlier, facilitating clinical trials.

Download Full-text