Abstract P52: Temporal Progression of Cerebral Small Vessel Disease Lesions on Brain Magnetic Resonance Imaging in Spontaneously Hypertensive Stroke Prone Rats

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Yousef Hannawi ◽  
Kimerly A Powell ◽  
Anna Bratasz ◽  
Mohamed G Ewees ◽  
Jay L Zweier
Keyword(s):  
Small Vessel Disease ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Volumetric Analysis ◽  
Cerebral Small Vessel Disease ◽  
Male Rats ◽  
Small Vessel ◽  
Spontaneously Hypertensive ◽  
Vessel Disease ◽  
Hemosiderin Deposition

Introduction: Spontaneously Hypertensive Rats- Stroke Prone (SHRSP) are a relevant model for human cerebral small vessel disease (cSVD). However, data are still lacking regarding the neuroimaging correlates of cSVD lesions in SHRSP and their temporal evolution in relationship to histological findings. Methods: 40 SHRSP and 40 Wistar Kyoto control (WKY) male rats were divided into 4 groups (10 WKY and 10 SHRSP) per group. Systolic blood pressure (SBP) was measured using tail-cuff device, weekly. Select animals of each group had brain MRI at 9.4T machine at 7, 16, 24, and 32 weeks of age. Volumetric analysis was completed using manual segmentation of the total brain, ventricles and bilateral hippocampi. Following MRI, brain histology was completed at the same time points. Results: At 6 weeks, SBP was similar (WKY 123.8±0.1 vs SHRSP 130.7±3.2, P=0.09). SHRSP developed hypertension between 9-11 weeks of age and maintained it throughout the experiment (SBP at 31 weeks: WKY 138.1±6 vs SHRSP 169.1±6.7, p=0.0006). At 7 weeks, brain MRI was normal in SHRSP and WKY. Histology was largely unremarkable except for few areas of red blood cell extravasation in couple of SHRSP. At 16 weeks, MRI was normal in WKY and it showed small subcortical hyperintensity on T2 sequences in one SHRSP while histology showed microbleeds (MBs) in 85% of SHRSP. At 24 weeks, brain MRI consistently identified subcortical hyperintensities in SHRSP and H&E showed MBs in all SHRSP in addition to hemosiderin deposition and arteriosclerosis. LFB staining showed areas of demyelination in the corpus callosum. At 32 weeks, SHRSP had hydrocephalus and H&E showed widespread hemosiderin deposition. Volumetric analysis showed larger ventricles in SHRSP (SHRSP 42.3±18.1 ml vs WKY 28.4±7.2 ml, p=0.013) and ventricle size significantly increased with age in SHRSP. Hippocampal and brain volumes were similar in both groups (hippocampal volume: WKY 84.5±8.1 ml vs SHRSP 81.6±2.6 ml, p=0.39; brain volume WKY 2103.4±100.4 ml vs SHRSP 2169.6 ±164.2 ml, p=0.2). Conclusions: SHRSP develop cSVD histological changes early in life and brain MRI showed consistent abnormalities at a later time point. These results have implications in defining cSVD phenotypes in SHRSP in future mechanistic studies.

Abstract 40: Time Course of Cerebral Small Vessel Disease Lesions and Sensory Motor Changes in Spontaneously Hypertensive Stroke Prone Rats

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Eder Caceres ◽  
Cameron Rink ◽  
Jay L Zweier ◽  
Yousef Hannawi
Keyword(s):  
Time Course ◽  
Small Vessel Disease ◽  
Brain Mri ◽  
Cerebral Small Vessel Disease ◽  
Male Rats ◽  
Small Vessel ◽  
Therapeutic Drug ◽  
Time Points ◽  
Vessel Disease ◽  
Average Group

Introduction: Animal models of human cerebral small vessel disease (CSVD) are important for the study of the disease underlying mechanisms and testing therapeutic interventions. Spontaneusly Hypertensive Rats - Stroke Prone (SHRSP) are used as an animal model of human CSVD. However, there is a lack of data regarding the time course of cognitive and motor impairment. Methods: Male age-matched SHRSP and Wistar Kyoto rats (WKY) were studied. Sensorimotor testing (open field test) and tail-cuff systolic blood pressure (SBP) measurements (Visitech Systems, Inc.) were performed weekly starting from 6 until 24 weeks of age. Brain MRI at 7 and 24 weeks was acquired using a 9.4T MRI system. Brain histology was completed at the same time points. Statistical analysis was performed using a linear mixed model with repeated measurements. P< 0.05 was considered significant. Results: 20 SHRSP and 20 WKY male rats were studied. 10 per group were euthanized following brain MRI at 7 weeks and the rest were followed until 24 weeks. SHRSP weighed on average 30 grams less than WKY throughout the study (P=0.0003). At 7 weeks SBP was not different (WKY 106.6±5.4 vs SHRSP 120.8±5.4, P=0.06). SHRSP started to develop hypertension at 9-12 weeks and maintained hypertension until 24 weeks (average group difference across time P<0.0001; SBP at 21 weeks WKY 134.8±5.4 vs SHRSP 168.9±5.4, P<0.0001). Sensorimotor testing showed higher total distance travelled (TDT) at 7 weeks in SHRSP that trended down with ageing. Both groups became similar at 21 weeks (TDT: at 7 weeks WKY 3.78±1.3 vs SHRSP 7.8±1.3, P =0.037; at 21 weeks: WKY 4±1.3 vs SHRSP 4.4±1.3, P=0.83; average group difference across time P=0.014). Brain MRI was normal at 7 weeks, but small white matter hyperintensities were seen at 24 weeks. Brain Histology showed normal histology on hematoxylin & eosin staining at 7 weeks in both groups, while at 24 weeks SHRSP showed CSVD histopathological changes including microbleed formation, homeostasis and vascular hyalinosis. Conclusions: SHRSP develops hypertension, sensorimotor deficits and CSVD pathology as they age suggesting their utility as human CSVD model. Intervention time points should be selected carefully in future therapeutic drug interventions.

scholarly journals Characterizing the Neuroimaging and Histopathological Correlates of Cerebral Small Vessel Disease in Spontaneously Hypertensive Stroke-Prone Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Yousef Hannawi ◽  
Eder Caceres ◽  
Mohamed G. Ewees ◽  
Kimerly A. Powell ◽  
Anna Bratasz ◽  
...  
Keyword(s):  
Diffusion Tensor ◽  
Small Vessel Disease ◽  
Brain Mri ◽  
Mean Diffusivity ◽  
Cerebral Small Vessel Disease ◽  
Study Time ◽  
Small Vessel ◽  
Perivascular Spaces ◽  
Spontaneously Hypertensive ◽  
Vessel Disease

Introduction: Spontaneously hypertensive stroke-prone rats (SHRSP) are used to model clinically relevant aspects of human cerebral small vessel disease (CSVD). To decipher and understand the underlying disease dynamics, assessment of the temporal progression of CSVD histopathological and neuroimaging correlates is essential.Materials and Methods: Eighty age-matched male SHRSP and control Wistar Kyoto rats (WKY) were randomly divided into four groups that were aged until 7, 16, 24 and 32 weeks. Sensorimotor testing was performed weekly. Brain MRI was acquired at each study time point followed by histological analyses of the brain.Results: Compared to WKY controls, the SHRSP showed significantly higher prevalence of small subcortical hyperintensities on T2w imaging that progressed in size and frequency with aging. Volumetric analysis revealed smaller intracranial and white matter volumes on brain MRI in SHRSP compared to age-matched WKY. Diffusion tensor imaging (DTI) showed significantly higher mean diffusivity in the corpus callosum and external capsule in WKY compared to SHRSP. The SHRSP displayed signs of motor restlessness compared to WKY represented by hyperactivity in sensorimotor testing at the beginning of the experiment which decreased with age. Distinct pathological hallmarks of CSVD, such as enlarged perivascular spaces, microbleeds/red blood cell extravasation, hemosiderin deposits, and lipohyalinosis/vascular wall thickening progressively accumulated with age in SHRSP.Conclusions: Four stages of CSVD severity in SHRSP are described at the study time points. In addition, we find that quantitative analyses of brain MRI enable identification of in vivo markers of CSVD that can serve as endpoints for interventional testing in therapeutic studies.

Total Cerebral Small Vessel Disease Score and Anthropometric Indices: A Population-Based Study in Older Adults of Amerindian Ancestry

2021 ◽  
pp. 1-4
Author(s):  
Oscar H. Del Brutto ◽  
Robertino M. Mera
Keyword(s):  
Older Adults ◽  
Small Vessel Disease ◽  
Brain Magnetic Resonance Imaging ◽  
Population Based ◽  
Cerebral Small Vessel Disease ◽  
The Body ◽  
Small Vessel ◽  
Population Based Study ◽  
Vessel Disease ◽  
Ordinal Logistic Regression Model

A total of 590 older adults of Amerindian ancestry living in rural Ecuador received anthropometric measurements and a brain magnetic resonance imaging to estimate the total cerebral small vessel disease (cSVD) score. A fully adjusted ordinal logistic regression model, with categories of the total cSVD score as the dependent variable, disclosed significant associations between the waist circumference, the waist-to-hip, and the waist-to-height ratios – but not the body mass index (BMI) – and the cSVD burden. Indices of abdominal obesity may better correlate with severity of cSVD than the BMI in Amerindians. Phenotypic characteristics of this population may account for these results.

scholarly journals Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review

2015 ◽  
Vol 36 (1) ◽  
pp. 72-94 ◽  
Author(s):  
Anna Poggesi ◽  
Marco Pasi ◽  
Francesca Pescini ◽  
Leonardo Pantoni ◽  
Domenico Inzitari
Keyword(s):  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Small Vessel Disease ◽  
Brain Magnetic Resonance Imaging ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Perivascular Spaces ◽  
Vessel Disease ◽  
Brain Changes

The term cerebral small vessel disease (SVD) refers to a group of pathologic processes with various etiologies that affect small arteries, arterioles, venules, and capillaries of the brain. Magnetic resonance imaging (MRI) correlates of SVD are lacunes, recent small subcortical infarcts, white-matter hyperintensities, enlarged perivascular spaces, microbleeds, and brain atrophy. Endothelial dysfunction is thought to have a role in the mechanisms leading to SVD-related brain changes, and the study of endothelial dysfunction has been proposed as an important step for a better comprehension of cerebral SVD. Among available methods to assess endothelial function in vivo, measurement of molecules of endothelial origin in peripheral blood is currently receiving selective attention. These molecules include products of endothelial cells that change when the endothelium is activated, as well as molecules that reflect endothelial damage and repair. This review examines the main molecular factors involved in both endothelial function and dysfunction, and the evidence linking endothelial dysfunction with cerebral SVD, and gives an overview of clinical studies that have investigated the possible association between endothelial circulating biomarkers and SVD-related brain changes.

Brain MRI in Monogenic Cerebral Small Vessel Diseases: A Practical Handbook

2021 ◽  
Vol 21 ◽  
Author(s):  
Leonardo Ulivi ◽  
Mirco Cosottini ◽  
Gianmichele Migaleddu ◽  
Giovanni Orlandi ◽  
Nicola Giannini ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Next Generation Sequencing ◽  
Small Vessel Disease ◽  
Brain Mri ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Next Generation ◽  
Vessel Disease ◽  
Generation Sequencing ◽  
Cerebral Small Vessel Diseases

: Monogenic cerebral small vessel diseases are a topic of growing interest, as several genes responsible have been recently described and new sequencing techniques such as Next generation sequencing are available. Brain imaging is a key exam in these diseases. First, since it is often the first exam performed, an MRI is key in selecting patients for genetic testing and for interpreting Next generation sequencing reports. In addition, neuroimaging can be helpful in describing the underlying pathological mechanisms involved in cerebral small vessel disease. With this review, we aim to provide Neurologists and Stroke physicians with an up-to date overview of the current neuroimaging knowledge on monogenic small vessel diseases.

Abstract P088: The Gut Microbiome Contributes To The Cerebral Small Vessel Disease Phenotype In Spontaneously Hypertensive Stroke Prone Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Robert M Bryan ◽  
Sharon C Phillips ◽  
David J Durgan
Keyword(s):  
Gut Microbiome ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
The Body ◽  
Small Vessel ◽  
Major Influence ◽  
16S Rrna Analysis ◽  
Spontaneously Hypertensive ◽  
Brain Physiology ◽  
Vessel Disease

In recent years, it has become apparent that the gut microbiome can influence the functioning and pathological states of organs and systems throughout the body. In this study we tested the hypothesis that the gut microbiome has a major role in the cascade of pathological events, including inflammation and hypertension, leading to the onset of cerebral small vessel disease (CSVD). To test this hypothesis, we used an animal model for hypertensive CSVD, the spontaneously hypertensive stroke prone rat (SHRSP). At birth, SHRSP pups were placed with foster dams of the SHRSP strain or dams of the WKY strain, the control strain that does not develop hypertensive CSVD. Similarly, WKY pups were placed with dams of the same or opposite strain. The rationale for cross fostering is that gut microbiomes are shaped by environmental bacteria of the foster dam and the nesting surroundings. Analysis of the bacterial genera in feces using 16S rRNA analysis demonstrated that the gut microbiome in the rat pups was strongly influenced by the foster dam. SHRSP offspring fostered on WKY dams had systolic blood pressures (SBPs) that were significantly decreased by 26 mmHg (P<0.001, N=5-7/group) at 20 weeks, compared to SHRSP offspring fostered on SHRSP dams. Similarly, WKY offspring fostered on SHRSP dams had significantly increased SBP compared to WKY offspring fostered on WKY dams, although the magnitude of SBP change was not as robust (9 mmHg, P<0.05, N=6-8/group). At ~20 weeks of age, rats fostered on SHRSP dams showed increased expression of IL-1a, TLR-2, E-CAD, Muc-2, and Il-17a in ileum regardless of the strain of the offspring (N=6/group, P<0.05). Loss of blood-brain barrier (BBB) integrity, an early marker of CSVD onset, was assessed by extravasation of IgG, which is confined to the plasma space under normal conditions. Extravasation of IgG was increased four-fold in SHRSP fostered on SHRSP dams compared to WKY rats fostered on WKY dams; however, extravasation of IgG was decreased in SHRSP fostered on WKY dams by ~ 50% (P=0.005, N=5/group). These findings demonstrate that although SHRSP is a genetic model for CSVD, the makeup of the gut microbiota has a major influence on gut and brain physiology, and ultimately in shaping the phenotype and onset of CSVD.

scholarly journals Pathomechanisms of HIV-Associated Cerebral Small Vessel Disease: A Comprehensive Clinical and Neuroimaging Protocol and Analysis Pipeline

2020 ◽  
Vol 11 ◽  
Author(s):  
Kyle D. Murray ◽  
Meera V. Singh ◽  
Yuchuan Zhuang ◽  
Md Nasir Uddin ◽  
Xing Qiu ◽  
...  
Keyword(s):  
Longitudinal Study ◽  
Small Vessel Disease ◽  
Brain Mri ◽  
Neurovascular Unit ◽  
Flow Cytometric Analysis ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Imaging Biomarkers ◽  
Vessel Disease ◽  
Inflammatory Monocytes

Rationale: We provide an in-depth description of a comprehensive clinical, immunological, and neuroimaging study that includes a full image processing pipeline. This approach, although implemented in HIV infected individuals, can be used in the general population to assess cerebrovascular health.Aims: In this longitudinal study, we seek to determine the effects of neuroinflammation due to HIV-1 infection on the pathomechanisms of cerebral small vessel disease (CSVD). The study focuses on the interaction of activated platelets, pro-inflammatory monocytes and endothelial cells and their impact on the neurovascular unit. The effects on the neurovascular unit are evaluated by a novel combination of imaging biomarkers.Sample Size: We will enroll 110 HIV-infected individuals on stable combination anti-retroviral therapy for at least three months and an equal number of age-matched controls. We anticipate a drop-out rate of 20%.Methods and Design: Subjects are followed for three years and evaluated by flow cytometric analysis of whole blood (to measure platelet activation, platelet monocyte complexes, and markers of monocyte activation), neuropsychological testing, and brain MRI at the baseline, 18- and 36-month time points. MRI imaging follows the recommended clinical small vessel imaging standards and adds several advanced sequences to obtain quantitative assessments of brain tissues including white matter microstructure, tissue susceptibility, and blood perfusion.Discussion: The study provides further understanding of the underlying mechanisms of CSVD in chronic inflammatory disorders such as HIV infection. The longitudinal study design and comprehensive approach allows the investigation of quantitative changes in imaging metrics and their impact on cognitive performance.

scholarly journals Increased Levels of Circulating Angiogenic Cells and Signaling Proteins in Older Adults With Cerebral Small Vessel Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Arunima Kapoor ◽  
Aimée Gaubert ◽  
Anisa Marshall ◽  
Irene B. Meier ◽  
Belinda Yew ◽  
...  
Keyword(s):  
Older Adults ◽  
Small Vessel Disease ◽  
Brain Magnetic Resonance Imaging ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Signaling Proteins ◽  
Angiogenic Growth Factors ◽  
Vessel Disease ◽  
Increased Risk ◽  
Age And Sex

Background: Cerebral small vessel disease (SVD) is associated with increased risk of stroke and dementia. Progressive damage to the cerebral microvasculature may also trigger angiogenic processes to promote vessel repair. Elevated levels of circulating endothelial progenitor cells (EPCs) and pro-angiogenic signaling proteins are observed in response to vascular injury. We aimed to examine circulating levels of EPCs and proangiogenic proteins in older adults with evidence of SVD.Methods: Older adults (ages 55–90) free of dementia or stroke underwent venipuncture and brain magnetic resonance imaging (MRI). Flow cytometry quantified circulating EPCs as the number of cells in the lymphocyte gate positively expressing EPC surface markers (CD34+CD133+CD309+). Plasma was assayed for proangiogenic factors (VEGF-A, VEGF-C, VEGF-D, Tie-2, and Flt-1). Total SVD burden score was determined based on MRI markers, including white matter hyperintensities, cerebral microbleeds and lacunes.Results: Sixty-four older adults were included. Linear regression revealed that older adults with higher circulating EPC levels exhibited greater total SVD burden [β = 1.0 × 105, 95% CI (0.2, 1.9), p = 0.019], after accounting for age and sex. Similarly, a positive relationship between circulating VEGF-D and total SVD score was observed, controlling for age and sex [β = 0.001, 95% CI (0.000, 0.001), p = 0.048].Conclusion: These findings suggest that elevated levels of circulating EPCs and VEGF-D correspond with greater cerebral SVD burden in older adults. Additional studies are warranted to determine whether activation of systemic angiogenic growth factors and EPCs represents an early attempt to rescue the vascular endothelium and repair damage in SVD.

scholarly journals Serum neurofilament light is sensitive to active cerebral small vessel disease

Neurology ◽  
2017 ◽  
Vol 89 (20) ◽  
pp. 2108-2114 ◽  
Author(s):  
Thomas Gattringer ◽  
Daniela Pinter ◽  
Christian Enzinger ◽  
Thomas Seifert-Held ◽  
Markus Kneihsl ◽  
...  
Keyword(s):  
Single Molecule ◽  
Small Vessel Disease ◽  
Brain Mri ◽  
Cerebral Small Vessel Disease ◽  
Community Dwelling ◽  
Small Vessel ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
Vessel Disease

Objective:To explore whether serum neurofilament light chain protein (NfL) levels are increased in patients with MRI-confirmed recent small subcortical infarcts (RSSI) compared to healthy controls and to determine the subsequent course and determinants of NfL levels in a longitudinal manner.Methods:In a prospectively collected group of symptomatic patients with an RSSI (n = 79, mean age 61 ± 11 years, 67% male), we analyzed brain MRI and serum NfL using a Single Molecule Array (Simoa) assay at baseline and at 3 and 15 months after stroke. Community-dwelling healthy age- and sex-matched individuals with comparable severity of MRI white matter hyperintensities (WMH) (n = 53) served as controls.Results:Patients with an RSSI had higher NfL baseline levels compared to controls (73.45 vs 34.59 pg/mL, p < 0.0001), and they were increasingly higher with the time from stroke symptom onset to blood sampling (median 4 days, range 1–11 days, rs = 0.51, p < 0.0001). NfL levels remained increased at the 3-month follow-up but returned to normal at 15 months after stroke. NfL levels were associated with RSSI size and baseline WMH severity and were especially high in patients with new, clinically silent cerebral small vessel disease (CSVD)–related lesions at follow-up.Conclusions:Serum NfL is increased in patients with an RSSI and the occurrence of new CSVD-related MRI lesions, even when clinically silent. This suggests NfL as a blood biomarker for active CSVD.

Cerebral small vessel disease predisposes to temporal lobe epilepsy in spontaneously hypertensive rats

2017 ◽  
Vol 130 ◽  
pp. 245-250 ◽  
Author(s):  
Emilio Russo ◽  
Antonio Leo ◽  
Francesca Scicchitano ◽  
Annalidia Donato ◽  
Edoardo Ferlazzo ◽  
...  
Keyword(s):  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Spontaneously Hypertensive Rats ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Vessel Disease
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