Clinical phenotype, atrophy, and small vessel disease in APOEε2 carriers with Alzheimer disease

Neurology ◽  
2018 ◽  
Vol 91 (20) ◽  
pp. e1851-e1859 ◽  
Author(s):  
Colin Groot ◽  
Carole H. Sudre ◽  
Frederik Barkhof ◽  
Charlotte E. Teunissen ◽  
Bart N.M. van Berckel ◽  
...  
Keyword(s):  
White Matter ◽  
Alzheimer Disease ◽  
Gray Matter ◽  
Small Vessel Disease ◽  
Clinical Phenotype ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Language Functions ◽  
Vessel Disease ◽  
Gray Matter Atrophy

ObjectiveTo examine the clinical phenotype, gray matter atrophy patterns, and small vessel disease in patients who developed prodromal or probable Alzheimer disease dementia, despite carrying the protective APOEε2 allele.MethodsWe included 36 β-amyloid-positive (by CSF or PET) APOEε2 carriers (all ε2/ε3) with mild cognitive impairment or dementia due to Alzheimer disease who were matched for age and diagnosis (ratio 1:2) to APOEε3 homozygotes and APOEε4 carriers (70% ε3/ε4 and 30% ε4/ε4). We assessed neuropsychological performance across 4 cognitive domains (memory, attention, executive, and language functions), performed voxelwise and region of interest analyses of gray matter atrophy on T1-weighted MRI, used fluid-attenuated inversion recovery images to automatically quantify white matter hyperintensity volumes, and assessed T2*-weighted images to identify microbleeds. Differences in cognitive domain scores, atrophy, and white matter hyperintensities between ε2 carriers, ε3 homozygotes, and ε4 carriers were assessed using analysis of variance analyses, and Pearson χ2 tests were used to examine differences in prevalence of microbleeds.ResultsWe found that ε2 carriers performed worse on nonmemory domains compared to both ε3 homozygotes and ε4 carriers but better on memory compared to ε4 carriers. Voxelwise T1-weighted MRI analyses showed asymmetric (left > right) temporoparietal-predominant atrophy with subtly less involvement of medial–temporal structures in ε2 carriers compared to ε4 carriers. Finally, ε2 carriers had larger total white matter hyperintensity volumes compared to ε4 carriers (mean 10.4 vs 7.3 mL) and a higher prevalence of microbleeds compared to ε3 homozygotes (37.5% vs 18.3%).ConclusionAPOEε2 carriers who develop Alzheimer disease despite carrying the protective allele display a nonamnestic clinical phenotype with more severe small vessel disease.

scholarly journals MRI Relaxometry for Quantitative Analysis of USPIO Uptake in Cerebral Small Vessel Disease

2019 ◽  
Vol 20 (3) ◽  
pp. 776 ◽  
Author(s):  
Michael Thrippleton ◽  
Gordon Blair ◽  
Maria Valdes-Hernandez ◽  
Andreas Glatz ◽  
Scott Semple ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Blood Volume ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Minor Stroke ◽  
Vessel Disease ◽  
Wide Range

A protocol for evaluating ultrasmall superparamagnetic particles of iron oxide (USPIO) uptake and elimination in cerebral small vessel disease patients was developed and piloted. B1-insensitive R1 measurement was evaluated in vitro. Twelve participants with history of minor stroke were scanned at 3-T MRI including structural imaging, and R1 and R2* mapping. Participants were scanned (i) before and (ii) after USPIO (ferumoxytol) infusion, and again at (iii) 24–30 h and (iv) one month. Absolute and blood-normalised changes in R1 and R2* were measured in white matter (WM), deep grey matter (GM), white matter hyperintensity (WMH) and stroke lesion regions. R1 measurements were accurate across a wide range of values. R1 (p < 0.05) and R2* (p < 0.01) mapping detected increases in relaxation rate in all tissues immediately post-USPIO and at 24–30 h. R2* returned to baseline at one month. Blood-normalised R1 and R2* changes post-infusion and at 24–30 h were similar, and were greater in GM versus WM (p < 0.001). Narrower distributions were seen with R2* than for R1 mapping. R1 and R2* changes were correlated at 24–30 h (p < 0.01). MRI relaxometry permits quantitative evaluation of USPIO uptake; R2* appears to be more sensitive to USPIO than R1. Our data are explained by intravascular uptake alone, yielding estimates of cerebral blood volume, and did not support parenchymal uptake. Ferumoxytol appears to be eliminated at 1 month. The approach should be valuable in future studies to quantify both blood-pool USPIO and parenchymal uptake associated with inflammatory cells or blood-brain barrier leak.

Abstract W MP58: The Relationship Between Carotid Stiffness, Diastolic Diameter, and White Matter Hyperintensity Volume: The Northern Manhattan Study

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Matthew S Markert ◽  
Chuanhui Dong ◽  
David Della-Morte ◽  
Eugene Roberts ◽  
Susanne Bartels ◽  
...  
Keyword(s):  
Risk Factors ◽  
White Matter ◽  
Small Vessel Disease ◽  
Vascular Risk Factors ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Large Artery ◽  
Vascular Risk ◽  
Vessel Disease ◽  
Carotid Stiffness

Background: Changes in the extracranial vasculature may be associated with small vessel disease in the brain. We sought to examine the association of carotid stiffness and carotid diastolic diameter with white matter hyperintensity volume (WMHV), a magnetic resonance imaging (MRI) measure for cerebral small vessel disease, in a multi-ethnic community-based cohort. Methods: We evaluated 1140 stroke-free participants in the Northern Manhattan study who underwent brain MRIs and high-resolution carotid ultrasounds. We used linear regression to examine carotid stiffness and diastolic diameter with WMHV after adjusting for sociodemographics, lifestyle behaviors, and traditional vascular risk factors. Results: Among 1140 participants (mean age: 70.6±9.0 years; 61% women; 15% White, 16% Black, 59% Hispanics), the mean carotid stiffness was 8.19 ± 5.39, mean carotid diastolic diameter was 6.16 ± 0.93 mm, and mean WMHV 0.68 ± 0.84. In a fully adjusted model, diastolic diameter was associated with log-WMHV (β=0.10, p=0.001). In a stratified multivariable linear model, greater carotid arterial stiffness and diastolic diameter were associated with log-WMHV among Hispanics (β=0.15, p=0.005 and β=0.13, p<0.001, respectively), but not among blacks or whites. Conclusion: Greater carotid stiffness and diastolic diameter were associated with greater WMHV independent of demographics and traditional vascular risk factors, especially among Hispanics. Further studies are needed to understand how these large artery characteristics relate to WMH formation and lesion load. Carotid ultrasound may be a useful tool to assess the risk of increased brain white matter disease in a pre-clinical stage.

Abstract 49: White Matter Hyperintensity Spatial Pattern Variations reflect distinct Cerebral Small Vessel Disease Pathologies

Stroke ◽  
2019 ◽  
Vol 50 (Suppl_1) ◽  
Author(s):  
Chia-Ling Phuah ◽  
Yasheng Chen ◽  
Ziyang Liu ◽  
Nirupama Yechoor ◽  
Helen Hwang ◽  
...  
Keyword(s):  
White Matter ◽  
Spatial Pattern ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Vessel Disease

scholarly journals Cerebral blood flow in small vessel disease: A systematic review and meta-analysis

2016 ◽  
Vol 36 (10) ◽  
pp. 1653-1667 ◽  
Author(s):  
Yulu Shi ◽  
Michael J Thrippleton ◽  
Stephen D Makin ◽  
Ian Marshall ◽  
Mirjam I Geerlings ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
White Matter ◽  
Small Vessel Disease ◽  
Meta Analysis ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Cross Sectional ◽  
Vessel Disease ◽  
Cross Sectional Studies

White matter hyperintensities are frequent on neuroimaging of older people and are a key feature of cerebral small vessel disease. They are commonly attributed to chronic hypoperfusion, although whether low cerebral blood flow is cause or effect is unclear. We systematically reviewed studies that assessed cerebral blood flow in small vessel disease patients, performed meta-analysis and sensitivity analysis of potential confounders. Thirty-eight studies ( n = 4006) met the inclusion criteria, including four longitudinal and 34 cross-sectional studies. Most cerebral blood flow data were from grey matter. Twenty-four cross-sectional studies ( n = 1161) were meta-analysed, showing that cerebral blood flow was lower in subjects with more white matter hyperintensity, globally and in most grey and white matter regions (e.g. mean global cerebral blood flow: standardised mean difference−0.71, 95% CI −1.12, −0.30). These cerebral blood flow differences were attenuated by excluding studies in dementia or that lacked age-matching. Four longitudinal studies ( n = 1079) gave differing results, e.g., more baseline white matter hyperintensity predated falling cerebral blood flow (3.9 years, n = 575); cerebral blood flow was low in regions that developed white matter hyperintensity (1.5 years, n = 40). Cerebral blood flow is lower in subjects with more white matter hyperintensity cross-sectionally, but evidence for falling cerebral blood flow predating increasing white matter hyperintensity is conflicting. Future studies should be longitudinal, obtain more white matter data, use better age-correction and stratify by clinical diagnosis.

scholarly journals Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials

2015 ◽  
Vol 36 (1) ◽  
pp. 228-240 ◽  
Author(s):  
Philip Benjamin ◽  
Eva Zeestraten ◽  
Christian Lambert ◽  
Irina Chis Ster ◽  
Owen A Williams ◽  
...  
Keyword(s):  
White Matter ◽  
Sample Size ◽  
Diffusion Tensor ◽  
Small Vessel Disease ◽  
Cognitive Change ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Vessel Disease ◽  
Size Estimates

Detecting treatment efficacy using cognitive change in trials of cerebral small vessel disease (SVD) has been challenging, making the use of surrogate markers such as magnetic resonance imaging (MRI) attractive. We determined the sensitivity of MRI to change in SVD and used this information to calculate sample size estimates for a clinical trial. Data from the prospective SCANS (St George’s Cognition and Neuroimaging in Stroke) study of patients with symptomatic lacunar stroke and confluent leukoaraiosis was used ( n = 121). Ninety-nine subjects returned at one or more time points. Multimodal MRI and neuropsychologic testing was performed annually over 3 years. We evaluated the change in brain volume, T2 white matter hyperintensity (WMH) volume, lacunes, and white matter damage on diffusion tensor imaging (DTI). Over 3 years, change was detectable in all MRI markers but not in cognitive measures. WMH volume and DTI parameters were most sensitive to change and therefore had the smallest sample size estimates. MRI markers, particularly WMH volume and DTI parameters, are more sensitive to SVD progression over short time periods than cognition. These markers could significantly reduce the size of trials to screen treatments for efficacy in SVD, although further validation from longitudinal and intervention studies is required.

scholarly journals Blood–brain barrier leakage in relation to white matter hyperintensity volume and cognition in small vessel disease and normal aging

2018 ◽  
Vol 13 (2) ◽  
pp. 389-395 ◽  
Author(s):  
C. Eleana Zhang ◽  
Sau May Wong ◽  
Renske Uiterwijk ◽  
Walter H. Backes ◽  
Jacobus F. A. Jansen ◽  
...  
Keyword(s):  
White Matter ◽  
Blood Brain Barrier ◽  
Small Vessel Disease ◽  
Normal Aging ◽  
Brain Barrier ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Vessel Disease ◽  
Blood Brain

scholarly journals Plasma soluble TREM2 is associated with white matter lesions independent of amyloid and tau

Brain ◽  
2021 ◽  
Author(s):  
Hsin-Hsi Tsai ◽  
Ya-Fang Chen ◽  
Ruoh-Fang Yen ◽  
Yen-Ling Lo ◽  
Kai-Chien Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Vessel Disease ◽  
Soluble Trem2 ◽  
Amyloid Load ◽  
Cerebral Amyloid

Abstract Cerebral small vessel disease is one of the most common causes of cognitive decline and stroke. While several lines of evidence have established a relationship between inflammation and cerebrovascular pathology, the mechanistic link has not yet been elucidated. Recent studies suggest activation of immune mediators, including the soluble form of triggering receptor expressed on myeloid cells 2 (TREM2), may be critical regulators. In this study, we compared the plasma levels of soluble TREM2 and its correlations with neuroimaging markers and cerebral amyloid load in ten patients with Alzheimer’s disease and 66 survivors of spontaneous intracerebral haemorrhage with cerebral amyloid angiopathy or hypertensive small vessel disease, two of the most common types of sporadic small vessel disease. We performed brain MRI and 11C-Pittsburgh compound B PET for all participants to evaluate radiological small vessel disease markers and cerebral amyloid burden, and 18F-T807 PET in a subgroup of patients to evaluate cortical tau pathology. Plasma soluble TREM2 levels were comparable between patients with Alzheimer’s disease and small vessel disease (P=0.690). In patients with small vessel disease, plasma soluble TREM2 was significantly associated with white matter hyperintensity volume (P&lt;0.001), but not with cerebral amyloid load. Among patients with Alzheimer’s disease and cerebral amyloid angiopathy, plasma soluble TREM2 was independently associated with a tau-positive scan (P=0.001) and white matter hyperintensity volume (P=0.013), but not amyloid load (P=0.221). Our results indicate plasma soluble TREM2 is associated with white matter hyperintensity independent of amyloid and tau pathology. These findings highlight the potential utility of plasma soluble TREM2 as a strong predictive marker for small vessel disease-related white matter injury and hold clinical implications for targeting the innate immune response when treating this disease.

scholarly journals Carotid Atheroinflammation Is Associated With Cerebral Small Vessel Disease Severity

2021 ◽  
Vol 12 ◽  
Author(s):  
Nicholas R. Evans ◽  
Jason M. Tarkin ◽  
Jessica Walsh ◽  
Mohammed M. Chowdhury ◽  
Andrew J. Patterson ◽  
...  
Keyword(s):  
White Matter ◽  
Carotid Artery ◽  
Disease Severity ◽  
Small Vessel Disease ◽  
Imaging Study ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Vessel Disease ◽  
Systemic Inflammatory Disease

Background: Atherosclerosis is a systemic inflammatory disease, with common inflammatory processes implicated in both atheroma vulnerability and blood-brain barrier disruption. This prospective multimodal imaging study aimed to measure directly the association between systemic atheroma inflammation (“atheroinflammation”) and downstream chronic cerebral small vessel disease severity.Methods: Twenty-six individuals with ischemic stroke with ipsilateral carotid artery stenosis of &gt;50% underwent 18fluoride-fluorodeoxyglucose-positron emission tomography within 2 weeks of stroke. Small vessel disease severity and white matter hyperintensity volume were assessed using 3-tesla magnetic resonance imaging also within 2 weeks of stroke.Results: Fluorodeoxyglucose uptake was independently associated with more severe small vessel disease (odds ratio 6.18, 95% confidence interval 2.1–18.2, P &lt; 0.01 for the non-culprit carotid artery) and larger white matter hyperintensity volumes (coefficient = 14.33 mL, P &lt; 0.01 for the non-culprit carotid artery).Conclusion: These proof-of-concept results have important implications for our understanding of the neurovascular interface and potential therapeutic exploitation in the management of systemic atherosclerosis, particularly non-stenotic disease previously considered asymptomatic, in order to reduce the burden of chronic cerebrovascular disease.

scholarly journals The Relationship Between ADAMTS13 Activity and Overall Cerebral Small Vessel Disease Burden: A Cross-Sectional Study Based on CSVD

2021 ◽  
Vol 13 ◽  
Author(s):  
Wenbo Sun ◽  
Yufan Luo ◽  
Shufan Zhang ◽  
Wenmei Lu ◽  
Luqiong Liu ◽  
...  
Keyword(s):  
White Matter ◽  
Confidence Interval ◽  
Small Vessel Disease ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
White Matter Hyperintensity ◽  
Adamts13 Activity ◽  
Vessel Disease ◽  
The Mean ◽  
Subcortical Infarction

Objectives: This study aimed to investigate the association between plasma von Willebrand factor (VWF) level, ADAMTS13 activity, and neuroimaging features of cerebral small vessel disease (CSVD), including the CSVD neuroimaging markers and the overall CSVD burden.Methods: CSVD patients admitted to our hospital from 2016 to 2020 were recruited. Plasma VWF level and ADAMTS13 activity were measured. The overall effect of CSVD on the brain was described as a validated CSVD score. We evaluated the association between VWF levels, ADAMTS13 activity, and the increasing severity of CSVD score by the logistic regression model.Results: We enrolled 296 patients into this study. The mean age of the sample was 69.0 years (SD 7.0). The mean VWF level was 1.31 IU/mL, and the ADAMTS13 activity was 88.01 (SD 10.57). In multivariate regression analysis, lower ADAMTS13 activity and higher VWF level was related to white matter hyperintensity (WMH) [β = −7.31; 95% confidence interval (CI) (−9.40, −4.93); p&lt;0.01; β = 0.17; 95% confidence interval (0.11, 0.23); p&lt;0.01], subcortical infarction (SI) [(β = −9.22; 95% CI (−11.37, −7.06); p&lt;0.01); β = 0.21; 95% confidence interval (0.15, 0.27); p&lt;0.01] independently, but not cerebral microbleed (CMB) [(β = −2.3; 95% CI (−4.95, 0.05); p = 0.22); β = 0.02; 95% confidence interval (−0.05, 0.08); p = 0.63]. Furthermore, ADAMTS13 activity was independently negatively correlated with the overall CSVD burden (odd ratio = 21.33; 95% CI (17.46, 54.60); p &lt; 0.01) after adjustment for age, history of hypertension, and current smoking.Conclusions: Reducing ADAMTS13 activity change is related to white matter hyperintensity, subcortical infarction, but not with cerebral microhemorrhage. In addition, ADAMTS13 may have played an essential role in the progression of CSVD.

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