Mixed Small Vessel Disease in a Patient with Dementia with Lewy Bodies

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.

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CNS small vessel disease

Neurology ◽

10.1212/wnl.0000000000007654 ◽

2019 ◽

Vol 92 (24) ◽

pp. 1146-1156 ◽

Cited By ~ 31

Author(s):

Rocco J. Cannistraro ◽

Mohammed Badi ◽

Benjamin H. Eidelman ◽

Dennis W. Dickson ◽

Erik H. Middlebrooks ◽

...

Keyword(s):

Risk Factors ◽

White Matter ◽

Small Vessel Disease ◽

Blood Oxygenation ◽

Small Vessel ◽

Imaging Biomarkers ◽

Amyloid Angiopathy ◽

Perivascular Spaces ◽

Advanced Imaging ◽

Vessel Disease

CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. CSVD can be asymptomatic; however, depending on location, lesions can cause mild cognitive dysfunction, dementia, mood disorders, motor and gait dysfunction, and urinary incontinence. CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity. Pathogenesis is thought to begin with an etiologically specific insult, with or without genetic predisposition, which results in dysfunction of the neurovascular unit. Uncertainties regarding pathogenesis have delayed development of effective treatment. The most widely accepted approach to treatment is to intensively control well-established vascular risk factors, of which hypertension is the most important. With better understanding of pathogenesis, specific therapies may emerge. Early identification of pathologic characteristics with advanced imaging provides an opportunity to forestall progression before emergence of symptoms.

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Small Vessel Disease: Neuropathology

International Psychogeriatrics ◽

10.1017/s1041610203008986 ◽

2003 ◽

Vol 15 (S1) ◽

pp. 67-69 ◽

Cited By ~ 12

Author(s):

David G. Munoz

Keyword(s):

Blood Vessels ◽

Small Vessel Disease ◽

Small Vessel ◽

Amyloid Angiopathy ◽

Cerebral Blood Vessels ◽

Vessel Disease ◽

Different Populations

Diseases of small cerebral blood vessels are heterogeneous in etiology and manifestations. Lipohyalinosis, venous collagenosis, amyloid angiopathy, and CADASIL affect different populations of blood vessels. Large and small hemorrhages, lacunae, cortical microinfarcts, and leukoaraiosis are the most important consequences of the small vessel angiopathies. Altered permeability as well as ischemia may be involved in the pathogenesis of the latter.

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Distribution of lacunes in cerebral amyloid angiopathy and hypertensive small vessel disease

Neurology ◽

10.1212/wnl.0000000000004007 ◽

2017 ◽

Vol 88 (23) ◽

pp. 2162-2168 ◽

Cited By ~ 43

Author(s):

Marco Pasi ◽

Gregoire Boulouis ◽

Panagiotis Fotiadis ◽

Eitan Auriel ◽

Andreas Charidimou ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Small Vessel Disease ◽

Small Vessel ◽

White Matter Hyperintensity ◽

Amyloid Angiopathy ◽

Vessel Disease ◽

Close Relationship ◽

Cerebral Amyloid ◽

Highly Correlated ◽

The Relationship

Objective:To evaluate whether the burden of deep and lobar lacunes differs between patients with intracerebral hemorrhage (ICH) with definite/probable cerebral amyloid angiopathy (CAA) per the Boston criteria and hypertensive small vessel disease (HTN-SVD; ICH in basal ganglia, thalami, brainstem).Methods:We defined lobar and deep lacunes similar to the topographic distribution used for ICH and cerebral microbleeds (CMBs). We then compared their distribution between patients with CAA-ICH and those with strictly deep CMB and ICH (HTN-ICH). The independent associations of lacune location with the diagnosis of CAA-ICH and HTN-ICH were evaluated with multivariable models. The relationship between lobar lacunes and white matter hyperintensity (WMH) volume was evaluated by means of partial correlation analyses adjusted for age and a validated visual scale.Results:In our final cohort of 316 patients with ICH, lacunes were frequent (24.7%), with similar rates in 191 patients with CAA and 125 with HTN-ICH (23% vs 27.2%, p = 0.4). Lobar lacunes were more commonly present in CAA (20.4% vs 5.7%, p < 0.001), while deep lacunes were more frequent in HTN-ICH (15.2% vs 2.1%, p < 0.001). After correction for demographics and clinical and neuroimaging markers of SVD, lobar lacunes were associated with CAA (p = 0.003) and deep lacunes with HTN-ICH (p < 0.001). Lobar lacunes in 80% of the cases were at least in contact with WMH, and after adjustment for age, they were highly correlated to WMH volume (r = 0.42, p < 0.001).Conclusions:Lobar lacunes are associated with CAA, whereas deep lacunes are more frequent in HTN-SVD. Lobar lacunes seem to have a close relationship with WMH, suggesting a possible common origin.

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Abstract 3208: Sensitivity and Reliability of SWI Compared to T2* GRE MRI for Detection of Microbleeds in Cerebral Amyloid Angiopathy

Stroke ◽

10.1161/str.43.suppl_1.a3208 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Ah-Ling Cheng ◽

Cheryl R McCreary ◽

M. L Lauzon ◽

Richard Frayne ◽

Mayank Goyal ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Small Vessel Disease ◽

Intraclass Correlation ◽

Case Series ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Amyloid Angiopathy ◽

Healthy Controls ◽

Vessel Disease ◽

Cerebral Amyloid

Introduction: Case examples and small case series suggest that MRI susceptibility weighted imaging (SWI) may be more sensitive for cerebral microbleed (CMB) detection compared to MRI T2* gradient-recalled echo (GRE). However, there are few data on CMB counts measured by SWI vs. GRE, or inter-rater reliability, in groups of patients with cerebral small vessel disease. We used data from a prospective cohort study of cerebral amyloid angiopathy (CAA), a cerebral small-vessel disease marked by high numbers of CMBs, to quantify the sensitivity and reliability of SWI vs. GRE for CMB detection. Methods: Nine patients with symptomatic CAA (mean age 71±8.3; 7 males and 2 females) and 21 healthy non-CAA controls (mean age 68±6.3; 10 M/11 F) underwent T2* GRE and SWI on a 3.0T MR scanner. Probable CAA was diagnosed according to the Boston criteria prior to study entry using information from clinical MRI with GRE sequences. Two raters (labeled 1 and 2) independently interpreted the GRE and SWI scans blinded to clinical information. The phase-filtered magnitude image was used for SWI interpretation. Agreement reliability was assessed using the kappa coefficient (where a kappa of ≥0.60 indicates good agreement) or the intraclass correlation coefficient (ICC). Results: Overall, the raters identified 1,432 CMBs in the 9 CAA cases (range 1-434 per patient) and 8 CMBs in the healthy controls (range 0-3). Rater 1 identified CMBs in 5/21 healthy controls on SWI and 5/21 on GRE, while rater 2 identified CMBs in 4/21 on SWI and 3/21 on GRE (kappa 0.70 for GRE and 0.57 for SWI). In CAA cases more CMBs were seen on SWI compared to the GRE sequence but the difference was significant only for rater 1 (rater 1: on average 85% more per patient on SWI than on GRE, p=0.008; rater 2: 19% more, p=0.25). Among CAA cases the reliability between raters was poor for GRE (ICC 0.36) but excellent for SWI (0.94, p<0.05 for comparison with GRE). Review suggested that the differing reliability was because rater 1 was less likely than rater 2 to identify faint lesions on GRE as CMB, whereas these lesions were more conspicuous on SWI. If SWI rather than GRE were used to determine CAA status according to the Boston criteria, all 9 CAA cases would remain classified as probable CAA but 2/21 controls would be reclassified as either possible (n=1) or probable (n=1) asymptomatic CAA based on the detection of one or more lobar microbleeds on SWI. Conclusions: SWI confers greater reliability as well as greater sensitivity for CMB detection compared to GRE, and should be the preferred sequence for quantifying CMBs. SWI may more frequently identify lobar microbleeds that could represent asymptomatic CAA. Further research is needed to determine whether the Boston criteria require revision to take into account the greater sensitivity of SWI for CMB detection.

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Brain hemorrhage recurrence, small vessel disease type, and cerebral microbleeds

Neurology ◽

10.1212/wnl.0000000000004259 ◽

2017 ◽

Vol 89 (8) ◽

pp. 820-829 ◽

Cited By ~ 71

Author(s):

Andreas Charidimou ◽

Toshio Imaizumi ◽

Solene Moulin ◽

Alexandro Biffi ◽

Neshika Samarasekera ◽

...

Keyword(s):

Small Vessel Disease ◽

Meta Analysis ◽

Brain Mri ◽

Recurrence Risk ◽

Cerebral Microbleeds ◽

Small Vessel ◽

Amyloid Angiopathy ◽

Random Effects Models ◽

Pooled Data ◽

Vessel Disease

Objective:We evaluated recurrent intracerebral hemorrhage (ICH) risk in ICH survivors, stratified by the presence, distribution, and number of cerebral microbleeds (CMBs) on MRI (i.e., the presumed causal underlying small vessel disease and its severity).Methods:This was a meta-analysis of prospective cohorts following ICH, with blood-sensitive brain MRI soon after ICH. We estimated annualized recurrent symptomatic ICH rates for each study and compared pooled odds ratios (ORs) of recurrent ICH by CMB presence/absence and presumed etiology based on CMB distribution (strictly lobar CMBs related to probable or possible cerebral amyloid angiopathy [CAA] vs non-CAA) and burden (1, 2–4, 5–10, and >10 CMBs), using random effects models.Results:We pooled data from 10 studies including 1,306 patients: 325 with CAA-related and 981 CAA-unrelated ICH. The annual recurrent ICH risk was higher in CAA-related ICH vs CAA-unrelated ICH (7.4%, 95% confidence interval [CI] 3.2–12.6 vs 1.1%, 95% CI 0.5–1.7 per year, respectively; p = 0.01). In CAA-related ICH, multiple baseline CMBs (versus none) were associated with ICH recurrence during follow-up (range 1–3 years): OR 3.1 (95% CI 1.4–6.8; p = 0.006), 4.3 (95% CI 1.8–10.3; p = 0.001), and 3.4 (95% CI 1.4–8.3; p = 0.007) for 2–4, 5–10, and >10 CMBs, respectively. In CAA-unrelated ICH, only >10 CMBs (versus none) were associated with recurrent ICH (OR 5.6, 95% CI 2.1–15; p = 0.001). The presence of 1 CMB (versus none) was not associated with recurrent ICH in CAA-related or CAA-unrelated cohorts.Conclusions:CMB burden and distribution on MRI identify subgroups of ICH survivors with higher ICH recurrence risk, which may help to predict ICH prognosis with relevance for clinical practice and treatment trials.

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Association between Intracranial Arterial Dolichoectasia and Cerebral Small Vessel Disease and Its Underlying Mechanisms

Journal of Stroke ◽

10.5853/jos.2019.02985 ◽

2020 ◽

Vol 22 (2) ◽

pp. 173-184

Author(s):

Dao Pei Zhang ◽

Suo Yin ◽

Huai Liang Zhang ◽

Dan Li ◽

Bo Song ◽

...

Keyword(s):

Small Vessel Disease ◽

Late Onset ◽

Basic Research ◽

Cerebral Small Vessel Disease ◽

Tissue Inhibitor Of Metalloproteinase ◽

Small Vessel ◽

Predisposing Factor ◽

Brain Vessels ◽

Small Vessels ◽

Vessel Disease

Intracranial arterial dolichoectasia (IADE), also known as dilatative arteriopathy of the brain vessels, refers to an increase in the length and diameter of at least one intracranial artery, and accounts for approximately 12% of all patients with stroke. However, the association of IADE with stroke is usually unclear. Cerebral small vessel disease (CSVD) is characterized by pathological changes in the small vessels. Clinically, patients with CSVD can be asymptomatic or present with stroke or cognitive decline. In the past 20 years, a series of studies have strongly promoted an understanding of the association between IADE and CSVD from clinical and pathological perspectives. It has been proposed that IADE and CSVD may be attributed to abnormal vascular remodeling driven by an abnormal matrix metalloproteinase/tissue inhibitor of metalloproteinase pathway. Also, IADErelated hemodynamic changes may result in initiation or progression of CSVD. Additionally, genetic factors are implicated in the pathogenesis of IADE and CSVD. Patients with Fabry’s disease and late-onset Pompe’s disease are prone to developing concomitant IADE and CSVD, and patients with collagen IV alpha 1 or 2 gene (<i>COL4A1/COL4A2</i>) and forkhead box C1 (<i>FOXC1</i>) variants present with IADE and CSVD. Race, strain, familial status, and vascular risk factors may be involved in the pathogenesis of IADE and CSVD. As well, experiments in mice have pointed to genetic strain as a predisposing factor for IADE and CSVD. However, there have been few direct genetic studies aimed towards determining the association between IADE and CSVD. In the future, more clinical and basic research studies are needed to elucidate the causal relationship between IADE and CSVD and the related molecular and genetic mechanisms.

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Contribution of Racial and Ethnic Differences in Cerebral Small Vessel Disease Subtype and Burden to Risk of Cerebral Hemorrhage Recurrence

Neurology ◽

10.1212/wnl.0000000000011932 ◽

2021 ◽

pp. 10.1212/WNL.0000000000011932

Author(s):

Juan Pablo Castello ◽

Marco Pasi ◽

Jessica R Abramson ◽

Axana Rodriguez-Torres ◽

Sandro Marini ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Ethnic Differences ◽

Small Vessel Disease ◽

Ethnic Disparities ◽

Recurrence Risk ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Amyloid Angiopathy ◽

Vessel Disease ◽

Racial Ethnic

Objective:Black and Hispanic survivors of Intracerebral Hemorrhage (ICH) are at higher risk of recurrent intracranial bleeding. MRI-based markers of chronic Cerebral Small Vessel Disease (CSVD) are consistently associated with recurrent ICH. We therefore sought to investigate whether racial/ethnic differences in MRI-defined CSVD subtype and severity contribute to disparities in ICH recurrence risk.Methods:We analyzed data from the Massachusetts General Hospital ICH study (MGH-ICH, n=593) and the ERICH (Ethnic/Racial Variations of Intracerebral Hemorrhage) study (n= 329). Using CSVD markers derived from MRIs obtained within 90 days of index ICH, we classified ICH cases as cerebral amyloid angiopathy (CAA)-related, hypertensive arteriopathy (HTNA)-related, and mixed etiology. We quantified CSVD burden using validated global, CAA-specific, and HTNA-specific scores. We compared CSVD subtype and severity among White, Black, and Hispanic ICH survivors and investigated its association with ICH recurrence risk.Results:We analyzed data for 922 ICH survivors (655 White, 130 Black, 137 Hispanic). Minority ICH survivors had greater global CSVD (p=0.011) and HTNA burden (p=0.021) on MRI. Furthermore, minority survivors of HTNA-related and mixed etiology ICH demonstrated higher HTNA burden, resulting in increased ICH recurrence risk (all p < 0.05).Conclusions:We uncovered significant differences in CSVD subtypes and severity among White and minority survivors of primary ICH, with direct implication for known disparities in ICH recurrence risk. Future studies of racial / ethnic disparities in ICH outcomes will benefit from including detailed MRI-based assessment of CSVD subtypes and severity, and investigating social determinants of health.

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Small vessel disease burden in cerebral amyloid angiopathy without symptomatic hemorrhage

Neurology ◽

10.1212/wnl.0000000000003655 ◽

2017 ◽

Vol 88 (9) ◽

pp. 878-884 ◽

Cited By ~ 16

Author(s):

Gregoire Boulouis ◽

Andreas Charidimou ◽

Michael J. Jessel ◽

Li Xiong ◽

Duangnapa Roongpiboonsopit ◽

...

Keyword(s):

Cerebral Amyloid Angiopathy ◽

Small Vessel Disease ◽

Summary Score ◽

Small Vessel ◽

Amyloid Angiopathy ◽

Perivascular Spaces ◽

Cognitive Symptoms ◽

Vessel Disease ◽

Age Related ◽

Cerebral Amyloid

Objective:Cerebral amyloid angiopathy (CAA) is a common age-related small vessel disease (SVD). Patients without intracerebral hemorrhage (ICH) typically present with transient focal neurologic episodes (TFNEs) or cognitive symptoms. We sought to determine if SVD lesion burden differed between patients with CAA first presenting with TFNEs vs cognitive symptoms.Methods:A total of 647 patients presenting either to a stroke department (n = 205) or an outpatient memory clinic (n = 442) were screened for eligibility. Patients meeting modified Boston criteria for probable CAA were included and markers of SVD were quantified, including cerebral microbleeds (CMBs), perivascular spaces, cortical superficial siderosis (cSS), and white matter hyperintensities (WMHs). Patients were classified according to presentation symptoms (TFNEs vs cognitive). Total CAA-SVD burden was assessed using a validated summary score. Individual neuroimaging markers and total SVD burden were compared between groups using univariable and multivariable models.Results:There were 261 patients with probable CAA included. After adjustment for confounders, patients first seen for TFNEs (n = 97) demonstrated a higher prevalence of cSS (p < 0.0001), higher WMH volumes (p = 0.03), and a trend toward higher CMB counts (p = 0.09). The total SVD summary score was higher in patients seen for TFNEs (adjusted odds ratio per additional score point 1.46, 95% confidence interval 1.16–1.84, p = 0.013).Conclusions:Patients with probable CAA without ICH first evaluated for TFNEs bear a higher burden of structural MRI SVD-related damage compared to those first seen for cognitive symptoms. This study sheds light on neuroimaging profile differences across clinical phenotypes of patients with CAA without ICH.

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Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

International Journal of Molecular Sciences ◽

10.3390/ijms21113862 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3862 ◽

Cited By ~ 3

Author(s):

Jayant Patwa ◽

Swaran Jeet Singh Flora

Keyword(s):

Heavy Metals ◽

Heavy Metal ◽

Blood Vessels ◽

Small Vessel Disease ◽

Vascular Dysfunction ◽

Cerebral Small Vessel Disease ◽

Small Vessel ◽

Amyloid Angiopathy ◽

Vessel Disease ◽

Antioxidant Defense Enzymes

Heavy metals are considered a continuous threat to humanity, as they cannot be eradicated. Prolonged exposure to heavy metals/metalloids in humans has been associated with several health risks, including neurodegeneration, vascular dysfunction, metabolic disorders, cancer, etc. Small blood vessels are highly vulnerable to heavy metals as they are directly exposed to the blood circulatory system, which has comparatively higher concentration of heavy metals than other organs. Cerebral small vessel disease (CSVD) is an umbrella term used to describe various pathological processes that affect the cerebral small blood vessels and is accepted as a primary contributor in associated disorders, such as dementia, cognitive disabilities, mood disorder, and ischemic, as well as a hemorrhagic stroke. In this review, we discuss the possible implication of heavy metals/metalloid exposure in CSVD and its associated disorders based on in-vitro, preclinical, and clinical evidences. We briefly discuss the CSVD, prevalence, epidemiology, and risk factors for development such as genetic, traditional, and environmental factors. Toxic effects of specific heavy metal/metalloid intoxication (As, Cd, Pb, Hg, and Cu) in the small vessel associated endothelium and vascular dysfunction too have been reviewed. An attempt has been made to highlight the possible molecular mechanism involved in the pathophysiology, such as oxidative stress, inflammatory pathway, matrix metalloproteinases (MMPs) expression, and amyloid angiopathy in the CSVD and related disorders. Finally, we discussed the role of cellular antioxidant defense enzymes to neutralize the toxic effect, and also highlighted the potential reversal strategies to combat heavy metal-induced vascular changes. In conclusion, heavy metals in small vessels are strongly associated with the development as well as the progression of CSVD. Chelation therapy may be an effective strategy to reduce the toxic metal load and the associated complications.

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