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BACKGROUND: Cerebral amyloid angiopathy (CAA) is an age-related small vessel disease, characterised pathologically by progressive deposition of amyloid ß in the cerebrovascular wall. The Boston criteria are used worldwide for the in-vivo diagnosis of CAA but have not been updated since 2010, before the emergence of additional MRI markers. We report an international collaborative study aiming to update and externally validate the Boston diagnostic criteria across the full spectrum of clinical CAA presentations. METHODS: In this multicentre, hospital-based, retrospective, MRI and neuropathology diagnostic accuracy study, we did a retrospective analysis of clinical, radiological, and histopathological data available to sites participating in the International CAA Association to formulate updated Boston criteria and establish their diagnostic accuracy across different populations and clinical presentations. Ten North American and European academic medical centres identified patients aged 50 years and older with potential CAA-related clinical presentations (ie, spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes), available brain MRI, and histopathological assessment for CAA diagnosis. MRI scans were centrally rated at Massachusetts General Hospital (Boston, MA, USA) for haemorrhagic and non-haemorrhagic CAA markers, and brain tissue samples were rated by neuropathologists at the contributing sites. We derived the Boston criteria version 2.0 (v2.0) by selecting MRI features to optimise diagnostic specificity and sensitivity in a prespecified derivation cohort (Boston cases 1994-2012, n=159), then externally validated the criteria in a prespecified temporal validation cohort (Boston cases 2012-18, n=59) and a geographical validation cohort (non-Boston cases 2004-18; n=123), comparing accuracy of the new criteria to the currently used modified Boston criteria with histopathological assessment of CAA as the diagnostic standard. We also assessed performance of the v2.0 criteria in patients across all cohorts who had the diagnostic gold standard of brain autopsy. FINDINGS: The study protocol was finalised on Jan 15, 2017, patient identification was completed on Dec 31, 2018, and imaging analyses were completed on Sept 30, 2019. Of 401 potentially eligible patients presenting to Massachusetts General Hospital, 218 were eligible to be included in the analysis; of 160 patient datasets from other centres, 123 were included. Using the derivation cohort, we derived provisional criteria for probable CAA requiring the presence of at least two strictly lobar haemorrhagic lesions (ie, intracerebral haemorrhages, cerebral microbleeds, or foci of cortical superficial siderosis) or at least one strictly lobar haemorrhagic lesion and at least one white matter characteristic (ie, severe visible perivascular spaces in centrum semiovale or white matter hyperintensities in a multispot pattern). The sensitivity and specificity of these criteria were 74·8% (95% CI 65·4-82·7) and 84·6% (71·9-93·1) in the derivation cohort, 92·5% (79·6-98·4) and 89·5% (66·9-98·7) in the temporal validation cohort, 80·2% (70·8-87·6) and 81·5% (61·9-93·7) in the geographical validation cohort, and 74·5% (65·4-82·4) and 95·0% (83·1-99·4) in all patients who had autopsy as the diagnostic standard. The area under the receiver operating characteristic curve (AUC) was 0·797 (0·732-0·861) in the derivation cohort, 0·910 (0·828-0·992) in the temporal validation cohort, 0·808 (0·724-0·893) in the geographical validation cohort, and 0·848 (0·794-0·901) in patients who had autopsy as the diagnostic standard. The v2.0 Boston criteria for probable CAA had superior accuracy to the current Boston criteria (sensitivity 64·5% [54·9-73·4]; specificity 95·0% [83·1-99·4]; AUC 0·798 [0·741-0854]; p=0·0005 for comparison of AUC) across all individuals who had autopsy as the diagnostic standard. INTERPRETATION: The Boston criteria v2.0 incorporate emerging MRI markers of CAA to enhance sensitivity without compromising their specificity in our cohorts of patients aged 50 years and older presenting with spontaneous intracerebral haemorrhage, cognitive impairment, or transient focal neurological episodes. Future studies will be needed to determine generalisability of the v.2.0 criteria across the full range of patients and clinical presentations. FUNDING: US National Institutes of Health (R01 AG26484).
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Angiopatia Amiloide Cerebral , Neuropatologia , Idoso , Peptídeos beta-Amiloides , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Hemorragia Cerebral/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: We postulated that cerebral amyloid angiopathy (CAA) is associated with white matter atrophy (WMA) and that WMA can be related to cognitive changes in CAA. METHODS: White matter volume expressed as percent of intracranial volume (pWMV) of prospectively enrolled patients without dementia diagnosed with probable CAA was compared to age-matched healthy controls (HC) and patients with Alzheimer disease (AD). Cognitive scores were also sought to understand the potential effects of WMA on cognitive function. RESULTS: Patients with CAA (n = 72) had significantly lower pWMV (27.97% ± 2.63) when compared to age-matched HC (n = 72; mean difference [MD], 2.38%; p < 0.0001) and patients with AD (n = 72; MD, 1.57%; p < 0.0001). Differences were most pronounced in the posterior occipital regions in both comparisons. When comparisons were restricted to groups of patients with CAA but no intracerebral hemorrhage (n = 32) or hypertension (n = 32), and age-matched HC and AD, the significant differences were unaltered. Within the CAA cohort, higher age, lobar microbleed counts, and presence of hypertension were associated with lower pWMV (p = 0.0007, p = 0.031, and p = 0.003, respectively). All associations remained independent in multivariable analyses. Within the CAA cohort, higher pWMV independently correlated with better scores of executive function. CONCLUSIONS: Patients with CAA show WMA when compared to age-matched HC and patients with AD. WMA independently correlates with the number of lobar microbleeds, a marker of CAA severity. Consistent spatial patterns of WMA especially in posterior regions might be related to CAA. The association between WMA and measures of executive function suggests that WMA might represent an important mediator of CAA-related neurologic dysfunction.
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Encéfalo/patologia , Angiopatia Amiloide Cerebral/patologia , Substância Branca/patologia , Idoso , Atrofia/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
Background and Purpose- Magnetic resonance imaging visible perivascular spaces in the centrum semiovale (CSO-PVS) have been associated with cerebral amyloid angiopathy (CAA).We aimed to further confirm this link by evaluating CSO-PVS volume in pathologically-demonstrated sporadic and genetically-demonstrated hereditary forms of the disease. Methods- We studied a retrospective hospital-based cohort consisting of 63 individuals aged >55 having brain magnetic resonance imaging and pathological assessment of CAA (mean age, 73.6±8.5; 46% female), and a separate cohort consisting of 26 carriers, and 28 noncarriers of the hereditary cerebral hemorrhage with amyloidosis-Dutch type (mean age, 46.7±12.8; 61.1% female). CSO-PVS volume was quantified on a single magnetic resonance imaging slice using a computer-assisted segmentation method and expressed as the relative volume of the intracranial volume in that particular slice (CSO-PVS relative volume). We compared CSO-PVS relative volume (1) between subjects with and without the disease in both cohorts; (2) between non-CAA, CAA without hemorrhage, and CAA with hemorrhage cases in the sporadic CAA cohort. All variables reaching P<0.1 in bivariate analyses were entered in logistic regression models. Results- In both sporadic and Dutch cohorts, cases with CAA had significantly higher CSO-PVS relative volume than cases without (median [IQR]: 3.7% [2.5-5.3] versus 1.8% [1.2-2.4], P<0.0001; 3.8% [0.6-6.2] versus 0.7% [0.4-1.6], P=0.007; respectively). In linear regression models, sporadic CAA was associated with higher CSO-PVS relative volume ( P=0.008). In the sporadic CAA cohort, compared with non-CAA cases, CSO-PVS relative volume was higher in both CAA with hemorrhage and without hemorrhage (4.4% [2.6-6.1] and 3% [2.4-3.6] versus 1.8% [1.2-2.4], P<0.001 and P=0.005, respectively). Higher CSO-PVS relative volume was associated with CAA in regression models, both when hemorrhage was present (odds ratio, 2.63; [95% confidence interval, 1.33-5.18]; P=0.005) and absent (odds ratio, 4.55; [95% confidence interval, 0.98-21.04]; P=0.05). Conclusions- Increased CSO-PVS volume is a consistent magnetic resonance imaging marker of cerebrovascular amyloid deposition and a promising diagnostic tool for sporadic CAA without hemorrhagic manifestations.
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Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/epidemiologia , Sistema Glinfático/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Humanos , Imageamento por Ressonância Magnética/tendências , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Estudos RetrospectivosRESUMO
OBJECTIVE: In order to explore the mechanisms of cortical superficial siderosis (cSS) multifocality and its clinical implications for recurrent intracerebral hemorrhage (ICH) risk in patients with cerebral amyloid angiopathy (CAA), we used a new rating method that we developed specifically to evaluate cSS extent at spatially separated foci. METHODS: Consecutive patients with CAA-related ICH according to Boston criteria from a single-center prospective cohort were analyzed. The new score that assesses cSS multifocality (total range 0-4) showed excellent interrater reliability (k = 0.87). The association of cSS with markers of CAA and acute ICH was investigated. Patients were followed prospectively for recurrent symptomatic ICH. RESULTS: The cohort included 313 patients with CAA. Multifocal cSS prevalence was 21.1%. APOE ε2 allele prevalence was higher in patients with multifocal cSS. In probable/definite CAA, cSS multifocality was independently associated with neuroimaging markers of CAA severity, including lobar microbleeds, but not with acute ICH features, which conversely, were determinants of cSS in possible CAA. During a median follow-up of 2.6 years (interquartile range 0.9-5.1 years), the annual ICH recurrence rates per cSS scores (0-4) were 5%, 6.5%, 13.5%, 16.2%, and 26.9%, respectively. cSS multifocality (presence and spread) was the only independent predictor of increased symptomatic ICH risk (hazard ratio 3.19; 95% confidence interval 1.77-5.75; p < 0.0001). CONCLUSIONS: The multifocality of cSS correlates with disease severity in probable CAA; therefore cSS is likely to be caused by discrete hemorrhagic foci. The new cSS scoring system might be valuable for clinicians in determining annual risk of ICH recurrence.
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Angiopatia Amiloide Cerebral/complicações , Córtex Cerebral/patologia , Hemorragia Cerebral/complicações , Siderose/etiologia , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Imageamento por Ressonância Magnética , Masculino , Modelos de Riscos Proporcionais , Índice de Gravidade de Doença , Siderose/diagnóstico por imagemRESUMO
INTRODUCTION: An MRI-based score of total small vessel disease burden (CAA-SVD-Score) in cerebral amyloid angiopathy (CAA) has been demonstrated to correlate with severity of pathologic changes. Evidence suggests that CAA-related intracerebral hemorrhage (ICH) recurrence risk is associated with specific disease imaging manifestations rather than overall severity. We compared the correlation between the CAA-SVD-Score with the risk of recurrent CAA-related lobar ICH versus the predictive role of each of its components. METHODS: Consecutive patients with CAA-related ICH from a single-center prospective cohort were analyzed. Radiological markers of CAA related SVD damage were quantified and categorized according to the CAA-SVD-Score (0-6 points). Subjects were followed prospectively for recurrent symptomatic ICH. Adjusted Cox proportional hazards models were used to investigate associations between the CAA-SVD-Score as well as each of the individual MRI signatures of CAA and the risk of recurrent ICH. RESULTS: In 229 CAA patients with ICH, a total of 56 recurrent ICH events occurred during a median follow-up of 2.8years [IQR 0.9-5.4years, 781 person-years). Higher CAA-SVD-Score (HR=1.26 per additional point, 95%CI [1.04-1.52], p=0.015) and older age were independently associated with higher ICH recurrence risk. Analysis of individual markers of CAA showed that CAA-SVD-Score findings were due to the independent effect of disseminated superficial siderosis (HR for disseminated cSS vs none: 2.89, 95%CI [1.47-5.5], p=0.002) and high degree of perivascular spaces enlargement (RR=3.50-95%CI [1.04-21], p=0.042). CONCLUSION: In lobar CAA-ICH patients, higher CAA-SVD-Score does predict recurrent ICH. Amongst individual elements of the score, superficial siderosis and dilated perivascular spaces are the only markers independently associated with ICH recurrence, contributing to the evidence for distinct CAA phenotypes singled out by neuro-imaging manifestations.
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Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Imageamento por Ressonância Magnética , Idoso , Angiopatia Amiloide Cerebral/epidemiologia , Angiopatia Amiloide Cerebral/fisiopatologia , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/fisiopatologia , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Recidiva , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Patients with cerebral amyloid angiopathy (CAA) show loss of white matter connectivity and cortical thinning on MRI, primarily in posterior brain regions. Here we examined whether a potential causal relationship exists between these markers of subcortical and cortical brain injury by examining whether changes in cortical thickness progress in tandem with changes in their underlying connections. Thirty-one patients with probable CAA with brain MRI at two time points were included (follow-up time: 1.3 ± 0.4 years). Brain networks were reconstructed using diffusion MRI-based fiber tractography. Of each network node, we calculated the change in fractional anisotropy-weighted connectivity strength over time and the change in cortical thickness. The association between change in connectivity strength and cortical thickness was assessed with (hierarchical) linear regression models. Our results showed that decline in posterior network connectivity over time was strongly related to thinning of the occipital cortex (ß = 0.65 (0.35-0.94), P < 0.001), but not to thinning of the other posterior or frontal cortices. However, at the level of individual network nodes, we found no association between connectivity strength and cortical thinning of the corresponding node (ß = 0.009 ± 0.04, P = 0.80). Associations were independent of age, sex, and other brain MRI markers of CAA. To conclude, CAA patients with greater progressive loss of posterior white matter connectivity also have greater progression of occipital cortical thinning, but our results do not support a direct causal relationship between them. The association can be better explained by a shared underlying mechanism, which may form a potential target for future treatments. Hum Brain Mapp 38:3723-3731, 2017. © 2017 Wiley Periodicals, Inc.
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OBJECTIVE: To assess MRI-visible enlarged perivascular spaces (EPVS) burden and different topographical patterns (in the centrum semiovale [CSO] and basal ganglia [BG]) in 2 common microangiopathies: cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). METHODS: Consecutive patients with spontaneous intracerebral hemorrhage (ICH) from a prospective MRI cohort were included. Small vessel disease MRI markers, including cerebral microbleeds (CMBs), cortical superficial siderosis (cSS), and white matter hyperintensities (WMH), were rated. CSO-EPVS/BG-EPVS were assessed on a validated 4-point visual rating scale (0 = no EPVS, 1 = <10, 2 = 11-20, 3 = 21-40, and 4 = >40 EPVS). We tested associations of predefined high-degree (score >2) CSO-EPVS and BG-EPVS with other MRI markers in multivariable logistic regression. We subsequently evaluated associations with CSO-EPVS predominance (i.e., CSO-EPVS > BG-EPVS) and BG-EPVS predominance pattern (i.e., BG-EPVS > CSO-EPVS) in adjusted multinomial logistic regression (reference group, BG-EPVS = CSO-EPVS). RESULTS: We included 315 patients with CAA-ICH and 137 with HA-ICH. High-degree CSO-EPVS prevalence was greater in CAA-related ICH vs HA-related ICH (43.8% vs 17.5%, p < 0.001). In multivariable logistic regression, high-degree CSO-EPVS was associated with lobar CMB (odds ratio [OR] 1.33, 95% confidence interval [CI] 1.10-1.61, p = 0.003) and cSS (OR 2.08, 95% CI 1.30-3.32, p = 0.002). Deep CMBs (OR 2.85, 95% CI 1.75-4.64, p < 0.0001) and higher WMH volume (OR 1.02, 95% CI 1.01-1.04, p = 0.010) were predictors of high-degree BG-EPVS. A CSO-EPVS-predominant pattern was more common in CAA-ICH than in HA-ICH (75.9% vs 39.4%, respectively, p < 0.0001). CSO-PVS predominance was associated with lobar CMB burden and cSS, while BG-EPVS predominance was associated with HA-ICH and WMH volumes. CONCLUSIONS: Different patterns of MRI-visible EPVS provide insights into the dominant underlying microangiopathy type in patients with spontaneous ICH.
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Angiopatia Amiloide Cerebral/diagnóstico por imagem , Artérias Cerebrais/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Hipertensão/diagnóstico por imagem , Espaço Subaracnóideo/diagnóstico por imagem , Idoso , Artérias Cerebrais/patologia , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Imageamento por Ressonância Magnética , Masculino , Índice de Gravidade de Doença , Siderose/complicaçõesRESUMO
OBJECTIVE: To characterize the temporal and spatial pattern of cerebral microbleeds (CMBs) after cranial irradiation in patients with medulloblastoma. METHODS: We retrospectively identified patients with medulloblastoma treated with craniospinal irradiation at the Massachusetts General Hospital between 1999 and 2015. Longitudinal MRI including T2*-weighted gradient-recalled echo (GRE) sequences were reviewed, and the prevalence, spatial pattern, and risk factors associated with CMBs were characterized. RESULTS: We identified a total of 27 patients; 5 patients were children (median age 6.3 years) and 22 patients were adults (median age 28.8 years). CMBs were found in 67% (18/27) of patients, who were followed for a median of 4.1 years. Patients with CMBs had longer GRE follow-up time compared to those without CMBs (4.9 vs 1.7 years, p = 0.035). The median latency of the appearance of CMBs was 2.79 years (interquartile range 1.76-4.26). The prevalence of CMBs increased with each year from time of radiation therapy, and the cumulative prevalence was highest in patients age <20 years (100% cumulative prevalence, vs 59% in adult patients treated at age ≥20 years). CMBs were mostly found in lobar distribution and predominately in bilateral occipital lobes. Patients using antithrombotic medications developed CMBs at a significantly higher rate (p = 0.041). CONCLUSIONS: Our data demonstrate a high prevalence of CMBs following cranial irradiation, progressively increasing with each year from time of radiation therapy.
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Neoplasias Encefálicas/radioterapia , Hemorragia Cerebral/etiologia , Irradiação Craniana/efeitos adversos , Meduloblastoma/radioterapia , Lesões por Radiação/etiologia , Adulto , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/cirurgia , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/prevenção & controle , Criança , Pré-Escolar , Feminino , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Seguimentos , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Meduloblastoma/epidemiologia , Meduloblastoma/cirurgia , Prevalência , Lesões por Radiação/epidemiologia , Lesões por Radiação/prevenção & controle , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
OBJECTIVE: To identify predictors of early lobar intracerebral hemorrhage (ICH) recurrence, defined as a new ICH within 6 months of the index event, in patients with cerebral amyloid angiopathy (CAA). METHODS: Participants were consecutive survivors (age ≥55 years) of spontaneous symptomatic probable or possible CAA-related lobar ICH according to the Boston criteria, drawn from an ongoing single-center cohort study. Neuroimaging markers ascertained in CT or MRI included focal (≤3 sulci) or disseminated (>3 sulci) cortical superficial siderosis (cSS), acute convexity subarachnoid hemorrhage (cSAH), cerebral microbleeds, white matter hyperintensities burden and location, and baseline ICH volume. Participants were followed prospectively for recurrent symptomatic ICH. Cox proportional hazards models were used to identify predictors of early recurrent ICH adjusting for potential confounders. RESULTS: A total of 292 patients were enrolled. Twenty-one patients (7%) had early recurrent ICH. Of these, 24% had disseminated cSS on MRI and 19% had cSAH on CT scan. In univariable analysis, the presence of disseminated cSS, cSAH, and history of previous ICH were predictors of early recurrent ICH (p < 0.05 for all comparisons). After adjusting for age and history of previous ICH, disseminated cSS on MRI and cSAH on CT were independent predictors of early recurrent ICH (hazard ratio [HR] 3.92, 95% confidence interval [CI] 1.38-11.17, p = 0.011, and HR 3.48, 95% CI 1.13-10.73, p = 0.030, respectively). CONCLUSIONS: Disseminated cSS on MRI and cSAH on CT are independent imaging markers of increased risk for early recurrent ICH. These markers may provide additional insights into the mechanisms of ICH recurrence in patients with CAA.
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Córtex Cerebral/patologia , Hemorragia Cerebral/complicações , Siderose/complicações , Siderose/patologia , Idoso , Apolipoproteínas E/genética , Angiopatia Amiloide Cerebral , Córtex Cerebral/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/genética , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Siderose/diagnóstico por imagem , Siderose/genética , Estatísticas não Paramétricas , Hemorragia Subaracnóidea/diagnóstico por imagem , Hemorragia Subaracnóidea/etiologia , Tomógrafos ComputadorizadosRESUMO
BACKGROUND: The association between cerebral small vessel diseases (cSVD) and intracranial atherosclerosis is debated and conflicting results have been reported. We sought to investigate this association in patients with intracerebral hemorrhage (ICH), due to severe cSVD. METHODS: Consecutive ICH patients were divided into those meeting criteria for cerebral amyloid angiopathy (CAA) and those with deep hypertensive ICH consistent with hypertensive cSVD (HTN-SVD). White matter hyperintensity volumes (WMH) and microbleed counts (MB) were measured on MRI. CTA was rated for severity of intracranial carotid calcifications and for presence of >50% intracranial stenosis (ICS). Associations of intracranial atherosclerosis severity with type of SVD (CAA vs HTN-cSVD) and with imaging and clinical markers of cSVD burden were analyzed. RESULTS: The cohort included 253 CAA and 90 HTN-SVD patients. In multivariable models, the type of cSVD (CAA vs. HTN-cSVD) was not associated with calcification severity (OR=1.04, 95% CI [0.62-3.5], p=0.37) or presence of ICS (OR=0.84, 95% CI [0.21-2.74], p=0.78). We found no association between intracranial atherosclerosis (calcifications and stenoses) and parenchymal markers of cSVD severity (WMH and MB, adjusted p≥0.2 for all comparisons) and no association with presence of dementia before ICH (adjusted p≥0.2 for both comparisons). CONCLUSIONS: We found no association between intracranial atherosclerosis and parenchymal or clinical consequences of cSVD, suggesting that cSVDs while sharing some risk factors are not influenced by upstream larger vessel pathologies.
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Hemorragia Cerebral/complicações , Doenças de Pequenos Vasos Cerebrais/complicações , Arteriosclerose Intracraniana/complicações , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/patologia , Doenças de Pequenos Vasos Cerebrais/patologia , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Arteriosclerose Intracraniana/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Substância Branca/diagnóstico por imagemRESUMO
OBJECTIVES: To identify in vivo MRI markers that might correlate with cerebral microinfarcts (CMIs) on autopsy in patients with cerebral amyloid angiopathy (CAA). METHODS: We included patients with neuropathologic evidence of CAA on autopsy and available antemortem brain MRI. Clinical characteristics and in vivo MRI markers of CAA-related small vessel disease were recorded, including white matter hyperintensities, cerebral microbleeds, cortical superficial siderosis, and centrum semiovale perivascular spaces. In addition, the presence of intracerebral hemorrhage on MRI was assessed. Evaluation of the presence and number of CMIs was performed in 9 standard histology sections. RESULTS: Of 49 analyzed patients with CAA, CMIs were present in 36.7%. The presence of ≥1 CMIs on autopsy was associated with higher numbers of microbleeds on antemortem MRI (median 8 [interquartile range 2.5-33.0] vs 1 [interquartile range 0-3], p = 0.003) and with the presence of intracerebral hemorrhage (44.4% vs 16.1%, p = 0.03). No associations between CMIs and other in vivo MRI markers of CAA were found. In a multivariable model adjusted for severe CAA pathology, higher numbers of microbleeds were independent predictors of the presence of CMIs on pathology. CONCLUSIONS: CMIs are a common finding at autopsy in patients with CAA. The strong association between MRI-observed microbleeds and CMIs at autopsy may suggest a shared underlying pathophysiologic mechanism between these lesions.
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Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/patologia , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/patologia , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/patologia , Fatores Etários , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologia , Infarto Encefálico/complicações , Infarto Encefálico/fisiopatologia , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/fisiopatologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Análise MultivariadaRESUMO
IMPORTANCE: Cerebral amyloid angiopathy (CAA) is characteristically associated with magnetic resonance imaging (MRI) biomarkers of small vessel brain injury, including strictly lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. Although these neuroimaging markers reflect distinct pathophysiologic aspects in CAA, no studies to date have combined these structural imaging features to gauge total brain small vessel disease burden in CAA. OBJECTIVES: To investigate whether a composite score can be developed to capture the total brain MRI burden of small vessel disease in CAA and to explore whether this score contributes independent and complementary information about CAA severity, defined as intracerebral hemorrhage during life or bleeding-related neuropathologic changes. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, cross-sectional study examined a single-center neuropathologic CAA cohort of eligible patients from the Massachusetts General Hospital from January 1, 1997, through December 31, 2012. Data analysis was performed from January 2, 2015, to January 9, 2016. Patients with pathologic evidence of CAA (ie, any presence of CAA from routinely collected brain biopsy specimen, biopsy specimen at hematoma evacuation, or autopsy) and available brain MRI sequences of adequate quality, including T2-weighted, T2*-weighted gradient-recalled echo, and/or susceptibility-weighted imaging and fluid-attenuated inversion recovery sequences, were considered for the study. MAIN OUTCOMES AND MEASURES: Brain MRIs were rated for lobar cerebral microbleeds, cortical superficial siderosis, centrum semiovale perivascular spaces, and white matter hyperintensities. All 4 MRI lesions were incorporated into a prespecified ordinal total small vessel disease score, ranging from 0 to 6 points. Associations with severity of CAA-associated vasculopathic changes (fibrinoid necrosis and concentric splitting of the wall), clinical presentation, number of intracerebral hemorrhages, and other imaging markers not included in the score were explored using logistic and ordinal regression. RESULTS: In total, 105 patients with pathologically defined CAA were included: 52 with autopsies, 22 with brain biopsy specimens, and 31 with pathologic samples from hematoma evacuations. The mean (range) age of the patients was 73 (71-74) years, and 55 (52.4%) were women. In multivariable ordinal regression analysis, severity of CAA-associated vasculopathic changes (odds ratio, 2.40; 95% CI, 1.06-5.45; P = .04) and CAA presentation with symptomatic intracerebral hemorrhage (odds ratio, 2.23; 95% CI, 1.07-4.64; P = .03) were independently associated with the total MRI small vessel disease score. The score was associated with small, acute, diffusion-weighted imaging lesions and posterior white matter hyperintensities in adjusted analyses. CONCLUSIONS AND RELEVANCE: This study provides evidence of concept validity of a total MRI small vessel disease score in CAA. After further validation, this approach can be potentially used in prospective clinical studies.
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Angiopatia Amiloide Cerebral/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Doenças de Pequenos Vasos Cerebrais/etiologia , Imageamento por Ressonância Magnética , Idoso , Biópsia , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Análise de Regressão , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Long-term exposure to ambient air pollution has been associated with impaired cognitive function and vascular disease in older adults, but little is known about these associations among people with concerns about memory loss. OBJECTIVE: To examine associations between exposures to fine particulate matter and residential proximity to major roads and markers of small vessel disease. METHODS: From 2004-2010, 236 participants in the Massachusetts Alzheimer's Disease Research Center Longitudinal Cohort participated in neuroimaging studies. Residential proximity to major roads and estimated 2003 residential annual average of fine particulate air pollution (PM2.5) were linked to measures of brain parenchymal fraction (BPF), white matter hyperintensities (WMH), and cerebral microbleeds. Associations were modeled using linear and logistic regression and adjusted for clinical and lifestyle factors. RESULTS: In this population (median age [interquartile range]â=â74 [12], 57% female) living in a region with median 2003 PM2.5 annual average below the current Environmental Protection Agency (EPA) standard, there were no associations between living closer to a major roadway or for a 2µg/m3 increment in PM2.5 and smaller BPF, greater WMH volume, or a higher odds of microbleeds. However, a 2µg/m3 increment in PM2.5 was associated with -0.19 (95% Confidence Interval (CI): -0.37, -0.005) lower natural log-transformed WMH volume. Other associations had wide confidence intervals. CONCLUSIONS: In this population, where median 2003 estimated PM2.5 levels were below the current EPA standard, we observed no pattern of association between residential proximity to major roads or 2003 average PM2.5 and greater burden of small vessel disease or neurodegeneration.
Assuntos
Poluição do Ar , Transtornos Cerebrovasculares/epidemiologia , Exposição Ambiental , Habitação , Veículos Automotores , Material Particulado , Idoso , Poluentes Atmosféricos , Encéfalo/diagnóstico por imagem , Transtornos Cerebrovasculares/diagnóstico por imagem , Feminino , Geografia Médica , Humanos , Modelos Lineares , Modelos Logísticos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Razão de Chances , Estados UnidosRESUMO
BACKGROUND: Loss of cortical grey matter is a diagnostic marker of many neurodegenerative diseases, and is a key mediator of cognitive impairment. We postulated that cerebral amyloid angiopathy (CAA), characterised by cortical vascular amyloid deposits, is associated with cortical tissue loss independent of parenchymal Alzheimer's disease pathology. We tested this hypothesis in patients with hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D), a monogenetic disease with minimal or no concomitant Alzheimer's disease pathology, as well as in patients with sporadic CAA and healthy and Alzheimer's disease controls. METHODS: In this observational case-control study, we included six groups of participants: patients diagnosed with HCHWA-D using genetic testing; healthy controls age-matched to the HCHWA-D group; patients with probable sporadic CAA without dementia; two independent cohorts of healthy controls age-matched to the CAA group; and patients with Alzheimer's disease age-matched to the CAA group. De-identified (but unmasked) demographic, clinical, radiological, and genetic data were collected at Massachusetts General Hospital (Boston, MA, USA), at Leiden University (Leiden, Netherlands), and at sites contributing to Alzheimer's Disease Neuroimaging Initiative (ADNI). The primary outcome measure was cortical thickness. The correlations between cortical thickness and structural lesions, and blood-oxygen-level-dependent time-to-peak (BOLD-TTP; a physiological measure of vascular dysfunction) were analysed to understand the potential mechanistic link between vascular amyloid and cortical thickness. The radiological variables of interest were quantified using previously validated computer-assisted tools, and all results were visually reviewed to ensure their accuracy. RESULTS: Between March 15, 2006, and Dec 1, 2014, we recruited 369 individuals (26 patients with HCHWA-D and 28 age-matched, healthy controls; 63 patients with sporadic CAA without dementia; two healthy control cohorts with 63 and 126 individuals; and 63 patients with Alzheimer's disease). The 26 patients with HCHWA-D had thinner cortices (2·31 mm [SD 0·18]) than the 28 healthy controls (mean difference -0·112 mm, 95% CI -0·190 to -0·034, p=0·006). The 63 patients with sporadic CAA without dementia had thinner cortices (2·17 mm [SD 0·11]) than the two healthy control cohorts (n=63, mean difference -0·14 mm, 95% CI -0·17 to -0·10, p<0·0001; and n=126, -0·10, -0·13 to -0·06, p<0·0001). All differences remained independent in multivariable analyses. The 63 patients with Alzheimer's disease displayed more severe atrophy than the patients with sporadic CAA (2·1 mm [SD 0·14], difference 0·07 mm, 95% CI 0·11 to 0·02, p=0·005). We found strong associations between cortical thickness and vascular dysfunction in the patients with HCHWA-D (ρ=-0·58, p=0·003) or sporadic CAA (r=-0·4, p=0·015), but not in controls. Vascular dysfunction was identified as a mediator of the effect of hereditary CAA on cortical atrophy, accounting for 63% of the total effect. INTERPRETATION: The appearance of cortical thinning in patients with HCHWA-D indicates that vascular amyloid is an independent contributor to cortical atrophy. These results were reproduced in patients with the more common sporadic CAA. Our findings also suggest that CAA-related cortical atrophy is at least partly mediated by vascular dysfunction. Our results also support the view that small vessel diseases such as CAA can cause cortical atrophy even in the absence of Alzheimer's disease, a conclusion that can help radiologists, neurologists, and other clinicians who diagnose these common geriatric conditions. FUNDING: National Institutes of Health.
Assuntos
Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Adulto , Idoso , Amiloidose/diagnóstico por imagem , Amiloidose/etiologia , Atrofia/diagnóstico por imagem , Atrofia/etiologia , Estudos de Casos e Controles , Angiopatia Amiloide Cerebral/genética , Córtex Cerebral/diagnóstico por imagem , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/etiologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
BACKGROUND: Cerebral amyloid angiopathy (CAA) is increasingly recognized as a cause of cognitive impairment in the elderly, but the cognitive profile in patients with the disease has not been well characterized. OBJECTIVE: To characterize the neuropsychological profile of CAA patients without dementia and to determine the association between cognitive performance in different domains and neuroimaging lesions characteristic of CAA. METHODS: Fifty-eight non-demented CAA patients were compared to 138 cognitively normal subjects using a standard neuropsychological test battery. Total brain volume (TBV), white matter hyperintensities, number of lobar cerebral microbleeds, hippocampal volume, and cortical superficial siderosis in all CAA patients were assessed. The association between these neuroimaging markers and neuropsychological performance in different cognitive domains in the CAA group were analyzed. RESULTS: Patients with CAA had significantly worse performance on all individual neuropsychological domains tested, when compared to the cognitive normal group. The cognitive decline of CAA patients was most noticeable in tests for processing speed with a Z score of -1.92±1.56 (mean±SD), then followed by executive function (-0.93±1.01), episodic memory (-0.87±1.29), semantic fluency (-0.73±1.06), and attention (-0.42±0.98). TBV of the CAA patients was correlated with processing speed (ß=â0.335, pâ=â0.03) and executive function (ß=â0.394, pâ=â0.01). CONCLUSIONS: Non-demented patients with CAA had cognitive deficits in multiple areas. Lower TBV was related to slower processing speed and worse executive function.
Assuntos
Encéfalo/diagnóstico por imagem , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/psicologia , Cognição , Imageamento por Ressonância Magnética , Idoso , Atrofia/diagnóstico por imagem , Atrofia/psicologia , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/terapia , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Acidente Vascular Cerebral/terapiaRESUMO
IMPORTANCE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is an important diagnosis to reach in clinical practice because many patients with the disease respond to immunosuppressive therapy. Reliable noninvasive diagnostic criteria for CAA-ri would allow some patients to avoid the risk of brain biopsy. OBJECTIVE: To test the sensitivity and specificity of clinical and neuroimaging-based criteria for CAA-ri. DESIGN, SETTING, AND PARTICIPANTS: We modified the previously proposed clinicoradiological criteria and retrospectively analyzed clinical medical records and magnetic resonance imaging fluid-attenuated inversion recovery and gradient-echo scans obtained from individuals with CAA-ri and noninflammatory CAA. At 2 referral centers between October 1, 1995, and May 31, 2013, and between January 1, 2009, and December 31, 2011, participants included 17 individuals with pathologically confirmed CAA-ri and 37 control group members with pathologically confirmed noninflammatory CAA. The control group was further divided into those with past lobar intracerebral hemorrhage (ICH) (n = 21) and those with cerebral microbleeds only and no history of ICH (n = 16). The dates of our analysis were September 1, 2012, to August 31, 2015. MAIN OUTCOMES AND MEASURES: The sensitivity and specificity of prespecified criteria for probable CAA-ri (requiring asymmetric white matter hyperintensities extending to the subcortical white matter) and possible CAA-ri (not requiring the white matter hyperintensities to be asymmetric). RESULTS: The 17 patients in the CAA-ri group were a mean (SD) of 68 (8) years and 8 (47%) were women. In the CAA-ri group, 14 of 17 (82%) met the criteria for both probable and possible CAA-ri. In the control group having noninflammatory CAA with lobar ICH, 1 of 21 (5%) met the criteria for possible CAA-ri, and none met the criteria for probable CAA-ri. In the control group having noninflammatory CAA with no ICH, 11 of 16 (69%) met the criteria for possible CAA-ri, and 1 of 16 (6%) met the criteria for probable CAA-ri. These findings yielded a sensitivity and specificity of 82% and 97%, respectively, for the probable criteria and a sensitivity and specificity of 82% and 68%, respectively, for the possible criteria. CONCLUSIONS AND RELEVANCE: Our data suggest that a reliable diagnosis of CAA-ri can be reached from basic clinical and magnetic resonance imaging information alone, with good sensitivity and excellent specificity.
Assuntos
Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/patologia , Feminino , Humanos , Inflamação/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Radiografia , Estudos RetrospectivosRESUMO
OBJECTIVE: To identify different white matter hyperintensity (WMH) patterns between 2 hemorrhage-prone cerebral small vessel diseases (SVD): cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy (HA). METHODS: Consecutive patients with SVD-related intracerebral hemorrhage (ICH) from a single-center prospective cohort were analyzed. Four predefined subcortical WMH patterns were compared between the CAA and HA groups. These WMH patterns were (1) multiple subcortical spots; (2) peri-basal ganglia (BG); (3) large posterior subcortical patches; and (4) anterior subcortical patches. Their associations with other imaging (cerebral microbleeds [CMBs], enlarged perivascular spaces [EPVS]) and clinical markers of SVD were investigated using multivariable logistic regression. RESULTS: The cohort included 319 patients with CAA and 137 patients with HA. Multiple subcortical spots prevalence was higher in the CAA compared to the HA group (29.8% vs 16.8%; p = 0.004). Peri-BG WMH pattern was more common in the HA- vs the CAA-ICH group (19% vs 7.8%; p = 0.001). In multivariable logistic regression, presence of multiple subcortical spots was associated with lobar CMBs (odds ratio [OR] 1.23; 95% confidence interval [CI] 1.01-1.50, p = 0.039) and high degree of centrum semiovale EPVS (OR 2.43; 95% CI 1.56-3.80, p < 0.0001). By contrast, age (OR 1.05; 95% CI 1.02-1.09, p = 0.002), deep CMBs (OR 2.46; 95% CI 1.44-4.20, p = 0.001), total WMH volume (OR 1.02; 95% CI 1.01-1.04, p = 0.002), and high BG EPVS degree (OR 8.81; 95% CI 3.37-23.02, p < 0.0001) were predictors of peri-BG WMH pattern. CONCLUSION: Different patterns of subcortical leukoaraiosis visually identified on MRI might provide insights into the dominant underlying microangiopathy type as well as mechanisms of tissue injury in patients with ICH.
Assuntos
Angiopatia Amiloide Cerebral/complicações , Hemorragia Cerebral/patologia , Hipertensão/patologia , Substância Branca/patologia , Idoso , Angiopatia Amiloide Cerebral/diagnóstico , Angiopatia Amiloide Cerebral/patologia , Doenças Arteriais Cerebrais/etiologia , Doenças Arteriais Cerebrais/patologia , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/etiologia , Diagnóstico Diferencial , Feminino , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico , Modelos Logísticos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Substância Branca/fisiopatologiaRESUMO
BACKGROUND: Cerebral amyloid angiopathy (CAA) is associated with many cases of spontaneous symptomatic lobar intracerebral haemorrhage in older individuals and is emerging as an important contributor to cognitive impairment. Cortical superficial siderosis (cSS) is an increasingly recognized haemorrhagic neuroimaging manifestation of CAA. We sought to investigate its prevalence and its association with underlying CAA among memory clinic patients. METHODS: We included consecutive eligible patients who presented to the out-patient memory clinic at the Massachusetts General Hospital from 2007 to 2010 and had appropriate MRI, including blood-sensitive sequences. We analyzed the prevalence and topography of cSS according to demographic, clinical, APOE and MRI data. RESULTS: Our cohort consisted of 339 memory clinic patients: Alzheimer's disease (n = 86); mild cognitive impairment (n = 162); vascular dementia/mixed dementia (n = 18); other dementia/undetermined (n = 42); and subjective cognitive complains (n = 31). cSS was detected in 10 patients (3%; 95% CI 1.4-5.4): in 7 cases cSS was focal and in 3 cases, it was disseminated. In multivariable logistic regression analysis, the presence of cSS was associated with lobar microbleeds (OR 1.08; 95% CI 1.03-1.13; p = 0.001, per each additional microbleed) and severe white matter hyperintensities (Fazekas score 5-6, OR 4.43; 95% CI 1.21-26.28; p = 0.028) after adjusting for age. These associations were not influenced by the clinical diagnosis. In patients with APOE data, the APOE ε4/ε4 genotype was overrepresented among subjects with vs. without cSS. In the subgroup of patients with probable CAA (n = 68; 9 with cSS) based on the presence of strictly lobar microbleeds, cSS was also associated with a higher prevalence of severe white matter hyperintensities (66.7 vs. 10.2%; p = 0.001), high centrum semiovale perivascular spaces burden (88.9 vs. 52.4%; p = 0.041) and higher counts of lobar microbleeds (median 13; IQR 10-36 vs. median 1; IQR 1-2; p < 0.00001), compared to patients without cSS. CONCLUSIONS: Our data provide further evidence supporting the hypothesis that cSS is a manifestation of advanced CAA in memory clinic populations. Future longitudinal studies should explore any direct effect of cSS on cognition or haemorrhage risk and disease progression.
Assuntos
Angiopatia Amiloide Cerebral/fisiopatologia , Memória/fisiologia , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Angiopatia Amiloide Cerebral/complicações , Hemorragia Cerebral/complicações , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , NeuroimagemRESUMO
Perivascular spaces are an emerging marker of small vessel disease. Perivascular spaces in the centrum semiovale have been associated with cerebral amyloid angiopathy. However, a direct topographical relationship between dilated perivascular spaces and cerebral amyloid angiopathy severity has not been established. We examined this association using post-mortem magnetic resonance imaging in five cases with evidence of cerebral amyloid angiopathy pathology. Juxtacortical perivascular spaces dilation was evaluated on T2 images and related to cerebral amyloid angiopathy severity in overlying cortical areas on 34 tissue sections stained for Amyloid ß. Degree of perivascular spaces dilation was significantly associated with cerebral amyloid angiopathy severity (odds ratio = 3.3, 95% confidence interval 1.3-7.9, p = 0.011). Thus, dilated juxtacortical perivascular spaces are a promising neuroimaging marker of cerebral amyloid angiopathy severity.
Assuntos
Peptídeos beta-Amiloides/análise , Angiopatia Amiloide Cerebral/patologia , Córtex Cerebral/irrigação sanguínea , Idoso , Idoso de 80 Anos ou mais , Córtex Cerebral/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , MasculinoRESUMO
BACKGROUND AND PURPOSE: Cerebral microinfarcts (CMI) are important contributors to vascular cognitive impairment. Magnetic resonance imaging diffusion-weighted imaging (DWI) hyperintensities have been suggested to represent acute CMI. We aim to describe a mathematical method for estimating total number of CMI based on the presence of incidental DWI lesions. METHODS: We reviewed magnetic resonance imaging scans of subjects with cognitive decline, cognitively normal subjects and previously reported subjects with past intracerebral hemorrhage (ICH). Based on temporal and spatial characteristics of DWI lesions, we estimated the annual rate of CMI needed to explain the observed rate of DWI lesion detection in each group. To confirm our estimates, we performed extensive sampling for CMI in the brain of a deceased subject with past lobar ICH who found to have a DWI lesion during life. RESULTS: Clinically silent DWI lesions were present in 13 of 343 (3.8%) cognitively impaired and 10 of 199 (5%) cognitively intact normal non-ICH patients, both lower than the incidence in the past ICH patients (23 of 178; 12.9%; P<0.0006). The predicted annual incidence of CMI ranges from 16 to 1566 for non-ICH and 50 to 5041 for ICH individuals. Histological sampling revealed a total of 60 lesions in 32 sections. Based on previously reported methods, this density of CMI yields an estimated total brain burden maximum likelihood estimate of 9321 CMIs (95% confidence interval, 7255-11 990). CONCLUSIONS: Detecting even a single DWI lesion suggests an annual incidence of hundreds of new CMI. The cumulative effects of these lesions may directly contribute to small-vessel-related vascular cognitive impairment.