OBJECTIVES:We sought to examine whether a posterior distribution of white matter hyperintensities (WMH) is an independent predictor of pathologically confirmed cerebral amyloid angiopathy (CAA) and ...whether it is associated with MRI markers of CAA, in patients without lobar intracerebral hemorrhage.
METHODS:We developed a quantitative method to measure anteroposterior (AP) distribution of WMH. A retrospective cohort of patients without intracerebral hemorrhage and with pathologic evaluation of CAA was examined to determine whether posterior WMH distribution was an independent predictor of CAA (n = 59). The relationship of AP distributions of WMH to strictly lobar microbleeds (MBs) (n = 259) and location of dilated perivascular spaces (DPVS) (n = 85) was examined in a separate cohort of patients evaluated in a memory clinic.
RESULTS:A more posterior WMH distribution was found to be an independent predictor of pathologic evidence of CAA (p = 0.001, odds ratio 95% confidence interval = 1.19 1.07–1.32), even in the subgroup without lobar MBs (p = 0.016, odds ratio 95% confidence interval = 1.18 1.03–1.36). In the memory clinic cohort, strictly lobar MBs were independently associated with more posterior WMH distribution (p = 0.009). AP distribution of WMH was also associated with location of DPVS (p = 0.001), in that patients with predominant DPVS in the white matter over the basal ganglia harbored a more posterior WMH distribution.
CONCLUSIONS:Our results suggest that AP distribution of WMH may represent an additional marker of CAA, irrespective of the presence of lobar hemorrhages.
CLASSIFICATION OF EVIDENCE:This study provides Class III evidence that there is a significant association between the AP distribution of WMH on MRI with the presence of pathologically confirmed CAA pathology.
Low levels of serum albumin may increase the risk of infections and mortality in critically ill patients. We tested the hypothesis that admission hypoalbuminemia predicted infectious complications ...and poor outcome in subjects with acute intracerebral hemorrhage (ICH). We analyzed a single center cohort of ICH patients collected between 1994 and 2015. Pneumonia, urinary tract infection and sepsis were retrospectively identified, according to validated criteria. Serum albumin was measured on admission and hypoalbuminemia was defined as total albumin ≤3.5 g/dL. The association between albumin levels, infections, and mortality at 90 days was tested with multivariable logistic regression analyses. A total of 2010 patients were included (median age 74 years, 54.5% males) of whom 444 (22.1%) had hypoalbuminemia on admission and 763 (38%) died within 90 days. The frequency of pneumonia, urinary tract infection, and sepsis was 19.9, 15.1, and 2.7%, respectively. Hypoalbuminemic patients had lower admission Glasgow coma scale, higher frequency of intraventricular hemorrhage and were more likely to have a history of chronic kidney or liver disease. After adjustment for potential confounders, hypoalbuminemia was an independent predictor of pneumonia odds ratio (OR) 1.76, 95% confidence interval (CI) 1.34–2.33,
p
< 0.001 and sepsis (OR 2.29, 95% CI 1.22–4.30,
p
= 0.010). Low levels of albumin were also independently associated with higher mortality at 90 days (OR 1.78, 95% CI 1.30–2.44,
p
< 0.001). In conclusion, early hypoalbuminemia is common and predicts poor outcome in ICH patients. Increased susceptibility to pneumonia and sepsis may be the pathophysiological mechanism underlying this association.
BACKGROUND AND PURPOSE—Although the computed tomographic angiography spot sign performs well as a biomarker for hematoma expansion (HE), computed tomographic angiography is not routinely performed in ...the emergency setting. We developed and validated a score to predict HE-based on noncontrast computed tomography (NCCT) findings in spontaneous acute intracerebral hemorrhage.
METHODS—After developing the score in a single-center cohort of patients with intracerebral hemorrhage (n=344), we validated it in a large clinical trial population (n=954) and in a multicenter intracerebral hemorrhage cohort (n=241). The following NCCT markers of HE were analyzedhypodensities, blend sign, hematoma shape and density, and fluid level. HE was defined as hematoma growth >6 mL or >33%. The score was created using the estimates from multivariable logistic regression after final predictors were selected from bootstrap samples.
RESULTS—Presence of blend sign (odds ratio, 3.09; 95% confidence interval CI,1.49–6.40; P=0.002), any intrahematoma hypodensity (odds ratio, 4.54; 95% CI, 2.44–8.43; P<0.0001), and time from onset to NCCT <2.5 hours (odds ratio, 3.73; 95% CI, 1.86–7.51; P=0.0002) were predictors of HE. A 5-point score was created (BAT score1 point for blend sign, 2 points for any hypodensity, and 2 points for timing of NCCT <2.5 hours). The c statistic was 0.77 (95% CI, 0.70–0.83) in the development population, 0.65 (95% CI 0.61–0.68) and 0.70 (95% CI, 0.64–0.77) in the 2 validation cohorts. A dichotomized score (BAT score ≥3) predicted HE with 0.50 sensitivity and 0.89 specificity.
CONCLUSIONS—An easy to use 5-point prediction score can identify subjects at high risk of HE with good specificity and accuracy. This tool requires just a baseline NCCT scan and may help select patients with intracerebral hemorrhage for antiexpansion clinical trials.
IMPORTANCE: Patients who have experienced intracerebral hemorrhage (ICH) appear to develop cognitive impairment at high rates, both early after ICH and over the long term. OBJECTIVE: To identify and ...compare risk factors for early and delayed dementia after ICH. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal study enrolled patients who had experienced ICH from January 1, 2006, to December 31, 2013. A total of 738 participants 18 years or older, without pre-ICH dementia, who presented to a tertiary care academic institution with primary ICH were included in the analyses of early post-ICH dementia (EPID). After accounting for incident dementia and mortality at 6 months, 435 participants were included in the analyses of delayed post-ICH dementia (DPID). EXPOSURES: Intracerebral hemorrhage. MAIN OUTCOMES AND MEASURES: Cognitive performance was captured using the modified Telephone Interview for Cognitive Status test. Outcomes included EPID, diagnosed within 6 months after ICH, and DPID, diagnosed beyond 6 months after ICH. RESULTS: Among 738 patients who had experienced ICH (mean SD age, 74.3 12.1 years; 384 men 52.0%), 140 (19.0%) developed dementia within 6 months. A total of 435 patients without dementia at 6 months were followed up longitudinally (median follow-up, 47.4 months; interquartile range, 43.4-52.1 months), with an estimated yearly incidence of dementia of 5.8% (95% CI, 5.1%-7.0%). Larger hematoma size (hazard ratio HR, 1.47 per 10-mL increase; 95% CI, 1.09-1.97; P < .001 for heterogeneity) and lobar location of ICH (HR, 2.04; 95% CI, 1.06-3.91; P = .02 for heterogeneity) were associated with EPID but not with DPID. Educational level (HR, 0.60; 95% CI, 0.40-0.89; P < .001 for heterogeneity), incident mood symptoms (HR, 1.29; 95% CI, 1.02-1.63; P = .01 for heterogeneity), and white matter disease as defined via computed tomography (HR, 1.70; 95% CI, 1.07-2.71; P = .04 for heterogeneity) were associated with DPID but not EPID. CONCLUSIONS AND RELEVANCE: Incident dementia early after ICH is strongly associated with hematoma size and location. Delayed incident dementia is frequent among patients who have experienced ICH and is not prominently associated with acute characteristics of ICH. These findings suggest the existence of heterogeneous biological mechanisms accounting for early vs delayed cognitive decline among patients who have experienced ICH.
Summary 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.
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.
Cerebral amyloid angiopathy is a common form of small-vessel disease and an important risk factor for cognitive impairment. The mechanisms linking small-vessel disease to cognitive impairment are not ...well understood. We hypothesized that in patients with cerebral amyloid angiopathy, multiple small spatially distributed lesions affect cognition through disruption of brain connectivity. We therefore compared the structural brain network in patients with cerebral amyloid angiopathy to healthy control subjects and examined the relationship between markers of cerebral amyloid angiopathy-related brain injury, network efficiency, and potential clinical consequences. Structural brain networks were reconstructed from diffusion-weighted magnetic resonance imaging in 38 non-demented patients with probable cerebral amyloid angiopathy (69 ± 10 years) and 29 similar aged control participants. The efficiency of the brain network was characterized using graph theory and brain amyloid deposition was quantified by Pittsburgh compound B retention on positron emission tomography imaging. Global efficiency of the brain network was reduced in patients compared to controls (0.187 ± 0.018 and 0.201 ± 0.015, respectively, P < 0.001). Network disturbances were most pronounced in the occipital, parietal, and posterior temporal lobes. Among patients, lower global network efficiency was related to higher cortical amyloid load (r = -0.52; P = 0.004), and to magnetic resonance imaging markers of small-vessel disease including increased white matter hyperintensity volume (P < 0.001), lower total brain volume (P = 0.02), and number of microbleeds (trend P = 0.06). Lower global network efficiency was also related to worse performance on tests of processing speed (r = 0.58, P < 0.001), executive functioning (r = 0.54, P = 0.001), gait velocity (r = 0.41, P = 0.02), but not memory. Correlations with cognition were independent of age, sex, education level, and other magnetic resonance imaging markers of small-vessel disease. These findings suggest that reduced structural brain network efficiency might mediate the relationship between advanced cerebral amyloid angiopathy and neurologic dysfunction and that such large-scale brain network measures may represent useful outcome markers for tracking disease progression.
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.
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.
The cohort included 313 patients with CAA. Multifocal cSS prevalence was 21.1%.
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;
< 0.0001).
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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