Total small vessel disease burden and brain network efficiency in cerebral amyloid angiopathy.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is associated with hemorrhagic and nonhemorrhagic markers small vessel disease (SVD). A composite score to quantify the total burden of SVD on MRI specifically for CAA patients was recently developed. Brain network alterations related to individual MRI markers of SVD in CAA were demonstrated. OBJECTIVES: Considering diffusion based network measures sensitive to detect different relevant SVD-related brain injury, we investigated if increased overall SVD injury on MRI corresponds to worse global brain connectivity in CAA. METHODS: Seventy-three patients (79.5% male, mean age 70.58±8.22years) with a diagnosis CAA were considered. SVD markers in total MRI SVD score included: lobar cerebral microbleeds, cortical superficial siderosis (cSS), white matter hyperintensities (WMH) and centrum semiovale-enlarged perivascular spaces. Diffusion imaging based network reconstruction was made. The associations between total MRI SVD score and global network efficiency (GNE) were analyzed. RESULTS: A modest significant inverse correlation between total MRI SVD score and GNE existed (p=0.013; R2=0.07). GNE was related with the presence of cSS and moderate-severe WMHs. CONCLUSIONS: An increased burden of SVD neuroimaging markers corresponds to more reductions in global brain connectivity, implying a possible cumulative effect of overall SVD markers on disrupted physiology. GNE was related with some components of the score, specifically cSS and moderate-severe WMHs.

Significance of admission hypoalbuminemia in acute intracerebral hemorrhage.

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.

A phase 2 study of tramiprosate for cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: No treatments have been identified to lower the risk of intracerebral hemorrhage due to cerebral amyloid angiopathy (CAA). A potential approach to prevention is the use of agents that interfere with the pathogenic cascade initiated by the beta-amyloid peptide (Abeta). Tramiprosate (3-amino-1-propanesulfonic acid) is a candidate molecule shown in preclinical studies to reduce CAA in a transgenic mouse model. METHODS: We performed a 5-center phase 2 double-blinded trial to evaluate the safety, tolerability, and pharmacokinetics of tramiprosate in subjects with lobar intracerebral hemorrhage. Twenty-four subjects age > or =55 years with possible or probable CAA were randomized to receive 12 weeks of tramiprosate at 1 of 3 oral doses (50, 100, or 150 mg twice daily). Subjects were followed for clinical adverse effects, laboratory, vital sign, electrocardiogram, cognitive, or functional changes, appearance of new symptomatic or asymptomatic hemorrhages, and pharmacokinetic parameters. RESULTS: Enrolled subjects were younger (mean age 70.8+/-5.4, range 61 to 78) and had more advanced baseline disease (measured by number of previous hemorrhages) than consecutive subjects in a CAA natural history cohort. No concerning safety issues were encountered with treatment. Nausea and vomiting were the most common adverse events and were more frequent at high doses. Nine subjects had new symptomatic or asymptomatic hemorrhages during treatment; all occurred in subjects with advanced baseline disease, with no apparent effect of drug dosing assignment. CONCLUSIONS: These data suggest that tramiprosate can be given safely to subjects with suspected CAA and support future efficacy trials.