Minocycline reduces spontaneous hemorrhage in mouse models of cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine whether spontaneous intracerebral hemorrhage could be reduced. METHODS: Tg2576 (n=16) and 5xFAD/ApoE4 knockin mice (n=16), aged 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, IP) or saline every other day for 2 months. Brains were extracted and stained with X-34 (to quantify amyloid), Perls' blue (to quantify hemorrhage), and immunostained to examined ß-amyloid peptide load, gliosis (glial fibrillary acidic protein [GFAP], Iba-1), and vascular markers of blood-brain barrier integrity (zonula occludins-1 [ZO-1] and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes. RESULTS: Minocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5xFAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (matrix metalloproteinase-9, NOX4, CD45, S-100b, and Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls. CONCLUSIONS: Minocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in 2 different mouse models of CAA, supporting the importance of matrix metalloproteinase-related and inflammatory pathways in intracerebral hemorrhage pathogenesis. As a Food and Drug Administration-approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related intracerebral hemorrhage.

Predictors of hematoma volume in deep and lobar supratentorial intracerebral hemorrhage.

IMPORTANCE: Hematoma volume is the strongest predictor of outcome in intracerebral hemorrhage (ICH). Despite known differences in the underlying biology between deep and lobar ICHs, limited data are available on location specificity of factors reported to affect hematoma volume. OBJECTIVE: To evaluate whether determinants of ICH volume differ by topography, we sought to estimate location-specific effects for potential predictors of this radiological outcome. DESIGN: Prospective cohort study. SETTING: Academic medical center. PARTICIPANTS: A total of 744 supratentorial primary ICH patients (388 deep and 356 lobar) aged older than 18 years admitted between January 1, 2000, and December 31, 2010. MAIN OUTCOMES AND MEASURES: Intracerebral hemorrhage volume measured from the computed tomography scan obtained on presentation to the emergency department. Linear regression analysis, stratified by ICH location, was implemented to identify determinants of log-transformed ICH volume. RESULTS: Median ICH volume was larger in lobar hemorrhages (39 mL; interquartile range, 16-75 mL) than in deep hemorrhages (13 mL; interquartile range, 5-40 mL; P < .001). In multivariable linear regression, independent predictors of deep ICH volume were intensity of anticoagulation (ß = 0.32; standard error [SE] = 0.08; P < .001; test for trend across 4 categories of the international normalized ratio), history of coronary artery disease (ß = 0.33; SE = 0.17; P = .05), male sex (ß = 0.28; SE = 0.14; P = .05), and age (ß = -0.02; SE = 0.01; P = .001). Independent predictors of lobar ICH volume were intensity of anticoagulation (ß = 0.14; SE = 0.06; P = .02) and antiplatelet treatment (ß = 0.27; SE = 0.13; P = .03). CONCLUSIONS AND RELEVANCE: Predictors of hematoma volume only partially overlap between deep and lobar ICHs. These findings suggest that the mechanisms that determine the extent of bleeding differ for deep and lobar ICHs. Further studies are needed to characterize the specific biological pathways that underlie the observed associations.

Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders.

The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initial evidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.

Effect of statins on intracerebral hemorrhage outcome and recurrence.

BACKGROUND AND PURPOSE: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, have been associated with improved outcome after ischemic stroke and subarachnoid hemorrhage but an increased risk of incident intracerebral hemorrhage (ICH). We investigated (1) whether statin use before ICH was associated with functional independence at 90 days, and (2) whether survivors exposed to statins after ICH had an increased risk of recurrence. METHODS: We analyzed 629 consecutive ICH patients with 90-day outcome data enrolled in a prospective cohort study between 1998 to 2005. Statin use was determined by patient interview at the time of ICH and supplemented by medical record review. Independent status was defined as Glasgow Outcome Scale 4 or 5. ICH survivors were followed by telephone interview every 6 months. RESULTS: Statins were used by 149/629 (24%) before ICH. There was no effect of pre-ICH statin use on the rates of functional independence (28% versus 29%, P=0.84) or mortality (46% versus 45%, P=0.93). Medical comorbidities and warfarin use were more common in statin users. Hematoma volumes were similar (median 28 cm(3) in pre-ICH statin users compared to 22 cm(3) in nonusers, P=0.18). The multivariable-adjusted odds ratio for independent status in pre-ICH statin users was 1.16 (95% CI 0.65 to 2.10, P=0.62). ICH survivors treated with statins after discharge did not have a higher risk of recurrence (adjusted HR 0.82, 95% CI 0.34 to 1.99, P=0.66). CONCLUSIONS: Pre-ICH statin use is not associated with improved ICH functional outcome or mortality. Post-ICH statin use is not associated with an increased risk of ICH recurrence.

A nifedipina de liberaçäo gastrointestinal no tratamento da hipertensäo arterial / The nifedipine gastrointestinal therapeutic system in the treatment of hypertension

Com o aumento do número de agentes anti-hipertensivos, a escolha da terapia ideal torna-se cada vez mais difícil. Deve-se considerar, evidentemente, os distúrbios hemodinâmicos causados tanto pelo estado mórbido como pela própria terapia. Também devem ser levados em conta a conveniência e o impacto sobre a qualidade de vida do paciente. As experiências preliminares sugerem que a formulaçäo de liberaçäo gastrointestinal (gastrointestinal therapeutic system, GITS) da nifedipina - com bombeamento osmótico de entrada e saída simétricas - é segura e eficaz no tratamento da hipertensäo. No presente estudo, a nifedipina GITS foi comparada ao propranolol de liberaçäo lenta em pacientes com hipertensäo leve a moderada que já recebiam diuréticos. No estudo, realizado em esquema duplo-cego após um período de duas semanas de depuraçäo medicamentosa sob placebo, os pacientes foram distribuídos aleatoriamente entre os grupos recebendo nifedipina GITS (n = 31) à dose diária única de 30, 60 ou 90mg ou propranolol de liberaçäo lenta (n = 32) à dose diária única de 80, 160 ou 240mg. A terapia diurética anterior foi mantida. Foram realizadas mediçöes da pressäo arterial em posiçäo sentada e depois de cinco minutos em posiçäo ereta, bem como da freqüência cardíaca, 24 horas após a administraçäo da dose. No ponto de aferiçäo, tanto a nifedipina GITS quanto o propranolol de liberaçäo lenta haviam reduzido a pressäo arterial em ambas as posiçöes de mediçäo quando comparados a placebo (p 0,001). A nifedipina GITS foi mais eficaz que o propranolol deliberaçäo lenta na reduçäo da pressäo sistólica em posiçäo tanto ereta (p < 0,005) quanto sentada (p < 0,001) e da pressäo diastólica em posiçäo sentada (p < 0,02). O propranolol de liberaçäo lenta reduziu a freqüência cardíaca em repouso, medida em posiçäo ereta (p < 0,01) e sentada (p < 0,0006), mais que a nifedipina GITS. Ambas as drogas foram bem toleradas. A nifedipina GITS é uma droga eficaz e segura em administraçäo diária única a pacientes com hipertensäo que já estejam recebendo diuréticos, e pode ser mais eficaz que o propranolol de liberaçäo lenta e melhor tolerada que a nifedipina convencional em cápsulas