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Cerebral amyloid angiopathy (CAA) is a common cause of symptomatic intracerebral hemorrhage (ICH), as well as small asymptomatic hemorrhage in the elderly. We used gradient-echo MRI to analyze spatial distribution of 321 hemorrhages in 59 patients with probable CAA-related ICH. Hemorrhagic lesions were found preferentially in the temporal (ratio of actual to expected hemorrhages = 1.37) and occipital lobes (ratio = 1.45, p < 0.0001). Within individuals, hemorrhages tended to cluster, regardless of lobe (p < 0.0001). Among subjects followed prospectively for recurrence, clustering of new symptomatic and asymptomatic hemorrhages was observed. These data suggest that regional differences within the brain play a role in the development of CAA-related hemorrhage.

Advanced cerebrovascular β-amyloid deposition (cerebral amyloid angiopathy, CAA) is associated with cerebral microbleeds, but the precise relationship between CAA burden and microbleeds is undefined. We used T2*-weighted MRI and noninvasive amyloid imaging with Pittsburgh Compound B (PiB) to analyze the spatial relationship between CAA and microbleeds. On co-registered PET and MRI images, PiB retention was increased at microbleed sites compared to simulated control lesions (p=0.002) and declined with increasing distance from the microbleed (p<0.0001). These findings indicate that microbleeds occur preferentially in local regions of concentrated amyloid and support therapeutic strategies aimed at reducing vascular amyloid deposition.Cerebrovascular deposition of β-amyloid (cerebral amyloid angiopathy, CAA) is most commonly recognized during life as a cause of brain hemorrhage. Hemorrhages associated with CAA can be large, symptomatic strokes or small, typically asymptomatic cerebral microbleeds (CMB). CMB are sensitively imaged by T2*-weighted MRI and have been implicated as markers of, and possible contributors to, small vessel-related brain injury.1Although the link between CAA and CMB is well established,1 the precise mechanism by which vascular amyloid leads to microhemorrhage remains incompletely understood. It is unknown, for example, whether CMB occur preferentially at sites of greatest amyloid deposition. Circumstantial evidence supports this possibility, as both CAA pathology2 and CAA-related CMB3 tend to favor occipital cortex. Further, a recent study suggested that brains with many CAA-related CMB have greater thickness of vascular amyloid than brains with few CMB. METHODS Image Acquisition and AnalysisWe performed T2*-weighted MR and PiB-PET imaging on 16 CAA patients (Table 1) recruited at Massachusetts General Hospital.3 All subjects were diagnosed as probable CAA based on the Boston criteria (7 with supporting pathology, 9 by multiple lobar hemorrhages/ CMB),7 were nondemented, and free of symptoms suggestive of new stroke for 1 year prior to PiB-PET. PiB was prepared and PET acquisition performed using methods previously described.5 PET data were reconstructed and expressed as a distribution volume ratio (DVR) with cerebellum as reference tissue. Each subject also underwent research T2*-weighted MRI for detection of CMB.Full details of MRI acquisition, processing, identification of CMB, co-registration of T2*-weighted and PET images (Figures. 1A and B), and scoring of PiB values are provided in the Supplemental Methods. MR imaging was performed at 1.5 Tesla using protocols for gradient-echo (GRE) or susceptibility-weighted imaging (SWI) as described.8 PiB-PET values within a CMB were measured and averaged to provide mean DVR per voxel for each microbleed. PiB-PET values were also measured in five concentric "shells," each 2 mm in thickness, surrounding each CMB ( Figure 1C). To provide an appropriate control comparison for the observed CMB, 200 "simulated" CMB lesions were distributed thr...

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Atorvastatin calcium (ATRC) is a poor water soluble drug used for treatment of hypercholesterolemia. This research is aimed to improve solubility and dissolution rate of ATRC by formulating into solid self-nanoemulsifying drug delivery system (S-SNEDDS) using N-methyl pyrrolidone (NMP) as cosolvent. Solubility of ATRC was determined in various vehicles. Ternary phase diagrams were constructed to identify stable nanoemulsion region. SNEDDS formulations were evaluated for robustness to dilution, thermodynamic stability study, % transmittance, self-emulsification time, globule size and transmission electron microscopy. The optimized liquid SNEDDS showed robust to all dilutions exhibiting no signs of phase separation or precipitation for 24 h. Liquid SNEDDS was transformed into S-SNEDDS using different adsorbents. Differential scanning calorimetry and scanning electron microscopy studies unravel the transformation of native crystalline state to amorphous state/solubilized state. In vitro dissolution study of S-SNEDDS was found to be significantly higher in comparison to that from plain drug, irrespective of pH (p < 0.001). Furthermore, ex vivo permeation studies showed a 4.45-fold improvement in apparent permeability coefficient (Papp) from S-SNEDDS compared to plain drug. In conclusion, S-SNEDDS prepared using NMP as cosolvent provides an effective approach for improved oral delivery of ATRC.

Summary. Disorders of immunoglobulin (Ig) synthesis that occur in malignant plasma-cell proliferation may result in either granular (LCDD) or ®brillar (AL) tissue deposition of light-chain monoclonal components. The structural features that govern the transition from soluble polypeptides to either ®brillar or granular conformational states remain unde®ned. Among the many factors presumed to play a role in these transitions the net charge of the molecule has been associated with folding conformation changes. The majority of the proteins involved in AL amyloidosis show acidic isoelectric points (pI 3´8±5´2), whereas most L chains with basic pIs deposit in granular patterns. In our studies a 12 kD VkIII fragment was puri®ed as the main component of the ®brils isolated from myocardium and adipose tissue of the pericardium obtained post-mortem from an individual with systemic AL amyloidosis. An apparently identical 12 kD VL fragment with the same N-terminal sequence constituted the BJ protein present in the urine. This urinary protein exhibited strikingly cathodic electrophoretic mobility on agarose gels and lacked retention by anionic exchange chromatography matrices, indicative of a highly basic pI (>10). When it was subjected to in vitro ®bril-formation experiments, the BJ protein adopted a ®brillar conformation only at acidic pHs, remaining aggregated but not ®brillar at physiological pH. The data indicate that a speci®c tissue deposition pattern involves not only structural properties of the protein but rather more complex mechanisms in which acidic micro-environments may contribute to the stabilization of amyloidogenic conformations.

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