Amyloid-β (Aβ) deposits have been identified as key players in the progression of Alzheimer’s disease (AD). Recent evidence indicates that the deposits probably precede and induce the neuronal atrophy. Therefore, methods that enable monitoring the pathology before clinical symptoms are observed would be beneficial for the early AD detection. Here, we report the design, synthesis, and testing of a curcumin derivatized near infrared (NIR) probe CRANAD-2. Upon interacting with Aβ aggregates, CRANAD-2 undergoes a range of changes, which include a 70-fold fluorescence intensity increase, a 90 nm blue-shift (from 805 nm to 715 nm), and a large increase in quantum yield. Moreover, this probe also shows a high affinity for Aβ aggregates (Kd = 38.0 nM), a reasonable Log P value (Log P = 3), considerable stability in serum and a weak interaction with albumin. After intravenous injection of this probe, 19-month old Tg2576 mice exhibited significantly higher relative signal than that of the control mice over the same period of time. In summary, CRANAD-2 meets all the requirements for a NIR contrast agent for the detection of Aβ plaques both in vitro and in vivo. Our data point towards the feasibility of monitoring the progress of the disease by NIR imaging with CRANAD-2. In addition, we believe that our probe could be potentially used as a tool for drug screening.

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...