Pulse wave velocity is associated with ß-amyloid deposition in the brains of very elderly adults.

OBJECTIVE: To determine arterial stiffness and ß-amyloid (Aß) deposition in the brain of dementia-free older adults. METHODS: We studied a cohort of 91 dementia-free participants aged 83-96 years. In 2009, participants completed brain MRI and PET imaging using Pittsburgh compound B (PiB; a marker of amyloid plaques in human brain). In 2011, we measured resting blood pressure (BP), mean arterial pressure (MAP), and arterial stiffness by pulse wave velocity (PWV) in the central, peripheral, and mixed (e.g., brachial ankle PWV [baPWV]) vascular beds, using a noninvasive and automated waveform analyzer. RESULTS: A total of 44/91 subjects were Aß-positive on PET scan. Aß deposition was associated with mixed PWV, systolic BP, and MAP. One SD increase in baPWV resulted in a 2-fold increase in the odds of being Aß-positive (p = 0.007). High white matter hyperintensity (WMH) burden was associated with increased central PWV, systolic BP, and MAP. Compared to Aß-negative individuals with low WMH burden, each SD increase in PWV was associated with a 2-fold to 4-fold increase in the odds of being Aß-positive and having high WMH. CONCLUSIONS: Arterial stiffness was associated with Aß plaque deposition in the brain, independent of BP and APOE ε4 allele. The associations differed by type of brain abnormality and vascular bed measured (e.g., WMH with central stiffness and Aß deposition and mixed stiffness). Arterial stiffness was highest in individuals with both high Aß deposition and WMH, which has been suggested to be a "double hit" contributing to the development of symptomatic dementia.

Cognitive trajectories associated with ß-amyloid deposition in the oldest-old without dementia.

OBJECTIVE: To determine whether a high prevalence (55%) of Aß deposition in a cohort of individuals remaining dementia-free into their 9th and 10th decades is associated with cognitive decline prior to imaging. METHODS: A total of 194 participants (mean age 85.5 years, range 82-95) who completed the Ginkgo Evaluation of Memory Study (GEMS) and remained dementia-free subsequently completed Pittsburgh compound B-PET imaging. We examined cross-sectional associations between Aß status and performance on a broad neuropsychological test battery completed at GEMS entry 7-9 years prior to neuroimaging. We also longitudinally examined cognition over annual evaluations using linear mixed models. RESULTS: At GEMS screening (2000-2002), participants who were Aß-positive in 2009 had lower performance on the Stroop test (p < 0.01) and Raven's Progressive Matrices (p = 0.05), with trend level difference for Block Design (p = 0.07). Longitudinal analyses showed significant slope differences for immediate and delayed recall of the Rey-Osterrieth figure, semantic fluency, and Trail-Making Test parts A and B, indicating greater performance decline prior to neuroimaging for Aß-positive relative to Aß-negative participants (ps < 0.05). CONCLUSIONS: Highly prevalent Aß deposition in oldest-older adults is associated with cognitive decline in visual memory, semantic fluency, and psychomotor speed beginning 7-9 years prior to neuroimaging. Mean differences in nonmemory domains, primarily executive functions, between Aß-status groups may be detectable 7-9 years before neuroimaging.

Development of a PET/SPECT agent for amyloid imaging in Alzheimer's disease.

In the search for a cure for Alzheimer's disease (AD), efforts have been focused on preventing or reversing amyloid deposition in the brain. Efficacy evaluation of these antiamyloid therapies would greatly benefit from development of a tool for the in vivo detection and quantitation of amyloid deposits in the brain. Toward this goal, we have developed a series of benzothiazole derivatives as amyloid-imaging agents for positron emission tomography (PET). To extend the potential of these amyloid-imaging agents for routine clinical studies, we also set out to develop iodinated benzothiazole derivatives that could be used as dual agents for either PET or the complementary single photon emission computed tomography (SPECT). Such dual agents would permit PET or SPECT studies using radiotracers with the same chemical identity but labeled with different radionuclides. This would facilitate the validation of clinical SPECT studies, based on quantitative PET studies. In this work we report the synthesis and biological evaluation of a potent, selective, and brain-permeable benzothiazole compound, 2-(3'-iodo-4'-methylaminophenyl)-6-hydroxy-benzothialzole, termed 6-OH-BTA-1-3'-I (4), which can be radiolabeled with either positron-emitting carbon-11 or single photon-emitting iodine-125/iodine-123. The synthesis and radiolabeling of [125I]4 or [11C]4 were achieved through direct iodination with sodium [125I]iodide in the presence of chloramine T or through radiomethylation with [11C]CH3I. In vitro amyloid binding assays indicated that [125I]4 bound to amyloid deposits in a saturable manner and exhibited affinities in the nanomolar concentration range. Binding studies of [125I]4 to postmortem human brain homogenates also showed preference of binding to frontal cortex in the AD homogenates relative to age-matched control homogenates or cerebellum from either AD or control. In vivo pharmacokinetic studies in normal mice following iv injection of [11C]4 indicated that the radioligand entered the brain readily at early time points and cleared from the brain rapidly at later time points with a 2- to 30-min ratio >3. These results suggest that the new radioiodinated benzothiazole ligand might be useful as a surrogate marker for the in vivo quantitation of amyloid deposition in human brain for use with either PET or SPECT.