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Alzheimer's disease and related dementias (ADRDs) are a global crisis facing the aging population and society as a whole. With the numbers of people with ADRDs predicted to rise dramatically across the world, the scientific community can no longer neglect the need for research focusing on ADRDs among underrepresented ethnoracial diverse groups. The Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART; alz.org/ISTAART) comprises a number of professional interest areas (PIAs), each focusing on a major scientific area associated with ADRDs. We leverage the expertise of the existing international cadre of ISTAART scientists and experts to synthesize a cross‐PIA white paper that provides both a concise “state‐of‐the‐science” report of ethnoracial factors across PIA foci and updated recommendations to address immediate needs to advance ADRD science across ethnoracial populations.

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-␤ protein is an initiating event in Alzheimer's disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n ϭ 5) and symptomatic (n ϭ 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n ϭ 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n ϭ 12) and controls from the general population (n ϭ 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

Objective We utilized the amyloid imaging ligand Pittsburgh Compound-B (PiB) to determine the presence of AD pathology in different MCI subtypes and to relate elevated PiB binding to other markers of early AD and longitudinal outcome. Methods Twenty-six patients with MCI – 13 single domain amnestic-MCI (sd a-MCI), 6 multiple domain amnestic-MCI (md a-MCI), and 7 non-amnestic MCI (na-MCI) – underwent PiB imaging. Twenty-three had clinical follow-up [21.2 ± 16.0 (SD) months] subsequent to their PiB scan. Results Using cutoffs established from a control cohort, 14 (54%) had elevated levels of PiB retention and were considered “amyloid-positive.” All subtypes were associated with a significant proportion of amyloid-positive patients (6/13 sd a-MCI, 5/6 md a-MCI, 3/7 na-MCI). There were no obvious differences in the distribution of PiB retention in the na-MCI group despite their atypical early AD phenotype. Predictors of conversion to clinical AD in a-MCI, including poorer episodic memory, increased age, and medial temporal atrophy, were found in the amyloid-positive relative to amyloid-negative a-MCI patients. Longitudinal follow-up revealed 5/13 amyloid-positive patients, but 0/10 amyloid-negative patients, converted to clinical AD. Further, 3/10 amyloid-negative patients “reverted to normal” on follow-up. Interpretation These data support the notion that amyloid-positive patients are likely to have early AD and that the use of amyloid imaging may have an important role in determining which patients are likely to benefit from disease-specific therapies. In addition, our data is consistent with longitudinal studies suggesting that a significant percentage of all MCI subtypes will develop clinical AD.

Rats with unilateral depletion of striatal dopamine (DA) show marked preferential use of the ipsilateral forelimb. Previous studies have shown that implementation of motor therapy after stroke improves functional outcome (Taub et al., 1999). Thus, we have examined the impact of forced use of the impaired forelimb during or soon after unilateral exposure to the DA neurotoxin 6-hydroxydopamine (6-OHDA). In one group of animals, the nonimpaired forelimb was immobilized using a cast, which forced exclusive use of the impaired limb for the first 7 d after infusion. The animals that received a cast displayed no detectable impairment or asymmetry of limb use, could use the contralateral (impaired) forelimb independently for vertical and lateral weight shifting, and showed no contralateral turning to apomorphine. The behavioral effects were maintained throughout the 60 d of observation. In addition to the behavioral sparing, these animals showed remarkable sparing of striatal DA, its metabolites, and the expression of the vesicular monoamine transporter, suggesting a decrease in the extent of DA neuron degeneration. Behavioral and neurochemical sparing appeared to be complete when the 7 d period of immobilization was initiated immediately after 6-OHDA infusion, only partial sparing was evident when immobilization was initiated 3 d postoperatively, and no sparing was detected when immobilization was initiated 7 d after 6-OHDA treatment. These results suggest that physical therapy may be beneficial in Parkinson's disease.

Inverse correlations between amyloid-␤ (A␤) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [18 F]fluoro-2-deoxy-D-glucose (FDG) in Alzheimer's disease (AD) patients, suggest local A␤-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of A␤ deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloidpositive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/ parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that A␤ deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating A␤ deposition or increasing the level of A␤ necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive A␤ deposition has been present for longer periods of time does A␤ become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

Objective: To determine arterial stiffness and b-amyloid (Ab) deposition in the brain of dementiafree 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 Ab-positive on PET scan. Ab 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 Ab-positive (p 5 0.007). High white matter hyperintensity (WMH) burden was associated with increased central PWV, systolic BP, and MAP. Compared to Ab-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 Ab-positive and having high WMH.Conclusions: Arterial stiffness was associated with Ab plaque deposition in the brain, independent of BP and APOE e4 allele. The associations differed by type of brain abnormality and vascular bed measured (e.g., WMH with central stiffness and Ab deposition and mixed stiffness). Arterial stiffness was highest in individuals with both high Ab deposition and WMH, which has been suggested to be a "double hit" contributing to the development of symptomatic dementia. Neurology ® 2013;81:1711-1718 GLOSSARY Ab 5 b-amyloid; AD 5 Alzheimer disease; baPWV 5 brachial-ankle pulse wave velocity; BMI 5 body mass index; BP 5 blood pressure; cfPWV 5 carotid-femoral pulse wave velocity; CI 5 confidence interval; DBP 5 diastolic blood pressure; faPWV 5 femoral-ankle pulse wave velocity; GEMS 5 Ginkgo Evaluation of Memory Study; hfPWV 5 heart-femoral pulse wave velocity; ICC 5 intraclass correlation coefficients; MAP 5 mean arterial pressure; MCI 5 mild cognitive impairment; OR 5 odds ratio; PiB 5 Pittsburgh compound B; PWV 5 pulse wave velocity; SBP 5 systolic blood pressure; WMH 5 white matter hyperintensities; WMHv 5 white matter hyperintensities volume.Hypertension is linked to cognitive impairment and the pathologic features of Alzheimer disease (AD), including neurofibrillary tangles and b-amyloid (Ab) plaques, 1 as well as small-vessel disease and white matter hyperintensities (WMH) in the brain.2 Arterial stiffness appears to play a major role in the relationship between hypertension and its consequences in the brain; mounting evidence implicates arterial stiffness in the pathogenesis of impaired cognitive function and dementia in the elderly. 4 Except for APOE e4 genotype and aging, the risk factors and determinants of Ab deposition in brain are poorly understood.Recent studies show that blood pressure (BP) is associated with brain Ab deposition as measured by PiB-PET 5,6 ; thus, arterial stiffness may pla...