Alzheimer's disease biomarker burden in primary motor cortices is associated with poorer dexterity performance.

INTRODUCTION: Motor function has correlated with longevity and functionality; however, there is limited research on those with Alzheimer's disease (AD). We studied the association between motor functionality and AD pathology in primary motor and medial temporal cortices. METHODS: A total of 206 participants with a clinical diagnosis of cognitively healthy, AD, or mild cognitive impairment (MCI) underwent imaging and motor assessment. Linear regressions and analyses of variance were applied to test the prediction from AD imaging biomarkers to motor performance and the diagnosis group differences in motor performance. RESULTS: Increased neurodegeneration was associated with worsening dexterity and lower walking speed, and increased amyloid and tau were associated with worsening dexterity. AD and MCI participants had lower motor performance than the cognitively healthy participants. DISCUSSION: Increased AD pathology is associated with worsening dexterity performance. The decline in dexterity in those with AD pathology may offer an opportunity for non-pharmacological therapy intervention. HIGHLIGHTS: Noted worsening dexterity performance was associated with greater Alzheimer's disease (AD) pathology (tau, amyloid beta, and neurodegeneration) in primary motor cortices. Similarly, increased neurodegeneration and tau pathology in parahippocampal, hippocampal, and entorhinal cortices is associated with worsening dexterity performance. Motor performance declined in those with clinical and preclinical AD among an array of motor assessments.

Cerebral cortical thickness and cognitive decline in Parkinson's disease.

In Parkinson's disease (PD), reduced cerebral cortical thickness may reflect network-based degeneration. This study performed cognitive assessment and brain MRI in 30 PD participants and 41 controls at baseline and 18 months later. We hypothesized that cerebral cortical thickness and volume, as well as change in these metrics, would differ between PD participants who remained cognitively stable and those who experienced cognitive decline. Dividing the participant sample into PD-stable, PD-decline, and control-stable groups, we compared mean cortical thickness and volume within segments that comprise the prefrontal cognitive-control, memory, dorsal spatial, and ventral object-based networks at baseline. We then compared the rate of change in cortical thickness and volume between the same groups using a vertex-wise approach. We found that the PD-decline group had lower cortical thickness within all 4 cognitive networks in comparison with controls, as well as lower cortical thickness within the prefrontal and medial temporal networks in comparison with the PD-stable group. The PD-decline group also experienced a greater rate of volume loss in the lateral temporal cortices in comparison with the control group. This study suggests that lower thickness and volume in prefrontal, medial, and lateral temporal regions may portend cognitive decline in PD.

Establishing a National Engagement Strategy for Recruiting Asian Americans and Other Minorities into Biomedical Research.

BACKGROUND: The All of Us Research Program seeks to advance precision medicine and reduce health disparities by recruiting people in demographic categories that are underrepresented in biomedical research. Asian Americans, Native Hawaiians and Pacific Islanders are the most understudied of all racial/ethnic groups in the United States. We propose a national engagement strategy for the recruitment of Asian Americans, Native Hawaiians and Pacific Islanders into biomedical research using a community-based participatory research approach. METHODS: We partnered with Asian serving community-based organizations across the United States to increase education and awareness and developed a culturally and linguistically tailored approach for the engagement of AANHPIs into All of Us Research Program. RESULTS: In the first year, our national engagement strategy reached more than 35,000 AANHPIs through promotional events and educational sessions. CONCLUSIONS: Our success is a result of our equal and mutually beneficial partnership with community-based organizations who have access to rich, local knowledge and hold a unique role within the community.

Cardiorespiratory fitness and cognition in persons at risk for Alzheimer's disease.

Introduction: This study examined the relationship between cardiorespiratory fitness (CRF) and longitudinal cognitive functioning in a cohort enriched with risk factors for Alzheimer's disease (AD). Methods: A total of 155 enrollees in the Wisconsin Registry for Alzheimer's Prevention completed repeat comprehensive neuropsychological evaluations that assessed six cognitive domains. Peak oxygen consumption (VO2peak) was the primary measure of CRF. Random effects regression was used to investigate the effect of CRF on cognitive trajectories. Results: Higher CRF was associated with slower decline in the cognitive domains of verbal learning and memory (P < .01) and visual learning and memory (P < .042). Secondary analyses indicated that these effects were stronger among men than women, and for noncarriers of the apolipoprotein E ε4 allele. Discussion: Higher CRF was associated with a slower rate of the decline in episodic memory that occurs as a natural consequence of aging in a cohort enriched with risk factors for AD.

Age-related differences in white matter microstructure measured by advanced diffusion MRI in healthy older adults at risk for Alzheimer's disease.

Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion imaging technique, which can detect more distinct microstructural features compared to conventional Diffusion Tensor Imaging (DTI). NODDI allows the signal to be divided into multiple water compartments and derive measures for orientation dispersion index (ODI), neurite density index (NDI) and volume fraction of isotropic diffusion compartment (FISO). This study aimed to investigate which diffusion metric-fractional anisotropy (FA), mean diffusivity (MD), NDI, ODI, or FISO-is most influenced by aging and reflects cognitive function in a population of healthy older adults at risk for Alzheimer's disease (AD). Age was significantly associated with all but one diffusion parameters and regions of interest. NDI and MD in the cingulate region adjacent to the cingulate cortex showed a significant association with a composite measure of Executive Function and was proven to partially mediate the relationship between aging and Executive Function decline. These results suggest that both DTI and NODDI parameters are sensitive to age-related differences in white matter regions vulnerable to aging, particularly among older adults at risk for AD.

The relationship of glucose-stimulated insulin secretion to cerebral glucose metabolism and cognition in healthy middle-aged and older adults.

Insulin resistance (IR) has been related to reduced cerebral glucose metabolism in regions identified as hypometabolic in Alzheimer's clinical syndrome. Insulin secretion (IS) has been less studied than IR despite findings that decreased IS is an early indicator of future type 2 diabetes and a potential predictor of Alzheimer's clinical syndrome. We investigated whether higher IR and lower IS would be associated with greater age-related reductions in regional cerebral glucose metabolism and worse cognitive performance. Two-hour oral glucose tolerance testing and 18F-fluorodeoxyglucose positron emission tomography were performed on 1-2 occasions on a sample of healthy middle-aged and older adults from the Wisconsin Alzheimer's Disease Research Center. Neuropsychological tests were completed during Alzheimer's Disease Research Center Clinical Core visits. Pattern of findings suggested that lower (not higher) IS was related to higher regional cerebral glucose metabolism in middle aged but not older adults, and lower (not higher) IS was also related to better immediate recall. In the context of healthy insulin sensitivity, lower IS may be beneficial to brain health.

Impact of sex and APOE ε4 on age-related cerebral perfusion trajectories in cognitively asymptomatic middle-aged and older adults: A longitudinal study.

Cerebral hypoperfusion is thought to contribute to cognitive decline in Alzheimer's disease, but the natural trajectory of cerebral perfusion in cognitively healthy adults has not been well-studied. This longitudinal study is consisted of 950 participants (40-89 years), who were cognitively unimpaired at their first visit. We investigated the age-related changes in cerebral perfusion, and their associations with APOE-genotype, biological sex, and cardiometabolic measurements. During the follow-up period (range 0.13-8.24 years), increasing age was significantly associated with decreasing cerebral perfusion, in total gray-matter (ß=-1.43), hippocampus (-1.25), superior frontal gyrus (-1.70), middle frontal gyrus (-1.99), posterior cingulate (-2.46), and precuneus (-2.14), with all P-values < 0.01. Compared with male-ɛ4 carriers, female-ɛ4 carriers showed a faster decline in global and regional cerebral perfusion with increasing age, whereas the age-related decline in cerebral perfusion was similar between male- and female-ɛ4 non-carriers. Worse cardiometabolic profile (i.e., increased blood pressure, body mass index, total cholesterol, and blood glucose) was associated with lower cerebral perfusion at all the visits. When time-varying cardiometabolic measurements were adjusted in the model, the synergistic effect of sex and APOE-ɛ4 on age-related cerebral perfusion-trajectories became largely attenuated. Our findings demonstrate that APOE-genotype and sex interactively impact cerebral perfusion-trajectories in mid- to late-life. This effect may be partially explained by cardiometabolic alterations.

Association of Neighborhood-Level Disadvantage With Cerebral and Hippocampal Volume.

Importance: Identifying risk factors for brain atrophy during the aging process can help direct new preventive approaches for dementia and cognitive decline. The association of neighborhood socioeconomic disadvantage with brain volume in this context is not well known. Objective: To test whether neighborhood-level socioeconomic disadvantage is associated with decreased brain volume in a cognitively unimpaired population enriched for Alzheimer disease risk. Design, Setting, and Participants: This study, conducted from January 6, 2010, to January 17, 2019, at an academic research neuroimaging center, used cross-sectional data on 951 participants from 2 large, ongoing cohort studies of Alzheimer disease (Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center clinical cohort). Participants were cognitively unimpaired based on National Institute on Aging-Alzheimer's Association workgroup diagnostic criteria for mild cognitive impairment and Alzheimer disease, confirmed through a consensus diagnosis panel. The cohort was enriched for Alzheimer disease risk based on family history of dementia. Statistical analysis was performed from April 3 to September 27, 2019. Main Outcomes and Measures: The Area Deprivation Index, a geospatially determined index of neighborhood-level disadvantage, and cardiovascular disease risk indices were calculated for each participant. Linear regression models were fitted to test associations between relative neighborhood-level disadvantage (highest 20% based on state of residence) and hippocampal and total brain tissue volume, as assessed by magnetic resonance imaging. Results: In the primary analysis of 951 participants (637 women [67.0%]; mean [SD] age, 63.9 [8.1] years), living in the 20% most disadvantaged neighborhoods was associated with 4.1% lower hippocampal volume (ß = -317.44; 95% CI, -543.32 to -91.56; P = .006) and 2.0% lower total brain tissue volume (ß = -20 959.67; 95% CI, -37 611.92 to -4307.43; P = .01), after controlling for intracranial volume, individual-level educational attainment, age, and sex. Robust propensity score-matched analyses determined that this association was not due to racial/ethnic or demographic characteristics. Cardiovascular risk score, examined in a subsample of 893 participants, mediated this association for total brain tissue but not for hippocampal volume. Conclusions and Relevance: For cognitively unimpaired individuals, living in the most disadvantaged neighborhoods was associated with significantly lower cerebral volumes, after controlling for maximal premorbid (total intracranial) volume. This finding suggests an association of community socioeconomic context, distinct from individual-level socioeconomic status, with brain volume during aging. Cardiovascular risk mediated this association for total brain tissue volume but not for hippocampal volume, suggesting that neighborhood-level disadvantage may be associated with these 2 outcomes via distinct biological pathways.

Predictors of Cervical Cancer Screening Awareness and Literacy Among Korean-American Women.

BACKGROUND: Korean-American women experience a higher incidence of cervical cancer than non-Hispanic White women as well as other Asian-American women. A prominent cause of such a disproportional health risk among Korean-American women is a lack of awareness and knowledge of cervical cancer screening. Identifying factors related to cervical cancer screening awareness and literacy is critical for increasing cervical cancer screening among this population. METHODS: Researchers surveyed 230 Korean-American women in a metro area in a Southeastern state, USA. Based on Anderson's Behavioral Model of Health Services Use, predisposing, enabling, and need factors were explored to predict cervical cancer screening awareness and literacy. RESULTS: Monthly income, education, English proficiency, and annual checkups had significantly positive associations with cervical cancer screening awareness. Having an acquaintance giving support and receiving an annual checkup had significantly positive relationships with cervical cancer screening literacy. DISCUSSION: This study recommends culture specific guidelines to promote annual checkups through primary care physicians and the transfer of information about cervical cancer screening through acquaintances giving support.

Cross-sectional and longitudinal associations between total and regional white matter hyperintensity volume and cognitive and motor function in Parkinson's disease.

BACKGROUND: White matter hyperintensities (WMH) are frequently observed on T2-weighted brain magnetic resonance imaging studies of healthy older adults and have been linked with impairments in balance, gait, and cognition. Nonetheless, few studies have investigated the longitudinal effects of comorbid WMH on cognition and motor function in Parkinson's disease. METHODS: The Lesion Segmentation Tool for Statistical Parametric Mapping was used to obtain total lesion volume and map regional WMH probabilities in 29 PD and 42 control participants at two study visits 18 months apart. Both cross-sectional and longitudinal comparisons were made between composite scores in the domains of executive function, memory, and language, and Unified Parkinson's Disease Rating Scale (UPDRS) scores. RESULTS: We found no difference between disease and control groups in total WMH volume or progression during the study. Greater regional and global WMH at baseline was more strongly associated with lower executive function in PD subjects than in controls. Increased regional WMH was also more strongly associated with impaired memory performance in PD relative to controls. Longitudinally, no associations between cognitive change and total or regional WMH progression were detected in either group. A positive relationship between baseline regional WMH and total UPDRS scores was present in the control group, but not PD. However, greater WMH increase was associated with a greater increase in UPDRS motor sub-scores in PD. CONCLUSIONS: These findings suggest that although PD patients do not experience greater mean WMH load than normal aged adults, comorbid WMH do exacerbate cognitive and motor symptoms in PD.

KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD.

OBJECTIVE: To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated ß-amyloid (Aß) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. METHODS: Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on Aß burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on Aß was different among KL-VS heterozygotes compared to noncarriers. RESULTS: APOE4 carriers exhibited greater Aß burden than APOE4-negative participants. This effect was stronger in CSF (t = -5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on Aß load was recapitulated among KL-VS noncarriers (CSF: t = -5.09, p < 0.001; PiB-PET: t = 3.77, p < 0 .001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher Aß burden than APOE4-negative individuals (CSF: t = -1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. CONCLUSION: In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated Aß aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.

Arterial spin labeling reveals relationships between resting cerebral perfusion and motor learning in Parkinson's disease.

Parkinson's disease (PD) is an age-related neurodegenerative disease that produces changes in movement, cognition, sleep, and autonomic function. Motor learning involves acquisition of new motor skills through practice, and is affected by PD. The purpose of the present study was to evaluate regional differences in resting cerebral blood flow (rCBF), measured using arterial spin labeling (ASL) MRI, during a finger-typing task of motor skill acquisition in PD patients compared to age- and gender-matched controls. Voxel-wise multiple linear regression models were used to examine the relationship between rCBF and several task variables, including initial speed, proficiency gain, and accuracy. In these models, a task-by-disease group interaction term was included to investigate where the relationship between rCBF and task performance was influenced by PD. At baseline, perfusion was lower in PD subjects than controls in the right occipital cortex. The task-by-disease group interaction for initial speed was significantly related to rCBF (p < 0.05, corrected) in several brain regions involved in motor learning, including the occipital, parietal, and temporal cortices, cerebellum, anterior cingulate, and the superior and middle frontal gyri. In these regions, PD patients showed higher rCBF, and controls lower rCBF, with improved performance. Within the control group, proficiency gain over 12 typing trials was related to greater rCBF in cerebellar, occipital, and temporal cortices. These results suggest that higher rCBF within networks involved in motor learning enable PD patients to compensate for disease-related deficits.

Brain Glucose Metabolism, Cognition, and Cardiorespiratory Fitness Following Exercise Training in Adults at Risk for Alzheimer's Disease.

Aerobic exercise has been associated with reduced burden of brain and cognitive changes related to Alzheimer's disease (AD). However, it is unknown whether exercise training in asymptomatic individuals harboring risk for AD improves outcomes associated with AD. We investigated the effect of 26 weeks of supervised aerobic treadmill exercise training on brain glucose metabolism and cognition among 23 late-middle-aged adults from a cohort enriched with familial and genetic risk of AD. They were randomized to Usual Physical Activity (PA) or Enhanced PA conditions. Usual PA received instruction about maintaining an active lifestyle. Enhanced PA completed a progressive exercise training program consisting of 3 sessions of treadmill walking per week for 26 weeks. By week seven, participants exercised at 70- 80% heart rate reserve for 50 minutes per session to achieve 150 minutes of moderate intensity activity per week in accordance with public health guidelines. Before and after the intervention, participants completed a graded treadmill test to assess VO2peak as a measure of cardiorespiratory fitness (CRF), wore an accelerometer to measure free-living PA, underwent 18F-fluorodeoxyglucose positron emission tomography imaging to assess brain glucose metabolism, and a neuropsychological battery to assess episodic memory and executive function. VO2peak increased, sedentary behavior decreased, and moderate-to-vigorous PA increased significantly in the Enhanced PA group as compared to Usual PA. Glucose metabolism in the posterior cingulate cortex (PCC) did not change significantly in Enhanced PA relative to Usual PA. However, change in PCC glucose metabolism correlated positively with change in VO2peak. Executive function, but not episodic memory, was significantly improved after Enhanced PA relative to Usual PA. Improvement in executive function correlated with increased VO2peak. Favorable CRF adaptation after 26 weeks of aerobic exercise training was associated with improvements in PCC glucose metabolism and executive function, important markers of AD.

Cardiorespiratory fitness attenuates age-associated aggregation of white matter hyperintensities in an at-risk cohort.

BACKGROUND: Age is the cardinal risk factor for Alzheimer's disease (AD), and white matter hyperintensities (WMH), which are more prevalent with increasing age, may contribute to AD. Higher cardiorespiratory fitness (CRF) has been shown to be associated with cognitive health and decreased burden of AD-related brain alterations in older adults. Accordingly, the aim of this study was to determine whether CRF attenuates age-related accumulation of WMH in middle-aged adults at risk for AD. METHODS: One hundred and seven cognitively unimpaired, late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention underwent 3 T magnetic resonance imaging and performed graded maximal treadmill exercise testing from which we calculated the oxygen uptake efficiency slope (OUES) as our measure of CRF. Total WMH were quantified using the Lesion Segmentation Tool and scaled to intracranial volume. Linear regression adjusted for APOE4 carriage, family history, body mass index, systolic blood pressure, and sex was used to examine relationships between age, WMH, and CRF. RESULTS: As expected, there was a significant association between age and WMH (p < .001). Importantly, there was a significant interaction between age and OUES on WMH (p = .015). Simple main effects analyses revealed that the effect of age on WMH remained significant in the Low OUES group (p < .001) but not in the High OUES group (p = .540), indicating that higher CRF attenuates the deleterious age association with WMH. CONCLUSIONS: Higher CRF tempers the adverse effect of age on WMH. This suggests a potential pathway through which increased aerobic fitness facilitates healthy brain aging, especially among individuals at risk for AD.

Longitudinal white matter microstructural change in Parkinson's disease.

Postmortem studies of Parkinson's disease (PD) suggest that Lewy body pathology accumulates in a predictable topographical sequence, beginning in the olfactory bulb, followed by caudal brainstem, substantia nigra, limbic cortex, and neocortex. Diffusion-weighted imaging (DWI) is sensitive, if not specific, to early disease-related white matter (WM) change in a variety of traumatic and degenerative brain diseases. Although numerous cross-sectional studies have reported DWI differences in cerebral WM in PD, only a few longitudinal studies have investigated whether DWI change exceeds that of normal aging or coincides with regional Lewy body accumulation. This study mapped regional differences in the rate of DWI-based microstructural change between 29 PD patients and 43 age-matched controls over 18 months. Iterative within- and between-subject tensor-based registration was completed on motion- and eddy current-corrected DWI images, then baseline versus follow-up difference maps of fractional anisotropy, mean, radial, and axial diffusivity were analyzed in the Biological Parametric Mapping toolbox for MATLAB. This analysis showed that PD patients had a greater decline in WM integrity in the rostral brainstem, caudal subcortical WM, and cerebellar peduncles, compared with controls. In addition, patients with unilateral clinical signs at baseline experienced a greater rate of WM change over the 18-month study than patients with bilateral signs. These findings suggest that rate of WM microstructural change in PD exceeds that of normal aging and is maximal during early stage disease. In addition, the neuroanatomic locations (rostral brainstem and subcortical WM) of accelerated WM change fit with current theories of topographic disease progression.

HPV Literacy: The Role of English Proficiency in Korean American Immigrant Women.

BACKGROUND: Although Korean American women have one of the highest cervical cancer incidence and mortality rates among all Asian American and non-Hispanic White women, they are less likely to receive the human papillomavirus (HPV) vaccine to prevent cervical cancer. OBJECTIVES: This study aimed to examine Korean American women's HPV literacy and factors related to HPV literacy to identify targeted intervention strategies. METHODS: A quota sampling strategy was used to recruit 243 Korean American women aged 19-85 years in the Atlanta, Georgia, metropolitan area. Multiple linear regression analysis was conducted using Andersen's Behavioral Model of Health Services Use to examine factors associated with HPV literacy. FINDINGS: HPV literacy of Korean American immigrant women was moderate, and knowledge about HPV detection items was particularly low. Age was the only predisposing factor that had a significantly negative association with HPV literacy, whereas education level and English proficiency had a significant positive relationship with HPV literacy. Health status as a need factor was significantly positively associated with HPV literacy.

Evaluation of striatonigral connectivity using probabilistic tractography in Parkinson's disease.

The cardinal movement abnormalities of Parkinson's disease (PD), including tremor, muscle rigidity, and reduced speed and frequency of movements, are caused by degeneration of dopaminergic neurons in the substantia nigra that project to the putamen, compromising information flow through frontal-subcortical circuits. Typically, the nigrostriatal pathway is more severely affected on the side of the brain opposite (contralateral) to the side of the body that manifests initial symptoms. Several studies have suggested that PD is also associated with changes in white matter microstructural integrity. The goal of the present study was to further develop methods for measuring striatonigral connectivity differences between PD patients and age-matched controls using diffusion weighted magnetic resonance imaging (MRI). In this cross-sectional study, 40 PD patients and 44 controls underwent diffusion weighted imaging (DWI) using a 40-direction MRI sequence as well as an optimized 60-direction sequence with overlapping slices. Regions of interest (ROIs) encompassing the putamen and substantia nigra were hand drawn in the space of the 40-direction data using high-contrast structural images and then coregistered to the 60-direction data. Probabilistic tractography was performed in the native space of each dataset by seeding the putamen ROI with an ipsilateral substantia nigra classification target. The effect of disease group (PD versus control) on mean putamen-SN connection probability and streamline density were then analyzed using generalized linear models controlling for age, gender, education, as well as seed and target region characteristics. Mean putamen-SN streamline density was lower in PD on both sides of the brain and in both 40- and 60-direction data. The optimized sequence provided a greater separation between PD and control means; however, individual values overlapped between groups. The 60-direction data also yielded mean connection probability values either trending (ipsilateral) or significantly (contralateral) lower in the PD group. There were minor between-group differences in average diffusion measures within the substantia nigra ROIs that did not affect the results of the GLM analyses when included as covariates. Based on these results, we conclude that mean striatonigral structural connectivity differs between PD and control groups and that use of an optimized 60-direction DWI sequence with overlapping slices increases the sensitivity of the technique to putative disease-related differences. However, overlap in individual values between disease groups limits its use as a classifier.

Performance-Based Risk-Sharing Arrangements for Pharmaceutical Products in the United States: A Systematic Review.

BACKGROUND: Value for money is a growing necessity in today's U.S. health care system in which drug spending is expected to increase by an average rate of 6.7% yearly through 2025. In response to uncertainty about real-world clinical and economic outcomes for many drugs, health insurers and pharmacy benefit managers (PBMs) have implemented various contracts and arrangements with drug manufacturers that can collectively be described as performance-based risk-sharing arrangements (PBRSAs). Little is known about U.S.-specific PBRSAs for drugs. OBJECTIVES: To conduct a systematic review of U.S.-specific PBRSAs for drugs to describe (a) trends over time and (b) key aspects including outcome measures and terms of arrangements between stakeholders. METHODS: A systematic review was conducted in MEDLINE (January 1, 1946-April 1, 2017), Embase (January 1, 1988-April 1, 2017), and the grey literature (up to April 1, 2017) to identify publicly disclosed PBRSAs. Articles and conference abstracts were included if they were published in English and described a U.S.-specific PBRSA for a drug. Articles and conference abstracts were excluded if they only described a PBRSA similar to a money-back guarantee to patients. They were also excluded if they only described a PBRSA between a PBM and a health insurer in which the latter would receive a discount for patients nonadherent to a drug. Results were summarized as counts and percentages. RESULTS: From the literature review, 26 publicly disclosed PBRSAs were identified. Of these, 16 (62%) were announced or initiated from 2015 to 2017, and 10 (38%) were announced or initiated from 1997 to 2012. Thirteen (50%) PBRSAs involved cardiometabolic indications; 5 (19%) involved oncology indications; and 8 (31%) involved other indications. Categorized by health insurer or PBM, 10 (38%) PBRSAs involved large multistate insurers; 5 (19%) involved the Centers for Medicare & Medicaid Services; 7 (27%) involved regional insurers; 3 (12%) involved PBMs; and 1 (4%) involved multiple unspecified insurers. Regarding the most active drug manufacturers, Amgen initiated 5 (19%) PBRSAs and Novartis initiated 4 (15%). Relative to the initial FDA approval of a treatment, 15 (58%) PBRSAs were announced or initiated within 5 years, and 11 (42%) were announced or initiated more than 5 years later. For data collection, electronic medical record (EMR) data would have been an appropriate source for 12 (46%) PBRSAs; claims data would have been an appropriate source for 11 (42%) PBRSAs; and EMR and claims data would have been appropriate sources for 2 (8%) PBRSAs; no description of the outcome measures was available for 1 (4%) PBRSA. CONCLUSIONS: The number of publicly disclosed U.S.-specific PBRSAs for drugs has increased over the years. This review's findings confirm the interest of stakeholders in such arrangements and their confidence in the use of the selected outcome measures. Each PBRSA represents a timely collaboration among stakeholders to provide access to a drug while generating evidence to better elucidate its clinical and economic value. DISCLOSURES: No funding supported this systematic review. Yu is an employee and shareholder of Allergan. Chin reports personal fees from Formulary Resources. Oh and Farias have nothing to disclose. Study concept and design were primarily contributed by Yu, along with the other authors. All authors contributed to the collection and interpretation of the data. The manuscript was written by Yu, Chin, Oh, and Farias and revised by Yu and Chin, along with the other authors.

Moderate Physical Activity is Associated with Cerebral Glucose Metabolism in Adults at Risk for Alzheimer's Disease.

The objective of this study was to investigate the relationship between accelerometer-measured physical activity (PA) and glucose metabolism in asymptomatic late-middle-aged adults. Ninety-three cognitively healthy late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention participated in this cross-sectional study. They underwent 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging and wore an accelerometer (ActiGraph GT3X+) to measure free-living PA. Accelerometer data yielded measures of light (LPA), moderate (MPA), and vigorous (VPA) intensity PA. FDG-PET images were scaled to the cerebellum and pons, and cerebral glucose metabolic rate was extracted from specific regions of interest (ROIs) known to be hypometabolic in AD, i.e., hippocampus, posterior cingulate, inferior temporal cortex, and angular gyrus. Regression analyses were utilized to examine the association between PA and glucose metabolism, while adjusting for potential confounds. There were associations between MPA and glucose metabolism in all ROIs examined. In contrast, LPA was not associated with glucose uptake in any ROI and VPA was only associated with hippocampal FDG uptake. Secondary analyses did not reveal associations between sedentary time and glucose metabolism in any of the ROIs. Exploratory voxel-wise analysis identified additional regions where MPA was significantly associated with glucose metabolism including the precuneus, supramarginal gyrus, amygdala, and middle frontal gyrus. These findings suggest that the intensity of PA is an important contributor to neuronal function in a late-middle-aged cohort, with MPA being the most salient. Prospective studies are necessary for fully elucidating the link between midlife engagement in PA and later life development of AD.

Family history and TOMM40 '523 interactive associations with memory in middle-aged and Alzheimer's disease cohorts.

INTRODUCTION: Family history (FH) of Alzheimer's disease (AD) affects mitochondrial function and may modulate effects of translocase of the outer mitochondrial membrane 40 kDa (TOMM40) rs10524523 ('523) poly-T length on memory decline. METHODS: For 912 nonapolipoprotein ε4 middle-aged adults and 365 aged adults across the AD spectrum, linear mixed models gauged FH and TOMM40 '523 interactions on memory and global cognition between baseline and up to 10 years later. A cerebrospinal fluid mitochondrial function biomarker was also assessed. RESULTS: For FH negative participants, gene-dose preservation of memory and global cognition was seen for "very long" versus "short" carriers. For FH positive, an opposite gene-dose decline was seen for very long versus short carriers. Maternal FH was a stronger predictor in aged, but not middle-aged, participants. Similar gene-dose effects were seen for the mitochondrial biomarker aspartate aminotransferase. DISCUSSION: These results may clarify conflicting findings on TOMM40 poly-T length and AD-related decline.