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Background: The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) will determine whether interventions that simultaneously include multiple risk reduction strategies can protect cognitive health in older adults. The primary outcome, a global cognitive composite score derived from the POINTER‐Modified Neuropsychological Test Battery (PmNTB), was developed to allow for outcome harmonization with its forerunner, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) and other large trials (e.g., A4, EXERT). Here we describe the PmNTB and its initial validation in the baseline U.S. POINTER sample. Method: U.S. POINTER is a Phase 3, multicenter, randomized 2‐year clinical trial of two interventions varying in intensity and format, in older adults at increased risk for cognitive decline and dementia. The PmNTB includes performance from 7 cognitive tests and is computed as the mean of three domain‐specific composites: Episodic Memory, Processing Speed, and Executive Function. The Episodic Memory Composite includes Free and Cued Selective Reminding Test, Story Recall, and Visual Paired Associates. The Processing Speed Composite includes Trail Making Test (TMTA) and Digit Symbol Substitution Test. The Executive Function Composite includes Number Span, Word Fluency, and TMTB. PmNTB was assessed in relation to age, clinical status (Clinical Dementia Rating‐CDR), and other cognitive composites able to be computed in the current sample using overlapping measures (i.e., FINGER NTB, Preclinical Alzheimer's Cognitive Composite‐PACC‐5). Result: 2094 participants completed the baseline assessment (mean age = 68.2±5.2 years; 68.8% female, 69.1% non‐hispanic white, mean MMSE = 28.9± 1.3). Global CDR was 0 for 79.5% of participants, and 0.5 for 20.5% of participants. After adjusting for education, race, ethnicity, and sex, each additional year in age was associated with a drop in PmNTB z‐score by ‐0.064 (95%CI = ‐0.071,‐0.056, p<0.001). Likewise, global CDR = 0.5 (questionable dementia) was associated with a lower PmNTB score (z = ‐0.549) compared with global CDR = 0 (‐0.134 z‐scores). PmNTB correlated with the FINGER NTB (r = 0.858, p<0.001) and the PACC‐5 (r = 0.876, p<0.001). Conclusion: The PmNTB is a valid measure of cognitive functioning, capturing age‐related cognitive decrements and is associated with clinically relevant, functional outcomes. It also exhibits convergent validity with established cognitive outcomes. [ABSTRACT FROM AUTHOR]

Background: The brain is particularly sensitive to excessive pressure and flow pulsatility. Disproportionate stiffening of the aorta can reduce wave reflection at the aorta‐carotid interface and facilitate transmission of excessive pulsatile energy into the cerebral microcirculation, leading to impaired cognitive function. The U.S. POINTER Neurovascular (POINTER‐NV) ancillary study is an ongoing study designed to evaluate vascular structure and function in participants from the U.S. POINTER trial. Here we describe the baseline characteristics of the POINTER‐NV participants, focusing on aortic and carotid variables and their association with cognitive function. Method: Ultrasound and tonometry were used to assess aortic and carotid measures. Hemodynamic and structural variables were compared according to cognitive status using the baseline Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) score categorized as normal (CDR‐SB = 0) or possibly impaired (CDR‐SB>0). Linear regression was used to assess cross‐sectional associations between aortic and carotid variables and composite scores for global cognition, executive function, memory, and processing speed, with and without adjustment for age, sex, race, and ethnicity. Result: Aortic and carotid hemodynamics were available for 165 POINTER‐NV participants (mean age: 67.9±5.1 years, 70% female, 37% people of color). A large proportion of the participants had evidence of subclinical cardiovascular disease based on a carotid intima‐media thickness ≥1.0 mm (n = 109/165, 66.1%) or increased aortic stiffness based on a carotid‐femoral pulse wave velocity >10 m/s (n = 70/131, 53.4%). There were no significant differences in aortic or carotid structure and function between participants with normal cognition (n = 109) and those with possible cognitive impairment (n = 56). Higher carotid‐femoral pulse wave velocity was associated with lower global cognition, executive function, and processing speed, even after adjustment for age, sex, race, and ethnicity (all p<0.05). Although there was some suggestion that higher carotid pulsatility, higher carotid transmission, and lower aorta‐carotid reflection may be associated with worse cognition, these associations were not consistent across cognitive domains and did not hold up after covariate adjustment. Conclusion: Age‐related changes in vascular structure and function can promote cognitive decline and dementia. Our data are consistent with prior evidence suggesting that higher aortic stiffness may be particularly important in this regard. [ABSTRACT FROM AUTHOR]

Background: The arterial baroreflex maintains stable blood flow to the brain. Reduced baroreflex sensitivity for modulation of heart rate (BRS) has been observed in patients with Alzheimer's disease (AD) and mild cognitive impairment and may be impacted by race, ethnicity, sex, and socioeconomic factors such as the Area Deprivation Index (ADI), a validated, neighborhood‐level composite index that incorporates 17 social determinants of health. However, these relationships have not been well described. Method: This study utilized baseline data from 196 participants enrolled in the U.S. POINTER Neurovascular study, an ancillary to the parent U.S. POINTER multi‐site lifestyle intervention trial that adds assessments of autonomic function and vascular structure and function. BRS was calculated from continuous blood pressure and electrocardiogram recording using the slope of the regression line between changes in systolic blood pressure and RR interval values in the same direction, with higher BRS indicating better autonomic function. ADI scores ranging from 1 to 10 were calculated using 9‐digit zip codes, with 10 indicating the greatest disadvantage. Analysis of variance and linear regression were used to evaluate associations between measures of interest. Result: The average age of the study population was 67.9 ± 5.4 years, 64 (17%) were males, and 60 (30.6%) identified as people of color (POC). Overall, the mean BRS was 9.2 ± 4.6 ms/mmHg, and the average ADI score was 4.56 ± 2.69 (range: 1 to 10), corresponding to a national ADI percentile of 40.7 ± 26.1 (range: 3 to 100). Less than a quarter of participants (n = 42, 21.4%) had an ADI percentile >67, indicating a moderate to high level of neighborhood disadvantage. White participants had lower BRS compared to POC (8.60 ± 4.49 vs. 10.60 ± 4.61 ms/mmHg, p = 0.0048). In a multiple regression model adjusting for demographics and ADI, sex (p = 0.0283), race and ethnicity (p = 0.0049), and education (p = 0.0196) were significantly associated with BRS, indicating better autonomic function in men, POC, and those with higher education. ADI was not associated with BRS. Conclusion: Race, ethnicity, and education impact autonomic function. Further investigations are needed to assess the impact of other demographic and socioeconomic factors on neurovascular health. [ABSTRACT FROM AUTHOR]

Background: Sleep disordered breathing (SDB) leads to nocturnal hypoxemia and sleep disruption, which are linked to adverse health conditions, particularly in older adults at risk for dementia. Few prospective studies of SDB examine cognitive decline among those at increased risk for cognitive impairment and dementia. POINTER‐zzz, a sleep ancillary study of U.S. study to PrOtect brain health through lifestyle INTErvention to Reduce risk (U.S. POINTER), allows us to examine the role of lifestyle intervention on sleep quality, and potential moderating effects of sleep on cognition to the intervention in medically and cognitively vulnerable older adults. Method: U.S. POINTER was designed to investigate the effects of two 2‐year lifestyle interventions on cognitive trajectories in 2,000 older, cognitively normal adults (aged 60‐79 yrs) at increased risk for cognitive decline and dementia due to physical inactivity, poor diet and cardiovascular disease. POINTER‐zzz enrolled a subset of parent trial participants and administered in‐home sleep assessments using WatchPAT (1 night) and ActiGraph (6 nights) devices. We summarize participants' baseline characteristics including apnea hypopnea index (AHI), sleep duration and sleep efficiency. Result: To date, 688 POINTER‐zzz participants enrolled and completed baseline WatchPAT and/or Actigraph assessments. Participant ages averaged 68.6 years old (standard deviation, 5.13); 21% of participants self‐identified as Black/African American, 4% Hispanic/Latino, and 66% White. More than half (68%) were female, and 69% had a Bachelor's degree or higher. Overall, 87% of participants had at least mild sleep apnea (AHI>5). Severe sleep apnea (AHI≥30) was observed in 14% of participants overall, and 21% of those aged ≥75 yrs. Severe sleep apnea was more prevalent among males (19%) than females (11%). Overall, nightly sleep duration for the cohort averaged 6.6 hours, with 83% sleep efficiency, and an average of 79.3 minutes awake after sleep onset. Conclusion: POINTER‐zzz participants have sleep characteristics that align with expectations for a cohort that is broadly representative of a diverse older adult population in the US. POINTER‐zzz provides an unparalleled opportunity to test the effects of a multi‐domain lifestyle intervention on sleep disturbances that are linked to cognitive decline and AD in a well‐characterized, diverse cohort of at‐risk older adults. [ABSTRACT FROM AUTHOR]

Background: The U.S. POINTER study is a phase 3, multicenter, 2‐year randomized controlled trial (RCT) of two lifestyle interventions varying in intensity and format, conducted in older adults living in the U.S. who do not have objective cognitive impairment at study entry, but have increased risk of cognitive decline and dementia. Inclusion criteria included specific risk factors (e.g., family history of dementia, vascular risk factors) but not subjective cognitive concerns (SCCs). However, SCCs are likely to be common in this group of at‐risk individuals. U.S. POINTER provides a unique opportunity to evaluate the prevalence of SCCs and their demographic and clinical correlates in an at‐risk group. Methods: Recruitment for the U.S. POINTER study is still ongoing, and the following is based on a partial sample. The sample includes 1811 U.S. POINTER participants with complete baseline data (collected by December 2022), mean age = 68.2y (SD = 5.2), 73.5% are female, 70.2% have18+ years education, and 29.3% are from underrepresented groups. SCCs were measured by the brief 12‐item Everyday Cognition (ECog) questionnaire which includes two items in each of 6 domains: everyday memory, language, visuospatial abilities, planning, organization and divided attention. Responses on the ECog range from 0 = no change/better compared to baseline, 1 = questionably/inconsistently worse, 2 = consistently a little worse, 3 = much worse. Neuropsychological performance was measured using a global composite and episodic memory, executive functioning, and processing speed composites. Other variables included demographics, depression (Geriatric Depression Scale total score; GDS) and sleep (Insomnia severity index (ISI)) and vascular disease burden index. Results: Thirty‐five percent of the cohort endorsed having a subjective complaint on the ECog (score ≥2 on any item). The most frequent complaint was "Remembering where I have placed objects" (23%). SCCs did not differ by age, sex or education. ECog‐12 Total were related to insomnia and depression (p<.0001). After adjusting for age, sex, education, vascular risk burden, GDS and ISI, greater SCC (ECog‐12 Total) was still associated with the global composite and all three domains (ps < 0.003). Conclusions: SCCs, particularly everyday memory complaints, were relatively common in this at‐risk cohort. While SCCs were related to depression and sleep, they were also independently associated with slightly worse cognitive function. [ABSTRACT FROM AUTHOR]

Background: Cognitive dispersion refers to the within‐person variability across tasks. Relative to the normative approach, cognitive dispersion may be more sensitive to subtle changes in preclinical Alzheimer's disease. Greater dispersion has been associated with increased risk for conversion to mild cognitive impairment and faster rates of medial temporal lobe atrophy. This metric can be derived from a regular neuropsychological assessment and complement traditional outcome approaches, particularly in those underrepresented in normative data. This study evaluated cognitive dispersion as an independent predictor of clinical status across racial and ethnic groups. Method: Baseline data on 1811 cognitively unimpaired older adults with high vascular risk from the U.S. POINTER multisite lifestyle intervention study were examined. Sample characteristics included mean age of 68 (SD = 5.2), 70% female, 30% less‐than‐college education, and 29% underrepresented groups (301 Black, 231 Other). Correlations between cognitive dispersion and other brain health risks (vascular, subjective cognitive decline (SCD), physical activity) were tested. Cognitive dispersion was defined as the standard deviation of individuals' z‐transformed scores of 8 cognitive tests. Vascular risk burden was the sum of 5 conditions (hypertension, diabetes, hypercholesterolemia, heart disease, obesity). Self‐report SCD was measured by the Cognitive Function Instrument (CFI) and Measurement of Everyday Cognition (ECOG12). Logistic Regression Models were fitted to predict Clinical Dementia Global Ratings (CDR 0.5 vs. 0) to evaluate cognitive dispersion as an independent predictor in the whole sample, White participants and Black participants, controlled for demographics, vascular risk, and physical activity. Logistic Regression Models were also evaluated with CFI or ECOG12 as additional covariate. Result: Greater cognitive dispersion was correlated with older age, greater vascular burden and less physical activity, but not SCD. Cognitive dispersion was significantly higher in men, Black participants, and participants with less education. Cognitive dispersion predicted CDR in Black participants (OR = 4.7, p<0.01), and trended in the whole sample (OR = 1.6, p = 0.05), but was not significant in White participants (OR = 1.2, p = 0.63). Results hold when controlled for SCD (Table 1). Conclusion: Results supported cognitive dispersion as a sensitive objective metric, in addition to self‐report SCD, to identify individuals showing the earliest clinical signs of decline, particularly among those underrepresented in traditional norms. [ABSTRACT FROM AUTHOR]

Background: Autonomic regulation plays a major role in maintaining stable blood supply to the brain. Impaired autonomic function, as evidenced by high blood pressure variability (BPV) and/or low heart rate variability (HRV), is common in older adults and is associated with reduced perfusion, which can ultimately lead to impaired cognitive function. The U.S. POINTER Neurovascular (POINTER‐NV) ancillary study is an ongoing study designed to evaluate autonomic function in participants from the U.S. POINTER trial. Here we describe the baseline characteristics of the POINTER‐NV participants, focusing on autonomic measures and their relationship to cognitive function. Method: Continuous blood pressure and ECG recordings were used to assess BPV, HRV, and sympathovagal balance. Autonomic variables were compared according to cognitive status using the baseline Clinical Dementia Rating Scale Sum of Boxes (CDR‐SB) score. Linear regression was used to assess cross‐sectional associations between sympathovagal balance and BPV variables and composite scores for global cognition, executive function, memory, and processing speed, with and without adjustment for age, sex, and race/ethnicity. Result: Autonomic measures were available for 212 POINTER‐NV participants (mean age: 67.9 ± 5.4 years, 67% female, 33% people of color). There were no significant differences in BPV or HRV measures between participants with normal cognition (CDR‐SB score = 0) and those with possible cognitive impairment (CDR‐SB score = 0.5–1.0). Higher sympathovagal balance was significantly associated with higher scores of global cognition, executive function, and processing speed; however, this association became statistically insignificant after adjustment for age, sex, and race/ethnicity. Higher BPV measured as standard deviation of mean arterial pressure (SDMAP) was associated with lower scores for episodic memory after adjustment for age, sex, and race/ethnicity (p = 0.03). There was some suggestion that lower HRV might be associated with worse cognition, however, these associations were inconsistent across cognitive domains and did not remain after covariate adjustment. Conclusion: Age‐related changes in autonomic function can promote cognitive decline and dementia. Our data are consistent with prior evidence suggesting a role for sympathovagal balance and blood pressure variability in modulating cognitive function [ABSTRACT FROM AUTHOR]

Background Low levels of the soluble receptor for advanced glycation endproducts (sRAGE) have been implicated in a number of chronic diseases. Previous studies indicate that sRAGE levels are ~ 30% lower in Blacks compared to Whites. However, the reasons for these differences are unclear. Purpose We aimed to identify predictors of circulating sRAGE biomarkers among Black and White adults at high cardiac risk. Methods Serum levels of total sRAGE, endogenous secretory RAGE (esRAGE), carboxymethyl-lysine (CML, a major RAGE ligand), and their ratios were measured in 99 Blacks and 454 Whites. Results Blacks had a more adverse cardiovascular risk profile, as well as lower median levels of total sRAGE (972 vs. 1564 pg/ml) and esRAGE (474 vs. 710 pg/ml) compared to Whites (p < 0.0001). In addition, the proportion of esRAGE was higher in Blacks (47% vs. 44%, p = 0.02), as were the CML/total sRAGE (0.89 vs. 0.56 ng/pg) and CML/esRAGE (1.72 vs. 1.20 ng/pg) ratios (p < 0.0001). Racial differences persisted after adjustment for key covariates including age, gender, tobacco use, comorbidities, BMI, blood pressure, glucose, insulin, triglycerides, C-reactive protein, and renal function (p < 0.05). Race alone accounted for nearly half of the variability in total sRAGE levels (10.6%; model explained 23.9%). In stratified analyses, gender and heart rate were independently associated with total sRAGE and esRAGE in Whites, while CML and C-reactive protein were associated with total sRAGE in Blacks. Conclusions We identified several independent predictors of sRAGE biomarkers. Notably, Black race was associated with an adverse AGE/RAGE profile, including lower sRAGE and higher CML/sRAGE ratios. [ABSTRACT FROM AUTHOR]

Background: U.S. POINTER is testing whether multidomain lifestyle interventions focused on physical exercise, nutrition, cognitive challenge, and risk factor management reduces risk of cognitive decline in a heterogeneous population of at‐risk older adults in America. The study adapts the FINGER (Finnish Intervention Geriatric Study to Prevent Cognitive Impairment and Disability) interventions to fit the United States culture and delivers the intervention within the community at 5 sites across the country. Method: U.S. POINTER is a 2‐year RCT that will enroll 2000 cognitively unimpaired older adults who are at risk for cognitive decline due sedentary lifestyle, poor diet and other factors. Participants are randomized to one of two lifestyle intervention groups that differ in format and intensity. In 2020, the COVID‐19 pandemic presented a number of challenges for the study that affected recruitment, assessment schedules, and intervention delivery. Result: As of March 2020, when COVID‐19 incidence was on an exponential rise in the US, 240 participants had been enrolled in U.S. POINTER. In response to local and national safety mandates, study activities were paused from March 23rd to July 13th. During the pause, sites remained in contact with study candidates and enrolled participants to provide ongoing support to keep them engaged in the trial. Enrollees also received regular telephone calls to encourage continued adherence to their assigned lifestyle intervention. In response to the multiple pandemic‐related challenges, study protocols and procedures were adapted to facilitate and encourage participant adherence to intervention activities. At study re‐start, retention was 98%. Despite climbing COVID‐19 infection rates nationwide, enrollment at all 5 sites has continued at a steady rate (N=540 as of Jan2021), virtual Team Meeting attendance for both lifestyle groups exceeds 80%, and participants continue to successfully work toward their intervention goals. Conclusion: The COVID‐19 pandemic presented unprecedented challenges, but it also provided a unique opportunity to adapt intervention delivery so that a nonpharmacological community‐based trial could continue – even during a debilitating global health crisis. U.S. POINTER's adaptations to pandemic‐related challenges may ultimately increase the resilience of its interventions to even the most challenging of circumstances that older adults will face now and in the future. [ABSTRACT FROM AUTHOR]

Introduction Consistent evidence linking habitual sleep duration with risks of mild cognitive impairment (MCI) and dementia is lacking. Methods We conducted a prospective study on 7444 community-dwelling women (aged 65–80 y) with self-reported sleep duration, within the Women's Health Initiative Memory Study in 1995–2008. Incident MCI/dementia cases were ascertained by validated protocols. Cox models were used to adjust for multiple sociodemographic and lifestyle factors, depression, cardiovascular disease (CVD), and other clinical characteristics. Results We found a statistically significant ( P = .03) V-shaped association with a higher MCI/dementia risk in women with either short (≤6 hours/night) or long (≥8 hours/night) sleep duration (vs. 7 hours/night). The multicovariate-adjusted hazard for MCI/dementia was increased by 36% in short sleepers irrespective of CVD, and by 35% in long sleepers without CVD. A similar V-shaped association was found with cognitive decline. Discussion In older women, habitual sleep duration predicts the future risk for cognitive impairments including dementia, independent of vascular risk factors. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The purpose of this study is to evaluate a percent change model of postoperative parathyroid hormone level in thyroidectomy patients as a predictor of hypocalcemia. Materials and methods: Chart review was completed on patients who had undergone total or completion thyroidectomy over a 22-month period in our department. Only those patients with a preoperative ionized calcium and parathyroid hormone (PTH) level and at least 1 postoperative result were included. Ionized calcium levels served as an internal control. The Student t test was used to compare PTH level between the normocalcemic and hypocalcemic groups at each time point. Logistic regression analysis was used to predict hypocalcemia based on the diagnostic criteria. Receiver operator curves were used to maximize sensitivity. Results: Fifty-two patients met the inclusion criteria during the study period. A total of 22 patients (42%) experienced hypocalcemia. We were unable to maximize both sensitivity and specificity at the same time point. When comparing preoperative to 6-hour postoperative PTH percent change, patients with a greater than 44% decrease are likely to have hypocalcemia, with a sensitivity of 100%. Likewise, in those patients without a greater than 44% decrease at 6 hours, early discharge can be considered safe, given the negative predictive value of 100%. Conclusion: In our series, patients with a greater than 44% PTH decrease from preoperative to 6-hour postoperative are very likely to develop hypocalcemia. We would propose that these patients need further inpatient monitoring to progress to safe discharge. Likewise, patients with a less than 44% decrease at the 6-hour time point are unlikely to develop hypocalcemia and may be considered safe for discharge. [Copyright &y& Elsevier]

Summary: Objectives/Hypothesis: Maximum phonation time (MPT), a clinical measurement of the longest time one can phonate a vowel, typically /a/, is a frequently used measure of vocal function, but normative data are lacking for MPT in healthy older adults. The aim of this study was to provide data on MPT in healthy older adults and to determine the effect of advanced age, gender, and repeated measures on MPT. Study Design: Prospective. Methods: Sixty-nine healthy older adult volunteers participated (ie, 15, 26, and 28 in the seventh, eighth, and ninth decades of life, respectively). The effects of age, gender, and repeated measures (three trials in a single session) on MPT were assessed. Mean, standard deviation, compound symmetry covariance, analysis of variance, and analysis of covariance were used for statistical analysis. Results: Neither age group, gender, trial, nor their interactions was statistically significant (P >0.05). Adults in the seventh, eighth, and ninth decades of life had mean MPTs of 22.27 (standard error [SE]=1.56), 22.97 (SE=1.11), and 21.14 (SE=0.97) seconds, respectively. Females and males had mean MPTs of 20.96 (SE=0.92) and 23.23 (SE=0.96) seconds, respectively. Finally, MPTs for trials 1, 2, and 3 were 21.77 (SE=1.09), 21.67 (SE=1.12), and 22.80 (SE=1.27), respectively. Conclusions: MPTs were longer in this group of older adults than previously reported and did not vary significantly with age or gender. Additionally, across a single short sampling session, measurements were relatively stable across three trials of MPTs. [Copyright &y& Elsevier]

Background: U.S. POINTER aims to test whether a multidomain lifestyle intervention focused on physical and cognitive activity, nutrition, and risk factor management reduces risk of cognitive decline in a heterogeneous population of older adults in the U.S. The study adapts the FINGER (Finnish Intervention Geriatric Study to Prevent Cognitive Impairment and Disability) interventions to fit American culture and works with community partners at 5 sites across the country to develop sustainable community‐based intervention programs. Methods: U.S. POINTER is a 2‐year RCT that is enrolling 2000 cognitively normal older adults (60‐79 years) who are at risk for decline due sedentary lifestyle, poor diet and other factors such as family history of memory impairment and suboptimum cardiovascular health. Recruitment utilizes electronic health records, as well as grassroots approaches to engage traditionally underrepresented groups. Participants are randomized to one of two lifestyle intervention groups – Self‐Guided or Structured Lifestyle Intervention – that differ in format, intensity and accountability. U.S. POINTER includes partnerships with local chapters of the Alzheimer's Association and lifestyle specialists to assist with intervention delivery. The primary outcome is 2‐year change in cognitive function measured with a composite score that permits harmonization with FINGER. Results: Recruitment began in 2019 at the vanguard site in North Carolina. Study progress at all 5 participating sites will be presented. Progress toward harmonization with FINGER and other international study teams in the WW‐FINGERS network will also be discussed. Conclusion: As a member of the WW‐FINGERS network of trials, U.S. POINTER provides an unprecedented opportunity to leverage lessons learned in FINGER and expand this work to test the generalizability of the findings to a heterogeneous American cohort with different cultural needs and practices. The results, in combination with those from other WW‐FINGERS studies, have the potential to identify a strategy to slow cognitive decline on a global scale. [ABSTRACT FROM AUTHOR]

Background: Non‐pharmacological approaches that target modifiable risks through lifestyle interventions provide the most promising evidence to delay disease. In older adults, chronic sleep disturbances marked by sleep‐disordered breathing (SDB) and sleep fragmentation are associated with impaired hippocampal functioning, increased beta‐amyloid burden, and greater Alzheimer's risk. These and other sleep abnormalities are associated with reduced vascular health. Although some evidence suggests that diet, exercise, and cardiovascular risk reduction can improve sleep and improved sleep benefits cognition in older adults, these effects have not been confirmed in a rigorous clinical trial. Methods: The U.S. study to PrOtect brain health through lifestyle INTErvention to Reduce risk (U.S. POINTER), funded by the Alzheimer's Association, was launched in the Fall of 2018. It is investigating whether lifestyle interventions ‐ Self‐Guided (SG) versus a Structured (STR) lifestyle intervention ‐ influence cognitive trajectories over 2 years in 2000 older cognitively normal adults (aged 60‐79 yrs) who are at increased risk for cognitive decline, Alzheimer's disease and other dementias. The NIH‐funded POINTER‐zzz ancillary study adds in‐home objective sleep assessments for 700 participants to examine the effects of lifestyle modification and cardiovascular risk management on sleep disturbances that are linked to cognitive decline and Alzheimer's disease and that may improve with U.S. POINTER interventions. Results: POINTER‐zzz methods and study design will be presented, which will permit over 2000 objective sleep assessments to be completed over 2 years. These assessments will provide extensive oximetry and actigraphy data for analysis by lifestyle intervention group assignment. Sleep data will be examined relative to intervention effects on cognition and other parent trial and ancillary study outcomes, including MRI and amyloid/tau PET brain imaging. POINTER‐zzz leverages resources provided by the parent trial and other funded ancillary studies, and by well‐established collaborations with sleep experts. Conclusions: POINTER‐zzz provides an unparalleled opportunity to test the effects of a multi‐domain lifestyle intervention on sleep abnormalities that are linked to cognitive decline and Alzheimer's in a well‐characterized, diverse cohort of at‐risk older adults. The study may identify an effective strategy for improving sleep that could have important consequences for reduced risk of Alzheimer's disease and related dementias. [ABSTRACT FROM AUTHOR]

Background: Clonal Hematopoiesis of Indeterminate Potential (CHIP) occurs when hematopoietic stem cells in bone marrow undergo somatic mutations and yield genetically distinct leukocyte subpopulations with increased expression of inflammatory genes in innate immune cells. Genes commonly mutated in CHIP are associated with DNA methylation, inflammation, generation of reactive oxygen species, and DNA damage response. Factors associated with CHIP, including inflammation, cardiovascular disease (CVD), metabolic disorders, and stroke are risks for Alzheimer's disease and other dementias, however the association between CHIP and dementia is unknown. We examined the association between CHIP and the incidence of MCI or probable dementia over 22 years of follow‐up in the Women's Health Initiative Memory Study (WHIMS). We also examined these associations by common driver mutations for CHIP. Method: Women without a baseline (1993‐1998) history of stroke, who participated in WHIMS and had baseline blood sample, were followed with annual cognitive assessments, adjudication of MCI or probable dementia, and provided self‐report of dementia diagnoses for up to 22 years. CHIP was defined by whole genome sequencing through TOPMed. Proportional hazards models were used to examine survival to onset of cognitive impairment (mild cognitive impairment (MCI), probable dementia, or self‐reported dementia). Result: We classified 934 women into two groups, CHIP (11%) and no CHIP (89%). A total of 300 women developed cognitive impairment by Year 22. Survival analyses for time to cognitive impairment was adjusted for baseline age, education, 3MS score, hypertension, diabetes, and BMI. There was no difference in risk of cognitive impairment between the women with and without CHIP (p = 0.63). When CHIP was categorized by gene‐specific driver mutations, survival free of impairment among women with DNMT3A mutations was not different from those without CHIP. Risk for impairment was higher among women with TET2 (HR 1.75, p=0.19). Overall results were not statistically significant, however power was limited by low numbers of women with CHIP (see Figure). Conclusion: CHIP was not associated with cognitive outcomes overall but when stratified by the primary CHIP mutations (DNMT3A or TET2), different trends emerged. Future work in WHIMS will explore the cognitive performance over time by different CHIP mutations. [ABSTRACT FROM AUTHOR]

Background: Sleep disturbances are common in individuals with Mild Cognitive Impairment (MCI); and sleep disturbances increase the risk of Alzheimer's disease (AD). Lower ratings of quality of life (QoL) are also found in MCI. We examined the association between sleep disturbances and QoL ratings among participants with MCI. Methods: Baseline in‐home sleep assessments using the WatchPAT (Itamar Medical) and the QoL in AD questionnaire were collected from amnestic MCI (aMCI) participants from the diet intervention trial, Brain Energy for Amyloid Transformation in Alzheimer's Disease (BEAT‐AD) at the Wake Forest ADRC. The WatchPAT assessed sleep time, efficiency, and sleep‐related hypoxemia measures including the apnea‐hypopnea index (AHI), oxygen desaturation index (ODI) and respiratory disturbance index (RDI), where higher values indicate greater disturbances in sleep. The QoL in AD scale ranged from 13–52 with lower scores indicating poorer QoL ratings. We assessed the association between total sleep time and sleep efficiency with QoL. Pearson correlations and regression models measured the association of sleep metrics with QoL scores. Results: Forty‐two aMCI participants (mean age =69.0 ± 7.4 years; N=23 female; mean BMI =27.6) were studied. Disturbed sleep indicated by the average number of apneas and hypopneas (AHI, mean = 18.6 ± 14.6) and respiratory events or related arousals (RDI, mean = 20.7 ± 14.2) was negatively associated with lower subjective measures of QoL. Higher AHI and RDI scores, indicating greater intermittent hypoxia and respiratory burden, were associated with lower QoL (AHI: r= ‐0.359, p=0.027; RDI: r= ‐0.340, p=0.037). There was a trend toward a negative association of ODI and QoL scores (r= ‐0.309, p=0.059). Regression models including age, sex, and BMI did not significantly predict QoL scores with AHI (F(4,35)=1.95, p>.1) or RDI (F(4,34)=1.76, p>.15), however, AHI and RDI individually added significantly to the prediction of QoL scores (AHI: B=‐.136, t=‐2.4,P<.05; RDI: B=‐.162, t=‐2.4, p<.05). Conclusions: Greater sleep disturbances related to hypoxic and respiratory events were associated with lower self‐ratings of QoL in MCI participants. Further research will increase the sample, investigate the impact of hypoxic and respiratory events on brain function, and whether longitudinal changes in diet influence the relationship of sleep‐related hypoxemia and QoL. [ABSTRACT FROM AUTHOR]