Sex Differences in the Role of Sleep on Cognition in Older Adults.

Study Objectives: The study aimed to investigate sex differences in the relationship between sleep quality (self-report and objective) and cognitive function across three domains (executive function, verbal memory, and attention) in older adults. Methods: We analyzed cross-sectional data from 207 participants with normal cognition or mild cognitive impairment (89 males and 118 females) aged over 60. The relationship between sleep quality and cognitive performance was estimated using generalized additive models. Objective sleep was measured with the GT9X Link Actigraph, and self-reported sleep was measured with the Pittsburgh Sleep Quality Index. Results: We found that females exhibited stable performance of executive function with up to about 400 minutes of total sleep time, with significant declines in performance (p = 0.02) when total sleep time was longer. Additionally, a longer total sleep time contributed to lower verbal memory in a slightly non-linear manner (p = 0.03). Higher self-reported sleep complaints were associated with poorer executive function in females with normal cognition (p = 0.02). In males, a positive linear relationship emerged between sleep efficiency and executive function (p = 0.04), while self-reported sleep was not associated with cognitive performance in males with normal cognition. Conclusions: Our findings suggest that the relationships between sleep quality and cognition differ between older males and females, with executive function being the most influenced by objective and self-reported sleep. Interventions targeting sleep quality to mitigate cognitive decline in older adults may need to be tailored according to sex, with distinct approaches for males and females.

A retrospective analysis of serious adverse events and deaths in U.S.-based lifestyle clinical trials for cognitive health.

Objective: This retrospective analysis examined serious adverse events (SAEs) and deaths in U.S. lifestyle clinical trials aimed at enhancing cognitive health in older adults. Methods: Data was gathered from trials completed between January 1, 2000, and July 19, 2023, via ClinicalTrials.gov's API. Results: Among these trials, 76% did not report results. The remaining studies fell into four intervention categories: Cognitive/Behavioral, Exercise/Movement, Diet/Supplement, and Multi-modal. When considering all trial types collectively, the findings suggest that lifestyle clinical trials are generally safe. There was no significant increase in the relative risk of experiencing an SAE in the intervention group compared to the control group. However, in terms of relative risk of death, an increase of 28% was observed in the intervention compared to the control, which was statistically significant (X2 (1, N = 36), p < 0.00688). Nevertheless, this increase did not surpass age-adjusted U.S. mortality rates. Assessing the data by intervention type, Diet/Supplement, and Multi-modal trials displayed an elevated relative risk of SAEs in the intervention. Diet/Supplement trials had a 16% increase (X2 (1, N = 2), p < 0.0263), and Multi-modal trials had a 365% increase (X2 (1, N = 5), p < 0.000213). Diet/Supplement trials also showed a 67% increased risk of death (X2 (1, N = 2), p < 0.000197). Conclusions: These findings should be cautiously considered due to the low rate of reporting, but underscore the significance of reporting clinical trial results, enhancing transparency, and facilitating more accurate safety assessments in cognitive aging and lifestyle interventions for older adults.

Changes in Cognitive Function After Kidney Transplantation: A Longitudinal Cohort Study.

RATIONALE & OBJECTIVE: Kidney disease negatively affects cognition. We assessed the effect of kidney transplantation (KT) on different cognitive domains. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We examined pre- versus post-KT cognition in patients waitlisted for KT at an academic center. PREDICTORS: Transplant status. We measured cognitive function before KT (n=101), 3 months after KT (n=78), and 1 year after KT (n = 83). OUTCOMES: Our primary outcome was change in cognitive function before versus after KT. We used standard neuropsychological tests to assess global cognition (Mini-Mental State Exam [MMSE]), episodic/declarative memory (Logical Memory), psychomotor speed/visuospatial function (Digit Symbol Substitution Test [DSST], Trail Making Test [TMT] A), working memory/attention (Digit Span), executive function (TMT B), and semantic memory/verbal fluency/language (Category Fluency). ANALYTICAL APPROACH: Using linear mixed model analysis, we evaluated the changes in neuropsychological test scores adjusted for age, sex, race, education, and number of assessments. RESULTS: Before KT, Logical Memory I and II, DSST, MMSE, Category Fluency (animal naming), and Digit Span backward scores were low compared with normative values from the National Alzheimer's Coordinating Center data. Logical Memory I and II scores improved after KT (pre- vs post-KT, estimated group difference [d]=3.3, P<0.001 for Logical Memory I; d=4.27, P<0.001 for Logical Memory II), such that post-KT scores were similar to normative values (post-KT vs normative values, d = -0.37, P=0.06 for Logical Memory I; d = -0.89, P=0.08 for Logical Memory II). Category Fluency (animal naming; d=2.4, P<0.001) and DSST (d=3.12, P=0.01) scores also improved with KT, but post-KT DSST scores remained lower than normative values (post-KT vs normative values, d = -5.17, P<0.001). MMSE, Digit Span, and TMT A and B scores did not change after KT. LIMITATIONS: Single-center study. CONCLUSIONS: Episodic and verbal declarative memory normalize after KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function show partial improvement. Cognitive impairment in kidney disease is therefore at least partly reversible with KT. PLAIN-LANGUAGE SUMMARY: Cognitive impairment in kidney disease affects self-esteem, vocational abilities, quality of life, health care costs, and mortality. It is not clear whether kidney transplantation (KT) improves cognition and whether the improvement is uniform across cognitive domains. The distinction between reversible and irreversible cognitive impairment has important implications in the clinical care of patients before and after KT. We assessed cognition before KT and 3 months and 12 months after KT and discovered that episodic and verbal declarative memory normalized with KT. Semantic memory, verbal fluency, language, psychomotor speed, and visuospatial function also improved with KT but did not reach normal levels. Cognitive impairment in kidney disease is therefore at least partly reversible.

Protocol for a single-arm, pilot trial of creatine monohydrate supplementation in patients with Alzheimer's disease.

BACKGROUND: Impaired brain bioenergetics is a pathological hallmark of Alzheimer's disease (AD) and is a compelling target for AD treatment. Patients with AD exhibit dysfunction in the brain creatine (Cr) system, which is integral in maintaining bioenergetic flux. Recent studies in AD mouse models suggest Cr supplementation improves brain mitochondrial function and may be protective of AD peptide pathology and cognition. AIMS: The Creatine to Augment Bioenergetics in Alzheimer's disease (CABA) study is designed to primarily assess the feasibility of supplementation with 20 g/day of creatine monohydrate (CrM) in patients with cognitive impairment due to AD. Secondary aims are designed to generate preliminary data investigating changes in brain Cr levels, cognition, peripheral and brain mitochondrial function, and muscle strength and size. METHODS: CABA is an 8-week, single-arm pilot study that will recruit 20 patients with cognitive impairment due to AD. Participants attend five in-person study visits: two visits at baseline to conduct screening and baseline assessments, a 4-week visit, and two 8-week visits. Outcomes assessment includes recruitment, retention, and compliance, cognitive testing, magnetic resonance spectroscopy of brain metabolites, platelet and lymphocyte mitochondrial function, and muscle strength and morphology at baseline and 8 weeks. DISCUSSION: CABA is the first study to investigate CrM as a potential treatment in patients with AD. The pilot data generated by this study are pertinent to inform the design of future large-scale efficacy trials. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05383833 , registered on 20 May 2022.

Design of a pragmatic randomized implementation effectiveness trial testing a health system wide hypertension program for older adults.

Hypertension control remains poor. Multiple barriers at the level of patients, providers, and health systems interfere with implementation of hypertension guidelines and effective lowering of BP. Some strategies such as self-measured blood pressure (SMBP) and remote management by pharmacists are safe and effectively lower BP but have not been effectively implemented. In this study, we combine such evidence-based strategies to build a remote hypertension program and test its effectiveness and implementation in large health systems. This randomized, controlled, pragmatic type I hybrid implementation effectiveness trial will examine the virtual collaborative care clinic (vCCC), a hypertension program that integrates automated patient identification, SMBP, remote BP monitoring by trained health system pharmacists, and frequent patient-provider communication. We will randomize 1000 patients with uncontrolled hypertension from two large health systems in a 1:1 ratio to either vCCC or control (usual care with education) groups for a 2-year intervention. Outcome measures including BP measurements, cognitive function, and a symptom checklist will be completed during study visits. Other outcome measures of cardiovascular events, mortality, and health care utilization will be assessed using Medicare data. For the primary outcome of proportion achieving BP control (defined as systolic BP < 130 mmHg) in the two groups, we will use a generalized linear mixed model analysis. Implementation outcomes include acceptability and feasibility of the program. This study will guide implementation of a hypertension program within large health systems to effectively lower BP.

Blood Biomarkers Discriminate Cerebral Amyloid Status and Cognitive Diagnosis when Collected with ACD-A Anticoagulant.

BACKGROUND: The development of biomarkers that are easy to collect, process, and store is a major goal of research on current Alzheimer's Disease (AD) and underlies the growing interest in plasma biomarkers. Biomarkers with these qualities will improve diagnosis and allow for better monitoring of therapeutic interventions. However, blood collection strategies have historically differed between studies. We examined the ability of various ultrasensitive plasma biomarkers to predict cerebral amyloid status in cognitively unimpaired individuals when collected using acid citrate dextrose (ACD). We then examined the ability of these biomarkers to predict cognitive impairment independent of amyloid status. METHODS: Using a cross-sectional study design, we measured amyloid beta 42/40 ratio, pTau-181, neurofilament-light, and glial fibrillary acidic protein using the Quanterix Simoa® HD-X platform. To evaluate the discriminative accuracy of these biomarkers in determining cerebral amyloid status, we used both banked plasma and 18F-AV45 PET cerebral amyloid neuroimaging data from 140 cognitively unimpaired participants. We further examined their ability to discriminate cognitive status by leveraging data from 42 cognitively impaired older adults. This study is the first, as per our knowledge, to examine these specific tests using plasma collected using acid citrate dextrose (ACD), as well as the relationship with amyloid PET status. RESULTS: Plasma AB42/40 had the highest AUC (0.833, 95% C.I. 0.767-0.899) at a cut-point of 0.0706 for discriminating between the two cerebral amyloid groups (sensitivity 76%, specificity 78.5%). Plasma NFL at a cut-point of 20.58pg/mL had the highest AUC (0.908, 95% CI 0.851- 0.966) for discriminating cognitive impairment (sensitivity 84.8%, specificity 89.9%). The addition of age and apolipoprotein e4 status did not improve the discriminative accuracy of these biomarkers. CONCLUSION: Our results suggest that the Aß42/40 ratio is useful in discriminating clinician-rated elevated cerebral amyloid status and that NFL is useful for discriminating cognitive impairment status. These findings reinforce the growing body of evidence regarding the general utility of these biomarkers and extend their utility to plasma collected in a non-traditional anticoagulant.

Patient Polypharmacy use Following a Multi-Disciplinary Dementia Care Program in a Memory Clinic: A Retrospective Cohort Study.

Introduction: Dementia increases the risk of polypharmacy. Timely detection and optimal care can stabilize or delay the progression of dementia symptoms, which may in turn reduce polypharmacy. We aimed to evaluate the change in polypharmacy use among memory clinic patients living with dementia who participated in a dementia care program compared to those who did not. We hypothesized that patients in the dementia care program would reduce their use of polypharmacy compared to those who were not in standard care. Methods: We retrospectively analyzed data extracted from electronic medical records from a university memory clinic. Data from a total of 381 patients were included in the study: 107 in the program and 274 matched patients in standard care. We used adjusted odds ratios to assess the association between enrollment in the program and polypharmacy use at follow-up (five or more concurrent medications), controlling for baseline polypharmacy use and stratified polypharmacy use by prescription and over-the-counter (OTC). Results: The two groups did not differ in the use of five or more overall and prescription medications at follow-up, controlling for the use of five or more of the respective medications at baseline and covariates. Being in the program was associated with a three-fold lower odds of using five or more OTC medications at follow-up (adjusted odds ratio = 0.30; p <0.001; 95% Confidence interval = 0.15-0.58) after controlling for using five or more OTC medications at baseline and covariates. Conclusions: Dementia care may reduce polypharmacy of OTC medications, potentially reducing risky drug-drug interactions. More research is needed to infer causality and understand how to reduce prescription medication polypharmacy.

Recruitment methods and yield rates for a multisite clinical trial exploring risk reduction for Alzheimer's disease (rrAD).

INTRODUCTION: The risk reduction for Alzheimer's disease (rrAD) trial was a multisite clinical trial to assess exercise and intensive vascular pharmacological treatment on cognitive function in community-dwelling older adults at increased risk for Alzheimer's disease. METHODS: Eligibility, consent, and randomization rates across different referral sources were compared. Informal interviews conducted with each site's project team were conducted upon study completion. RESULTS: Initially, 3290 individuals were screened, of whom 28% were eligible to consent, 805 consented to participate (87.2% of those eligible), and 513 (36.3% of those consented) were randomized. Emails sent from study site listservs/databases yielded the highest amount (20.9%) of screened individuals. Professional referrals from physicians yielded the greatest percentage of consented individuals (57.1%). Referrals from non-professional contacts (ie, friends, family; 75%) and mail/phone contact from a site (73.8%) had the highest yield of randomization. DISCUSSION: Professional referrals or email from listservs/registries were most effective for enrolling participants. The greatest yield of eligible/randomized participants came from non-professional and mail/phone contacts. Future trials should consider special efforts targeting these recruitment approaches. Highlights: Clinical trial recruitment is commonly cited as a significant barrier to advancing our understanding of cognitive health interventions.The most cited referral source was email, followed by interviews/editorials on the radio, television, local newspapers, newsletters, or magazine articles.The referral method that brought in the largest number of contacts was email but did not result in the greatest yield of consents or eligible participants.The sources that yielded the greatest likelihood of consent were professional referrals (ie, physician), social media, and mail/phone contact from study site.The greatest yield of eligible/randomized participants came from non-professional contacts and mail/phone contact from a site.Findings suggest that sites may need to focus on more selective referral sources, such as using contact mailing and phone lists, rather than more widely viewed recruitment sources, such as social media or TV/radio advertisements.

Alzheimer's disease cortical morphological phenotypes are associated with TOMM40'523-APOE haplotypes.

Both the APOE ε4 and TOMM40 rs10524523 ("523") genes have been associated with risk for Alzheimer's disease (AD) and neuroimaging biomarkers of AD. No studies have investigated the relationship of TOMM40'523-APOE ε4 on the structural complexity of the brain in AD individuals. We quantified brain morphology and multiple cortical attributes in individuals with mild cognitive impairment (MCI) and AD, then tested whether APOE ε4 or TOMM40 poly-T genotypes were related to AD morphological biomarkers in cognitively unimpaired (CU) and MCI/AD individuals. We identified several AD-specific phenotypes in brain morphology and found that TOMM40 poly-T short alleles are associated with early, AD-specific brain morphological differences in healthy aging. We observed decreased cortical thickness, sulcal depth, and fractal dimension in CU individuals with the poly-T short alleles. Moreover, in MCI/AD participants, the APOE ε4 (TOMM40 L) individuals had a higher rate of gene-related morphological markers indicative of AD. Our data suggest that TOMM40'523 is associated with early brain structure variations in the precuneus, temporal, and limbic cortices.

A Retrospective Analysis of Serious Adverse Events and Deaths in US-Based Lifestyle Clinical Trials for Cognitive Health.

This retrospective analysis assessed the serious adverse events and deaths reported in lifestyle clinical trials designed to enhance cognitive health in older adults living in the United States. Data was collected from studies conducted between January 1, 2000, and July 19, 2023, using the ClinicalTrials.gov application programming interface. Our query revealed that 76% of these studies did not report trial results. The remaining studies with reported results were categorized under one of four intervention types: Cognitive/Behavioral, Exercise/Movement, Diet/Supplement, and Multi-modal. When all trial types are considered together, the results indicate that lifestyle clinical trials are safe, with no significant increase in relative risk of experiencing an SAE in an intervention group over a control group. And although the increase in relative risk of death in an intervention group over a control group was significant at 28% (X2 (1, N = 36), p < 0.00688), the probability of death was not higher than the U.S. mortality rates by age. When assessing the data using intervention type, Diet/Supplement trials and Multi-modal trials both had an increase in relative risk of experiencing an SAE in the intervention over the control group, with Diet/Supplement trials at 16% (X2 (1, N = 2), p < 0.0263) and Multi-modal trials at 365% (X2 (1, N = 5), p < 0.000213). The Diet/Supplement trials also had an increased risk of death at 67% (X2 (1, N = 2), p < 0.000197). These results should be taken with careful consideration. Due to such a low reporting rate, the 36 studies included in this analysis do not accurately represent the majority of lifestyle clinical trials conducted in the U.S. This study is valuable in that it highlights the importance of reporting clinical trial results, which will improve transparency in trial results and allow for more accurate assessments of safety in the growing field of cognitive aging and lifestyle interventions for older adults.

Development of a Culturally Adapted Dietary Intervention to Reduce Alzheimer's Disease Risk among Older Black Adults.

The objective of this study is to identify and understand knowledge and attitudes that influence dietary practices among older Black adults using a community-engaged approach. This is a non-interventional mixed methods study designed to inform the development of an adapted brain-healthy soul food diet intervention. A purposive sampling approach was used to conduct seven semi-structured focus group discussions and an online quantitative survey. In total, 39 participants who self-identified as Black, aged 55 years and older, English speaking, and who were cognitively normal with an AD8 < 2; (25.6% men; 74.4% women) participated in the online survey and one of the seven 60 min virtual focus group discussions (5-7 per focus group). Quantitative frequency data from the online surveys were analyzed using descriptive statistics. Qualitative focus group data were analyzed using a 6-step thematic analysis process. Five themes emerged: dementia awareness; practices shaping food choices and consumption; barriers to eating healthy; instrumental support; and elements of a culturally adapted brain-healthy dietary intervention. Older Black adults perceived an adapted MIND dietary model as the most acceptable with the incorporation of salient cultural characteristics and strategies within both the design and delivery phases.

Driving Automation for Older Adults with Preclinical Alzheimer's Disease.

INTRODUCTION: Older adults with preclinical Alzheimer's disease (AD) show changes in on-road driving performance. The impact of preclinical AD on using automated vehicle (AV) technology is unknown. The aim was to evaluate safety and cognitive workload while operating AV technology in drivers with preclinical AD. INTRODUCTION: This cross-sectional study included 40 participants: 19 older adults (age 74.16 ± 4.78; MOCA scores 26.42 ± 2.52) with preclinical AD, evidenced by elevated cortical beta-amyloid; and 21 controls (age 73.81 ± 5.62; MOCA scores 28.24 ± 1.67). All participants completed two scenarios in a driving simulator. Scenario 1 included conditional automation with an emergency event that required a manual take-over maneuver. Scenario 2 was identical but with a cognitive distractor task. Emergency response time was the main safety outcome measure. Cognitive workload was calculated using moment-to-moment changes in pupillary size and converted into an Index of Cognitive Activity (ICA). Mann-Whitney U and independent t tests were used to compare group differences. RESULTS: Emergency response times were similar between drivers with preclinical AD and controls in scenario 1 (20.85 s ± 1.08 vs. 20.52 s ± 3.18; p = 0.83) and scenario 2 (14.83 s ± 7.37 vs. 13.45 s ± 10.43; p = 0.92). Likewise, no differences were found in ICA between drivers with preclinical AD and controls in scenario 1 (0.34 ± 0.08 vs. 0.33 ± 0.17; p = 0.74) or scenario 2 (0.30 ± 0.07 vs. 0.29 ± 0.17; p = 0.93). CONCLUSIONS: Older drivers with preclinical AD may safely operate AV technology, without increased response times or cognitive workload. Future on-road studies with AV technology should confirm these preliminary results in drivers with preclinical AD.

First-Line Immunotherapy with Check-Point Inhibitors: Prospective Assessment of Cognitive Function.

Approximately 40% of patients with cancer are eligible for check-point inhibitor (CPI) therapy. Little research has examined the potential cognitive impact of CPIs. First-line CPI therapy offers a unique research opportunity without chemotherapy-related confounders. The purpose of this prospective, observational pilot was to (1) demonstrate the feasibility of prospective recruitment, retention, and neurocognitive assessment for older adults receiving first-line CPI(s) and (2) provide preliminary evidence of changes in cognitive function associated with CPI(s). Patients receiving first-line CPI(s) (CPI Group) were assessed at baseline (n = 20) and 6 months (n = 13) for self-report of cognitive function and neurocognitive test performance. Results were compared to age-matched controls without cognitive impairment assessed annually by the Alzheimer's Disease Research Center (ADRC). Plasma biomarkers were measured at baseline and 6 months for the CPI Group. Estimated differences for CPI Group scores prior to initiating CPIs (baseline) trended to lower performance on the Montreal Cognitive Assessment-Blind (MOCA-Blind) test compared to the ADRC controls (p = 0.066). Controlling for age, the CPI Group's 6-months MOCA-Blind performance was lower than the ADRC control group's 12-months performance (p = 0.011). No significant differences in biomarkers were detected between baseline and 6 months, although significant correlations were noted for biomarker change and cognitive performance at 6 months. IFNγ, IL-1ß, IL-2, FGF2, and VEGF were inversely associated with Craft Story Recall performance (p < 0.05), e.g., higher levels correlated with poorer memory performance. Higher IGF-1 and VEGF correlated with better letter-number sequencing and digit-span backwards performance, respectively. Unexpected inverse correlation was noted between IL-1α and Oral Trail-Making Test B completion time. CPI(s) may have a negative impact on some neurocognitive domains and warrant further investigation. A multi-site study design may be crucial to fully powering prospective investigation of the cognitive impact of CPIs. Establishment of a multi-site observational registry from collaborating cancer centers and ADRCs is recommended.

Primary Care Provider Preferences on Dementia Training: A Qualitative Study.

BACKGROUND: Dementia has no cure, but interventions can stabilize the progression of cognitive, functional, and behavioral symptoms. Primary care providers (PCPs) are vital for the early detection, and long-term management of these diseases, given their gatekeeping role in the healthcare system. However, PCPs rarely implement evidence-based dementia care due to time limitations and knowledge about diagnosis and treatment. Training PCPs may help address these barriers. OBJECTIVE: We explored the preferences of PCPs for dementia care training programs. METHODS: We conducted qualitative interviews with 23 PCPs recruited nationally via snowball sampling. We conducted remote interviews and organized the transcripts for qualitative review to identify codes and themes, using thematic analysis methods. RESULTS: PCP preferences varied regarding many aspects of ADRD training. Preferences varied regarding how to best increase PCP participation in training, and what content and materials were needed to help them and the families they serve. We also found differences regarding the duration and timing of training, and the modality of training sessions (remote versus in-person). CONCLUSION: The recommendations arising from these interviews have the potential to inform the development and refinement of dementia training programs to optimize their implementation and success.

Effect of Cognitive Reserve on Physiological Measures of Cognitive Workload in Older Adults with Cognitive Impairments.

BACKGROUND: Cognitive reserve may protect against cognitive decline. OBJECTIVE: This cross-sectional study investigated the association between cognitive reserve and physiological measures of cognitive workload in older adults with cognitive impairment. METHODS: 29 older adults with cognitive impairment (age: 75±6, 11 (38%) women, MoCA: 20±7) and 19 with normal cognition (age: 74±6; 11 (58%) women; MoCA: 28±2) completed a working memory test of increasing task demand (0-, 1-, 2-back). Cognitive workload was indexed using amplitude and latency of the P3 event-related potential (ERP) at electrode sites Fz, Cz, and Pz, and changes in pupillary size, converted to an index of cognitive activity (ICA). The Cognitive Reserve Index questionnaire (CRIq) evaluated Education, Work Activity, and Leisure Time as a proxy of cognitive reserve. Linear mixed models evaluated the main effects of cognitive status, CRIq, and the interaction effect of CRIq by cognitive status on ERP and ICA. RESULTS: The interaction effect of CRIq total score by cognitive status on P3 ERP and ICA was not significant. However, higher CRIq total scores were associated with lower ICA (p = 0.03). The interaction effects of CRIq subscores showed that Work Activity affected P3 amplitude (p = 0.03) and ICA (p = 0.03) differently between older adults with and without cognitive impairments. Similarly, Education affected ICA (p = 0.02) differently between the two groups. No associations were observed between CRIq and P3 latency. CONCLUSION: Specific components of cognitive reserve affect cognitive workload and neural efficiency differently in older adults with and without cognitive impairments.

Increased Functional Connectivity of the Precuneus in Individuals with a Family History of Alzheimer's Disease.

BACKGROUND: First-degree relatives of individuals with late-onset Alzheimer's disease (AD) have increased risk for AD, with children of affected parents at an especially high risk. OBJECTIVE: We aimed to investigate default mode network connectivity, medial temporal cortex volume, and cognition in cognitively healthy (CH) individuals with (FH+) and without (FH-) a family history of AD, alongside amnestic mild cognitive impairment (aMCI) and AD individuals, to determine the context and directionality of dysfunction in at-risk individuals. Our primary hypothesis was that there would be a linear decline (CH FH- > CH FH+ > aMCI > AD) within the risk groups on all measures of AD risk. METHODS: We used MRI and fMRI to study cognitively healthy individuals (n = 28) with and without AD family history (FH+ and FH-, respectively), those with aMCI (n = 31) and early-stage AD (n = 25). We tested connectivity within the default mode network, as well as measures of volume and thickness within the medial temporal cortex and selected seed regions. RESULTS: As expected, we identified decreased medial temporal cortex volumes in the aMCI and AD groups compared to cognitively healthy groups. We also observed patterns of connectivity across risk groups that suggest a nonlinear relationship of change, such that the FH+ group showed increased connectivity compared to the FH- and AD groups (CH FH+ > CH FH- > aMCI > AD). This pattern emerged primarily in connectivity between the precuneus and frontal regions. CONCLUSION: These results add to a growing literature that suggests compensatory brain function in otherwise cognitively healthy individuals with a family history of AD.

Implementing a home-based virtual hypertension programme-a pilot feasibility study.

INTRODUCTION: Implementing a health system-based hypertension programme may lower blood pressure (BP). METHODS: We performed a randomized, controlled pilot study to assess feasibility, acceptability, and safety of a home-based virtual hypertension programme integrating evidence-based strategies to overcome current barriers to BP control. Trained clinical pharmacists staffed the virtual collaborative care clinic (vCCC) to remotely manage hypertension using a BP dashboard and phone "visits" to monitor BP, adherence, side effects of medications, and prescribe anti-hypertensives. Patients with uncontrolled hypertension were identified via electronic health records. Enrolled patients were randomized to either vCCC or usual care for 3 months. We assessed patients' home BP monitoring behaviour, and patients', physicians', and pharmacists' perspectives on feasibility and acceptability of individual programme components. RESULTS: Thirty-one patients (vCCC = 17, usual care = 14) from six physician clinics completed the pilot study. After 3 months, average BP decreased in the vCCC arm (P = 0.01), but not in the control arm (P = 0.45). The vCCC participants measured BP more (9.9 vs. 1.2 per week, P < 0.001). There were no intervention-related adverse events. Participating physicians (n = 6), pharmacists (n = 5), and patients (n = 31) rated all programme components with average scores of >4.0, a pre-specified benchmark. Nine adaptations in vCCC design and delivery were made based on potential barriers to implementing the programme and suggestions. CONCLUSION: A home-based virtual hypertension programme using team-based care, technology, and a logical integration of evidence-based strategies is safe, acceptable, and feasible to intended users. These pilot data support studies to assess the effectiveness of this programme at a larger scale.

Evaluation of noise regression techniques in resting-state fMRI studies using data of 434 older adults.

Subject motion is a well-known confound in resting-state functional MRI (rs-fMRI) and the analysis of functional connectivity. Consequently, several clean-up strategies have been established to minimize the impact of subject motion. Physiological signals in response to cardiac activity and respiration are also known to alter the apparent rs-fMRI connectivity. Comprehensive comparisons of common noise regression techniques showed that the "Independent Component Analysis based strategy for Automatic Removal of Motion Artifacts" (ICA-AROMA) was a preferred pre-processing technique for teenagers and adults. However, motion and physiological noise characteristics may differ substantially for older adults. Here, we present a comprehensive comparison of noise-regression techniques for older adults from a large multi-site clinical trial of exercise and intensive pharmacological vascular risk factor reduction. The Risk Reduction for Alzheimer's Disease (rrAD) trial included hypertensive older adults (60-84 years old) at elevated risk of developing Alzheimer's Disease (AD). We compared the performance of censoring, censoring combined with global signal regression, non-aggressive and aggressive ICA-AROMA, as well as the Spatially Organized Component Klassifikator (SOCK) on the rs-fMRI baseline scans from 434 rrAD subjects. All techniques were rated based on network reproducibility, network identifiability, edge activity, spatial smoothness, and loss of temporal degrees of freedom (tDOF). We found that non-aggressive ICA-AROMA did not perform as well as the other four techniques, which performed table with marginal differences, demonstrating the validity of these techniques. Considering reproducibility as the most important factor for longitudinal studies, given low false-positive rates and a better preserved, more cohesive temporal structure, currently aggressive ICA-AROMA is likely the most suitable noise regression technique for rs-fMRI studies of older adults.

Sex Differences in Resilience and Resistance to Brain Pathology and Dysfunction Moderated by Cerebrovascular Response to Exercise and Genetic Risk for Alzheimer's Disease.

Sex as a biological variable appears to contribute to the multifactorial etiology of Alzheimer's disease. We tested sex-based interactions between cerebrovascular function and APOE4 genotype on resistance and resilience to brain pathology and cognitive executive dysfunction in cognitively-normal older adults. Female APOE4 carriers had higher amyloid-ß deposition yet achieved similar cognitive performance to males and female noncarriers. Further, female APOE4 carriers with robust cerebrovascular responses to exercise possessed lower amyloid-ß. These results suggest a unique cognitive resilience and identify cerebrovascular function as a key mechanism for resistance to age-related brain pathology in females with high genetic vulnerability to Alzheimer's disease.

Statin contribution to middle cerebral artery blood flow velocity in older adults at risk for dementia.

PURPOSE: It is plausible that statins could improve cerebral blood flow through pleiotropic mechanisms. The purpose of this investigation was to assess the contribution of statins to cerebrovascular variables in older adults with dyslipidemia and familial history of dementia. Furthermore, we explored the interaction between statin use and sex due to prevalent bias in statin trials. METHODS: Middle cerebral artery blood flow velocity (MCAv) was measured using transcranial Doppler ultrasound. Continuous supine rest recordings lasted 8 min. Participants included in analyses were statin (n = 100) or non-statin users (n = 112). RESULTS: MCAv and cerebrovascular conductance were significantly higher in statin users (p = 0.047; p = 0.04), and pulsatility index (PI) was significantly lower in statin users (p < 0.01). An interaction effect between statin use and sex was present for PI (p = 0.02); female statin users had significantly lower cerebrovascular resistance than the other three groups. CONCLUSION: In this cross-sectional analysis, statin use was positively associated with cerebrovascular variables in older adults at risk for dementia. Female statin users had significantly higher resting MCAv and cerebrovascular conductance than female non-statin users. The greatest contribution of statin use was the association with reduced cerebrovascular resistance. Given that cerebrovascular dysregulation is one of the earliest changes in Alzheimer's disease and related dementia pathology, targeting the cerebrovasculature with statins may be a promising prevention strategy.