Stephen R. Rapp’s research while affiliated with Wake Forest University and other places

Objective Compare the changes in neuropsychological test scores between remote and in-person follow-up assessment over a 1-year period using standardized regression–based (SRB) change indices. Method Participants were from the Wake Forest Alzheimer’s Disease Research Center (ADRC; N = 230) [mean age: 68.6 (7.8) years; education: 16.3 (2.3) years; 71% female; 86% White] and cognitively normal (as defined by a CDR of 0) at baseline and follow-up [mean days: 420.03 (48.53)]. Follow-up testing with the Uniform Data Set v3 Cognitive Battery was completed in person (n = 121) or remotely (n = 109) via phone (n = 61) or video (n = 48). SRB change scores were calculated using published formulas. Chi-square analysis compared the frequency of scores falling outside of an SRB cut-point +/−1.645 for follow-up assessments and mean SRB change scores were compared. Results There were no significant differences in the frequency of SRB change scores for in-person versus remote follow-up assessments at the SRB cut-point. Similarly, one-way ANOVAs comparing mean SRB change scores revealed no significant differences between in-person, telephone, and video follow-up means for any of the tests. Conclusions Telephone and video cognitive assessments performed similarly to in-person assessment and offer a valuable tool for research and clinical applications.

Objective The objective of this study was to examine the interrelationships between cognitive performance, race/ethnicity, discrimination, health behaviors, and physiological dysregulation. Methods We used data from the Multi-Ethnic Study of Atherosclerosis (MESA) ( N = 1667). We used path analyses to examine the association between discrimination, physiological dysregulation, health behaviors, and cognitive performance using the Cognitive Ability Screening Instrument (CASI) at Exam 5 (2010-12) and Exam 6 (2016-18). We examined the relationship between discrimination at Exam 1 (2000-02) and physiological dysregulation at Exam 5. We used overall and ethnoracial-stratified path analysis. All models were adjusted for age, sex, site, depression, stress, socioeconomic status, and APOE -e4. Results Physiological dysregulation was associated with worse cognitive performance in the full sample and among the White ethnoracial subgroup. Everyday discrimination was associated with better cognitive performance among Black participants. Discussion Associations between discrimination, physiological dysregulation, and cognitive performance vary and should be examined longitudinally.

INTRODUCTION Little is known about how Alzheimer’s disease (AD) plasma biomarkers relate to cerebral small vessel disease (cSVD) neuroimaging biomarkers. METHODS The study involved 251 Wake Forest Multi-Ethnic Study of Atherosclerosis (MESA) Exam 6 participants with plasma AD biomarkers, MRI, amyloid PET, and adjudicated cognitive status. Multivariable models examined cross-sectional relationships between plasma and neuroimaging biomarkers, considering comorbidities. RESULTS Lower Aβ42/Aβ40, and higher GFAP, NfL, and p-tau217 were associated with greater neurodegeneration. Lower plasma Aβ42/Aβ40 and higher p-tau217 and p-tau231 were associated with greater Aβ PET deposition. NfL was positively associated with WMH and WM Free Water. P-tau measures were positively associated with WM Free Water. Lower Aβ42/Aβ40 was associated with presence of microbleeds. GFAP was positively associated with WMH. DISCUSSION We observed expected associations of plasma biomarkers with cognitive status and imaging biomarkers. GFAP, NfL, p-tau181, p-tau217, and p-tau231 are associated with cSVD in addition to AD-related pathology.

Importance Blood-based biomarkers (BBMs) are clinically available to aid in the diagnosis of Alzheimer disease (AD) and AD-related dementias (ADRD), but their association with cognition among older adults with specific chronic conditions has not been examined. Objective To longitudinally examine associations between baseline AD and ADRD BBMs and change in BBMs with cognition among participants with type 2 diabetes (T2D) and overweight or obesity. Design, Setting, and Participants The Look AHEAD (Action for Health in Diabetes) study was a clinical trial of older adults with T2D and overweight or obesity randomized to a 10-year intensive lifestyle intervention for weight loss or a diabetes support and education condition. Participants were recruited and followed up at 16 clinical sites across the US. Enrollment occurred from January 1, 2001, to December 31, 2004. The primary intervention spanned the first 4 years after participants’ enrollment (January 1, 2008, to December 31, 2011). The clinical trial was stopped in September 2012 and was converted to an observational study. Blood samples were drawn at baseline and 8 to 12 years later. Cognitive assessments were performed from January 1, 2013, to December 31, 2014, and from January 1, 2018, to December 31, 2020. Data for the present cohort study were analyzed between January and August 2024. Exposures Baseline and 8- to 12-year change in plasma levels of amyloid-β (Aβ) 40 , Aβ 42 , Aβ 42/40 ratio, phosphorylated tau 181 (pTau-181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Main Outcomes and Measures Cognitive composite z score and adjudicated mild cognitive impairment or probable dementia. Results The mean (SD) baseline age of 758 participants was 61.5 (6.1) years, and 424 participants [55.9%] were female. Mean (SD) body mass index was 34.8 (5.3). Of the participants, 373 were randomized to diabetes support and education and 385 to intensive lifestyle intervention. Increasing baseline BBM levels were not associated with any cognitive composite z score. Increasing levels of NfL (β = −0.032 [SE, 0.013]; P = .01) and GFAP (β = −0.087 [SE, 0.025]; P < .001), but not the Aβ 42/40 ratio (β = 0.006 [SE, 0.040]; P = .88) or pTau-181 (β = 0.026 [SE, 0.025]; P = .31), were associated with worsening cognitive function and incident mild cognitive impairment or probable dementia. The intervention had no association with 8- to 12-year change in BBM levels. Conclusions and Relevance In this study of participants with T2D and overweight or obesity, increasing plasma NfL and GFAP levels over time, but not Aβ 42/40 or pTau-181 levels, were associated with cognitive decline and incident cognitive impairment. These results suggest that plasma NfL and GFAP may be important biomarkers of cognitive change among this patient population.

Background and objectives: The Systolic Blood Pressure Intervention Trial suggested that intensive lowering of systolic blood pressure (SBP) decreases the risk of developing dementia. However, an insufficient number of probable dementia cases stemming from the trial's early termination made results inconclusive. The goal of this study was to estimate the effect of intensive vs standard SBP lowering on the longer term incidence of cognitive impairment leveraging extended follow-up for cognitive status. Methods: This is a prespecified secondary analysis of a randomized clinical trial. Between 2010 and 2013, patients aged 50 years and older with hypertension and increased cardiovascular risk excluding those with diabetes mellitus or history of stroke were recruited from 102 clinics in the United States and Puerto Rico. Participants were randomized to a SBP goal of <120 mm Hg (intensive treatment) or <140 mm Hg (standard treatment) and received treatment for 3.3 years. In-person cognitive assessment follow-up occurred through July 2018. Continued ascertainment of cognitive status by telephone began in December 2019 for participants who had not withdrawn consent or been previously adjudicated with probable dementia, but provided consent for future research. Data were analyzed using survival analyses. Results: Of 9,361 randomized participants, 7,221 (77%) were eligible to be re-contacted. Cognitive status of 4,232 (59%) was ascertained (mean age 67 years, 36% female). We accrued a total of 216 new cases of probable dementia, less than our target of 326. Over a median follow-up of 7 years, 248 participants of the intensive treatment group (8.5 per 1,000 person-years) were adjudicated with probable dementia, compared with 293 participants (10.2 per 1,000 person-years) in the standard treatment group (hazard ratio [HR], 0.86; 95% CI, 0.72-1.02). Consistent with earlier results from the trial, the rate of both mild cognitive impairment (MCI; HR, 0.87 95% CI, 0.76-1.00) and a composite of MCI or probable dementia was lower with intensive treatment (HR, 0.89; 95% CI, 0.79, 0.99). Discussion: Among ambulatory adults with hypertension and high cardiovascular risk, intensive treatment vs standard treatment of SBP for 3.3 years resulted in a lower risk of MCI and cognitive impairment including MCI or probable dementia, but not for probable dementia alone. Classification of evidence: This study provides Class II evidence that intensively reducing SBP (target <120 mm Hg) decreases the risk of cognitive impairment in individuals aged 50 years and older with hypertension. Clinical trial information: Clinical trial number NCT01206062.

Background Video interfacing is increasingly being used in research and health care. The ‘VCog’ Study seeks to determine whether remote research cognitive assessments are reliable and valid by directly comparing results from in‐person administration of a standardized cognitive battery to the same battery administered remotely by video. The study also assesses technology use and comfort amongst participants of varying levels of cognitive impairment. Methods Participants (Table 1) were recruited from 12 Alzheimer’s Disease Research Centers (ADRCs). 313 ADRC enrollees who were previously classified as having normal cognition (CN), Mild Cognitive Impairment (MCI), or mild dementia were administered the Uniform Data Set v3 (UDSv3) cognitive battery remotely by video 4‐8 weeks before or after their annual in‐person UDSv3 cognitive assessments, in counterbalanced order. Participants also completed questionnaires assessing their typical use and confidence using various forms of technology. Results More than 50% of participants reported daily‐to‐monthly use of technology, with 74‐92% of participants reporting daily smartphone use (Table 2). All participants reported moderate‐to‐high confidence when using technology (Range: 5.57‐8.10 on a 0‐10 scale, with 0 being ‘not confident at all’ and 10 being ‘extremely confident’). As expected, both frequency and confidence using technology varied with cognitive status; poorer cognitive status was typically associated with less usage and lower confidence (Table 3). Despite this, ‘dislike of video interfacing’ was not endorsed more frequently by those with cognitive impairment as the reason for study refusal (dementia = 8%; MCI = 13%; CN = 18% of total refusals). Conclusion Technology is rapidly becoming a routine part of our lives though little is known about the relationship older adults have with it, especially those with cognitive impairment. This research indicates that among older adults of varied cognitive status, including dementia, both utilization and confidence in use are relatively high. Some group differences exist, with worse cognition being associated with less use and confidence. Despite this, persons with dementia were not likely to refuse participation because of dislike of videoconferencing. Future reports from the VCog study will report the validity and reliability of remote assessments. Funded by R01 AG075959

Background For clinical trials or patient care, reports from a person familiar with the trajectory of a participant’s cognitive and functional performance (i.e., proxies) may improve adjudication of events, such as mild cognitive impairment and dementia. Proxies offer a unique perspective on cognitive status that is different from what is captured through standard cognitive examinations. Clinical trials in which cognitive status is adjudicated, such as the Systolic Blood Pressure Intervention (SPRINT) trial, provide information about the contributions and consistency of proxies throughout extended follow‐up. Method SPRINT participants named proxies and relationship to them at study onset. Proxies provided information for the Functional Activities Questionnaire and Dementia Questionnaire. We collapsed proxy relationships into seven categories and evaluated the proportion of proxies in each category at baseline and how frequently the same proxy was retained to the last visit. We explored associations between proxy relationship and various baseline demographics and examined the association between not having a proxy, as well as proxy relationship, and adjudicated outcome. Result Of the 9,361 randomized SPRINT participants (35.6% female, mean age 67.9 years), 7,586 (81%) participants listed a proxy relationship from which we identified 7 categories: spouse/partner (51.7%), child (23.6%), sibling (8.7%), other family member (6.2%), and unrelated (8.8%). Male participants were more likely to name a spouse as their proxy (64%) while female participants more likely to name a child (42%). The overall consistency of proxy continuation between the baseline and final SPRINT visit (mean 6.9 years) was 90.7%. Proxy consistency from first visit to last visit for a child was 94.8%, spouse/partner (91.9%) brother/sister (87.5%), other family member (82.4%), non‐related (81.2%), and parent (78.2%). Adjudications that resulted in ‘Cannot Classify’ were greatest for proxies who were parents (15%) followed by none (12%), sibling and grandchild (9%), child and unrelated (7%), spouse and other family (6%). Conclusion The majority of proxies in SPRINT were immediate family members (spouse, child, or sibling). Over 90% of identified proxies at baseline continued to be available over a mean of almost 7 years of follow‐up. Not having a proxy available led to a higher rate of ‘cannot classify’ adjudications.

Background The Systolic Blood Pressure Intervention Trial (SPRINT) included a specific aim on the effect of blood pressure lowering the risk of cognitive impairment (mild cognitive impairment (MCI) and dementia). Early termination of the trial and fewer than expected cases left the study under powered to detect cases of probable dementia, but the intervention reduced the risk for MCI and for a composite of MCI or probable dementia (PD). To increase the length of follow‐up and number of cases of probable dementia, two studies were funded: one from October 2017 through June 2018 and a second, the SPRINT MIND 2020 study, from December 2019 through December 2023. Method In the main trial, 9361 participants were randomized to either Intensive or Standard BP control, systolic BP < 120 or < 140 mmHg, respectively. For the cognitive aim, outcomes were adjudicated PD and MCI. Result Of the 9361 participants in the SPRINT trial, 8563 completed one or more cognitive assessment, and 325 were adjudicated to have probable dementia at the end of the first extended follow‐up. The SPRINT MIND 2020 follow‐up ascertained an additional 216 cases of probable dementia. An additional 170 cases of mild cognitive impairment were also ascertained. Conclusion SPRINT MIND 2020 successfully extended follow‐up time for the SPRINT MIND study and increased the number of observed cognitive outcomes substantially enabling an analysis of legacy treatment effects.