Subjective cognitive complaints in White and African American older adults: associations with demographic, mood, cognitive, and neuroimaging features.

Subjective cognitive complaints (SCC) in cognitively intact older adults have been investigated as a clinically important symptom that may portend the onset of a neurodegenerative disorder such as Alzheimer's disease. Few studies have concurrently incorporated demographic features, depressive symptoms, neuropsychological status, and neuroimaging correlates of SCC and evaluated whether these differ in White and African American older adults. In the current study, 131 (77 White, 54 African American) healthy participants ≥50 years old completed the Cognitive Function Instrument (CFI) to assess SCC, and they underwent objective cognitive testing, assessment of mood, and brain magnetic resonance imaging. Pearson Product Moment correlations were performed to evaluate associations of the CFI self-ratings with the above measures for the combined group and separately for White and African American participants. SCC were associated with greater depressive symptoms in both White and African American participants in adjusted models controlling for overall cognitive status, education, and hypertension. Greater white matter hyperintensities, lower cortical thickness, older age, and slower set shifting speed were associated with increased SCC in White participants. Although the correlations were not significant for African Americans, the strength of the associations were comparable to White participants. Hippocampal volume was not associated with either total SCC or items specific to memory functioning in the entire group. Longitudinal studies are needed to further evaluate the clinical significance of these associations with risk of conversion to mild cognitive impairment and dementia.

Development of digital voice biomarkers and associations with cognition, cerebrospinal biomarkers, and neural representation in early Alzheimer's disease.

Introduction: Advances in natural language processing (NLP), speech recognition, and machine learning (ML) allow the exploration of linguistic and acoustic changes previously difficult to measure. We developed processes for deriving lexical-semantic and acoustic measures as Alzheimer's disease (AD) digital voice biomarkers. Methods: We collected connected speech, neuropsychological, neuroimaging, and cerebrospinal fluid (CSF) AD biomarker data from 92 cognitively unimpaired (40 Aß+) and 114 impaired (63 Aß+) participants. Acoustic and lexical-semantic features were derived from audio recordings using ML approaches. Results: Lexical-semantic (area under the curve [AUC] = 0.80) and acoustic (AUC = 0.77) scores demonstrated higher diagnostic performance for detecting MCI compared to Boston Naming Test (AUC = 0.66). Only lexical-semantic scores detected amyloid-ß status (p = 0.0003). Acoustic scores associated with hippocampal volume (p = 0.017) while lexical-semantic scores associated with CSF amyloid-ß (p = 0.007). Both measures were significantly associated with 2-year disease progression. Discussion: These preliminary findings suggest that derived digital biomarkers may identify cognitive impairment in preclinical and prodromal AD, and may predict disease progression. Highlights: This study derived lexical-semantic and acoustics features as Alzheimer's disease (AD) digital biomarkers.These features were derived from audio recordings using machine learning approaches.Voice biomarkers detected cognitive impairment and amyloid-ß status in early stages of AD.Voice biomarkers may predict Alzheimer's disease progression.These markers significantly mapped to functional connectivity in AD-susceptible brain regions.

Effects of candesartan on cerebral microvascular function in mild cognitive impairment: Results of two clinical trials.

BACKGROUND: Cerebral microvascular dysfunction is commonly seen in Alzheimer's disease (AD) and vascular cognitive impairment (VCI). Cerebrovascular reactivity (CVR) to CO2 reflects cerebral microvascular health and may be modulated by the renin-angiotensin system (RAS). This study aimed to investigate the effects of RAS modulation on CVR in individuals with mild cognitive impairment (MCI) due to underlying vascular or AD etiologies. METHODS: This study presents findings of candesartan's effects on the secondary outcomes of two double-blind randomized clinical trials of 12-month therapy of candesartan versus lisinopril in VCI (CALIBREX (Candesartan vs Lisinopril Effects on the Brain and Endothelial Function in Executive MCI)) and candesartan versus placebo in prodromal AD (Candesartan's Effects on Alzheimer's Disease and Related Biomarkers (CEDAR)). Primary outcome results of these trials have been reported in previous publications. Participants underwent identical brain blood oxygenation level dependent (BOLD)-CVR in response to a 2-min CO2 challenge at baseline and 12 months. Regions of interest and voxel-wise CVR maps were derived from BOLD signal changes during CO2 challenge. CVR effects were compared between candesartan and lisinopril (CALIBREX) and candesartan and placebo (CEDAR) using mixed-model repeated measures. RESULTS: Data from 102 participants in the CALIBREX study (mean age = 65 years, 45% female, 63% African American) and 59 in the CEDAR study (mean age = 67 years, 32% female, 20% African American) were analyzed. Candesartan was associated with improved whole brain CVR compared to placebo in the CEDAR study (adjusted within-group mean difference for candesartan = 0.27 (95% confidence interval (CI) = 0.006, 0.53) vs placebo = -0.17 (95% CI = 0.42, 0.08), p-value = 0.018), and compared to lisinopril in the CALIBREX study (adjusted within-group mean difference for candesartan = 0.28 (95% CI = 0.10, 0.46) vs lisinopril = -0.08 (95% CI = -0.31, 0.14), p-value = 0.012), independent of blood pressure. In an exploratory meta-analysis of the two trials, improved CVR in the hippocampus was linked to improved attention and working memory (p = 0.044) and a trend for improved executive function (p = 0.087) with candesartan therapy. CONCLUSION: This study suggests that candesartan is associated with improved microvascular function in MCI, and these findings are independent of its blood pressure effect in these VCI and prodromal AD populations.

Safety and biomarker effects of candesartan in non-hypertensive adults with prodromal Alzheimer's disease.

Observational studies suggest that angiotensin receptor blockers in hypertensive adults are associated with lower post-mortem indicators of Alzheimer's disease pathology. Candesartan, an angiotensin receptor blocker, has a positive cognitive effect in mild cognitive impairment with hypertension. However, its safety and effects in non-hypertensive individuals with Alzheimer's disease are unclear. This is the first double-blind randomized placebo-controlled trial aimed to assess safety and effects of 1-year therapy of candesartan on biomarkers and clinical indicators of Alzheimer's disease in non-hypertensive individuals with biomarker-confirmed prodromal Alzheimer's disease. Seventy-seven non-hypertensive participants 50 years or older (mean age: 68.1 years; 62% women; 20% African American) with mild cognitive impairment and biomarker confirmed Alzheimer's disease were randomized to escalating doses of once daily oral candesartan (up to 32 mg) or matched placebo. Main outcomes included safety and tolerability of candesartan, cerebrospinal fluid biomarkers (amyloid-ß42, amyloid-ß40, total tau and phospho-tau). Additional exploratory outcomes included PET imaging (Pittsburgh Compound-B (11C-PiB) and 18F-flortaucipir), brain MRI (structural and connectivity measures) and cognitive functioning. Analyses used intention-to-treat approach with group comparisons of safety measures using Chi-square test, and repeated measures mixed effects models were used to assess candesartan effects on main and exploratory outcomes (ClinicalTrials.gov, NCT02646982). Candesartan was found to be safe with no significant difference in safety measures: symptoms of hypotension, renal failure or hyperkalemia. Candesartan was also found to be associated with increases in cerebrospinal fluid Aß40 (between-group mean difference: 1211.95 pg/ml, 95% confidence interval: 313.27, 2110.63) and Aß42 (49.51 pg/ml, 95% confidence interval: -98.05, -0.98) reflecting lower brain amyloid accumulation. Candesartan was associated with decreased 11C-PiB in the parahippocampal region (-0.1104, 95% confidence interval: -0.19, -0.029) which remained significant after false discovery rate correction, and with an increase in functional network connectivity in the subcortical networks. Candesartan was further associated with improved executive function (Trail Making Test Part B) performance (-11.41 s, 95% confidence interval: -11.94, -10.89) and trended for an improved global cognitive functioning reflected by a composite cognitive score (0.002, 95% confidence interval: -0.0002, 0.005). We did not observe significant effects on tau levels, hippocampal volume or other cognitive measures (memory or clinical dementia rating scale-sum of boxes). In conclusion, among non-hypertensive prodromal Alzheimer's disease, candesartan is safe and likely decreases brain amyloid biomarkers, enhances subcortical brain connectivity and has favourable cognitive effects. These findings suggest that candesartan may have an important therapeutic role in Alzheimer's disease, and warrant further investigation given the lack of clear treatment options for this devastating illness.

Association of Plasma and Cerebrospinal Fluid Alzheimer Disease Biomarkers With Race and the Role of Genetic Ancestry, Vascular Comorbidities, and Neighborhood Factors.

Importance: Differences in cerebrospinal fluid (CSF) tau Alzheimer dementia (AD) biomarkers by self-identified race have been observed in prior studies. More recently, plasma biomarkers have been gaining recognition, but whether they exhibit similar differences is unclear. Furthermore, the underlying explanation for these differences in AD biomarkers is still unexplored. Objectives: To investigate differences in plasma biomarkers by race and genetic ancestry and explore potential underlying explanations for these differences. Design, Setting, and Participants: This cross-sectional study used participant data from the Brain, Stress, Hypertension, and Aging Research Program (B-SHARP), an observational study conducted in the greater Atlanta metropolitan area. Participants were enrolled from March 1, 2016, to January 1, 2020. Main Outcomes and Measures: Main outcomes were plasma and CSF amyloid-ß (Aß) 42, Aß40, phosphorylated tau181 (p-tau181), and neurofilament light. General linear models were used for key comparisons. Exposures: Main independent variables were self-identified race and genetic ancestry. Additional variables were cardiovascular factors, APOE4, educational attainment, Area Deprivation Index, and C-reactive protein (reflecting systemic inflammation state). Results: This analysis included 617 participants (mean [SD] age, 66 [7.9] years; 300 [49%] African American and 317 [51%] White; 429 [70%] with mild cognitive impairment). On the basis of self-reported race, plasma levels of Aß42 (adjusted mean difference, -1.20 pg/mL; 95% CI, -2.33 to -0.07 pg/mL), Aß40 (adjusted mean difference, -37.78 pg/mL; 95% CI, -60.16 to -15.39 pg/mL), p-tau181 (adjusted mean difference, -4.66 pg/mL; 95% CI, -7.05 to -1.90 pg/mL), and neurofilament light (adjusted mean difference, -1.58; 95% CI, -2.83 to -0.19 pg/mL) were consistently lower in African American individuals after adjusting for demographic characteristics, educational attainment, cognition, APOE4, and cardiovascular factors. A similar pattern was observed in the CSF biomarkers except for Aß42 and Aß40. Although unadjusted analyses revealed an association between these biomarkers and African ancestry, these associations were not significant after adjusting for the same covariates. Differences by self-reported race were not explained by varied cardiovascular risk factors, C-reactive protein, educational attainment, or Area Deprivation Index. Conclusions and Relevance: In this cross-sectional study of plasma biomarkers by race and genetic ancestry, the results indicated that plasma p-tau181, Aß40, and NFL were lower in African American individuals based on self-reported race but not genetic ancestry. These differences were not explained by cardiovascular risks or clinical stage differences. These racial differences should be considered in clinical interpretations and clinical trial screenings to avoid an additional increase in underrepresentation of African American individuals in AD trials.

Effects of Candesartan vs Lisinopril on Neurocognitive Function in Older Adults With Executive Mild Cognitive Impairment: A Randomized Clinical Trial.

Importance: Observational studies have suggested that angiotensin receptor blockers are associated with a unique cognitive protection. It is unclear if this is due to reduced blood pressure (BP) or angiotensin receptors type 1 blockade. Objective: To determine neurocognitive effects of candesartan vs lisinopril in older adults with mild cognitive impairment (MCI). Design, Setting, and Participants: This randomized clinical trial included participants aged 55 years or older with MCI and hypertension. Individuals were withdrawn from prior antihypertensive therapy and randomized in a 1 to 1 ratio to candesartan or lisinopril from June 2014 to December 2018. Participants underwent cognitive assessments at baseline and at 6 and 12 months. Brain magnetic resonance images were obtained at baseline and 12 months. This intent-to-treat study was double-blind and powered for a sample size accounting for 20% dropout. Data were analyzed from May to October 2019. Interventions: Escalating doses of oral candesartan (up to 32 mg) or lisinopril (up to 40 mg) once daily. Open-label antihypertensive drug treatments were added as needed to achieve BP less than 140/90 mm Hg. Main Outcomes and Measures: The primary outcome was executive function (measured using the Trail Making Test, Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research tool) and secondary outcomes were episodic memory (measured using the Hopkins Verbal Learning Test-Revised) and microvascular brain injury reflected by magnetic resonance images of white matter lesions. Results: Among 176 randomized participants (mean [SD] age, 66.0 [7.8] years; 101 [57.4%] women; 113 [64.2%] African American), 87 were assigned to candesartan and 89 were assigned to lisinopril. Among these, 141 participants completed the trial, including 77 in the candesartan group and 64 in the lisinopril group. Although the lisinopril vs candesartan groups achieved similar BP (12-month mean [SD] systolic BP: 130 [17] mm Hg vs 134 [20] mm Hg; P = .20; 12-month mean [SD] diastolic BP: 77 [10] mm Hg vs 78 [11] mm Hg; P = .52), candesartan was superior to lisinopril on the primary outcome of executive function measured by Trail Making Test Part B (effect size [ES] = -12.8 [95% CI, -22.5 to -3.1]) but not Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research score (ES = -0.03 [95% CI, -0.08 to 0.03]). Candesartan was also superior to lisinopril on the secondary outcome of Hopkins Verbal Learning Test-Revised delayed recall (ES = 0.4 [95% CI, 0.02 to 0.8]) and retention (ES = 5.1 [95% CI, 0.7 to 9.5]). Conclusions and Relevance: These findings suggest that in older adults with MCI, 1-year treatment with candesartan had superior neurocognitive outcomes compared with lisinopril. These effects are likely independent of the BP-lowering effect of candesartan. Trial Registration: ClinicalTrials.gov Identifier: NCT01984164.

Perceived Stress is Associated with Alzheimer's Disease Cerebrospinal Fluid Biomarkers in African Americans with Mild Cognitive Impairment.

BACKGROUND: African Americans (AA) have a higher Alzheimer's disease (AD) prevalence and report more perceived stress than White Americans. The biological basis of the stress-AD link is unclear. This study investigates the connection between stress and AD biomarkers in a biracial cohort. OBJECTIVE: Establish biomarker evidence for the observed association between stress and AD, especially in AA. METHODS: A cross-sectional study (n = 364, 41.8% AA) administering cognitive tests and the perceived stress scale (PSS) questionnaire. A subset (n = 309) provided cerebrospinal fluid for measurement of Aß42, Tau, Ptau, Tau/Aß42 (TAR), and Ptau/Aß42 (PTAR). Multivariate linear regression, including factors that confound racial differences in AD, was performed. RESULTS: Higher PSS scores were associated with higher Ptau (ß= 0.43, p = 0.01) and PTAR (ß= 0.005, p = 0.03) in AA with impaired cognition (mild cognitive impairment). CONCLUSION: Higher PSS scores were associated with Tau-related AD biomarker indices in AA/MCI, suggesting a potential biological connection for stress with AD and its racial disparity.

18F-Flortaucipir PET Associations with Cerebrospinal Fluid, Cognition, and Neuroimaging in Mild Cognitive Impairment due to Alzheimer's Disease.

BACKGROUND: Tau positron emission tomography (PET) imaging is used in research, but its relation to cerebrospinal fluid (CSF) tau and other Alzheimer's disease (AD)-related clinical measures is unclear in mild cognitive impairment with AD biomarkers (MCI-AD). OBJECTIVE: To determine associations between 18F-flortaucipir PET and CSF AD biomarkers, cognitive functioning, and neuroimaging measures in MCI-AD. METHODS: In 29 participants 50 years or older with MCI-AD, 18F-flortaucipir PET, CSF total tau (T-tau), phosphorylated tau181p (P-tau), amyloid-ß (Aß), structural MRI, and neuropsychological testing were collected as baseline assessments of an ongoing clinical trial. 11C-Pittsburgh compound B PET was simultaneously conducted in 20 participants. Associations between 18F-flortaucipir PET and these measures were assessed by multiple linear regression adjusted for potential confounders and using global, lobar, and voxel-wise standardized uptake value ratio (SUVr). RESULTS: Whole brain 18F-flortaucipir SUVr was significantly associated with CSF T-tau (r = 0.68, p < 0.001) and P-tau (r = 0.42, p = 0.04) after adjusting for age, sex, race, and education, with strongest associations in the temporal region (T-tau: r = 0.69, p < 0.001; P-tau: r = 0.49, p = 0.02). Voxel-wise analysis confirmed these regional associations. 18F-flortaucipir PET was also associated with CSF Aß (r = -0.45, p = 0.03), episodic memory (r = -0.61, p = 0.001), visuospatial working memory (r = -0.46, p = 0.02), and brain cortical thickness (r = -0.44, p = 0.03) but not hippocampal volume. In the amyloid PET subset, although 11C-PiB PET associated strongly with 18F-flortaucipir (r = 0.79, p≤0.001), associations were stronger between 11C-PiB and key outcomes, compared to 18F-flortaucipir. CONCLUSION: 18F-flortaucipir PET is moderately associated with CSF AD biomarkers and other AD-related phenotypes. The associations in this MCI-AD sample are stronger than previously described in other populations.

Evolving Landscape of Clinical Trials in Heart Failure: Patient Populations, Endpoint Selection, and Regions of Enrollment.

PURPOSE OF REVIEW: Clinical trial design and execution are evolving as increasingly important considerations with respect to the success of heart failure trials. The current review highlights temporal trends in characteristics of heart failure clinical trials. RECENT FINDINGS: Recent trials in heart failure have required longer recruitment phases, displayed inefficient enrollment rates, increased use of composite and nonfatal endpoints, undergone rapid globalization, and gradually increased focus on heart failure with preserved ejection fraction. Understanding patterns and trends in clinical trial design and execution may inform future planning and conduct of trials of heart failure therapeutics.

Effectiveness of asthma principles and practice course in increasing nurse practitioner knowledge and confidence in the use of asthma clinical guidelines.

PURPOSE: The Asthma Principle and Practice (APP) course, an evidence-based blended distance-learning educational encounter, was designed to aid in the dissemination of the 2007 asthma clinical guidelines (EPR-3) and priority messages, increase knowledge of content of the guidelines as well as create an environment to enable participants to apply knowledge and skills into clinical practice. Students received a self-study binder 6-week period prior to attendance at an interactive study day. The APP is grounded in adult education principle and practices. DATA SOURCES: A questionnaire was completed before reading the study binder and post study day to measure demographic variables as well as awareness of and changes in knowledge and confidence in key attributes of the clinical guidelines including patient education. CONCLUSIONS: The results showed that by taking the APP course confidence levels related to knowledge of asthma and its management increased with specific reference to the asthma clinical guidelines. Confidence in the use of patient education/communication strategies improved as well as the use of pulmonary function tests and the interpretation of test results. IMPLICATIONS FOR PRACTICE: Nurse practitioners are an important audience to target in the dissemination of clinical guidelines and benefit from educational materials based on adult education strategies.