Hemodynamic Reactivity to Mental Stress and Cognitive Function in Coronary Artery Disease.

OBJECTIVE: People with coronary artery disease (CAD) are at higher risk of cognitive impairment than those without CAD. Psychological stress is a risk factor for both conditions and assessing the hemodynamic reactivity to mental stress could explain the link between stress and cognitive function. METHODS: Individuals with stable CAD from two prospective cohort studies were included. All individuals underwent acute mental stress testing, as well as conventional stress testing. Cognitive function was assessed both at baseline and at a 2-year follow-up. The rate-pressure product (RPP) was calculated as the mean systolic blood pressure times the mean heart rate at rest. RPP reactivity was defined as the maximum RPP during standardized mental stress test minus the RPP at rest. RESULTS: After multivariable adjustment, every standard deviation decrease in RPP reactivity with mental stress was associated with slower completion of Trail-A and Trail-B in both cohorts (13% and 11% in cohort 1, and 15% and 16% in cohort 2, respectively, p for all <0.01). After a 2-year follow-up period, every standard deviation decrease in RPP reactivity with mental stress was associated with a 8%, and 9% slower completion of Trail-A and Trail-B, respectively (p for all <0.01). There was no significant association between RPP reactivity with conventional stress testing and any of the cognitive tests. CONCLUSION: In the CAD population, a blunted hemodynamic response to mental stress is associated with slower visuomotor processing and worse executive function at baseline and with greater decline in these abilities over time.

Characterization of African-American Super-Agers in the National Alzheimer's Coordinating Center cohort.

BACKGROUND: "Super-agers" are adults aged ≥80 with cognitive performance similar to persons two to three decades younger. Characteristics such as larger hippocampal volume, APOE-ε4 allele absence, higher educational attainment, female sex, and lifelong cognitive stimulation are associated with cognitive performance compatible with super-aging. These findings are based on predominantly white research samples. Limited data are available on African-American super-agers. To fill this gap, we explored potential factors associated with super-aging in older African-American adults. METHODS: Data from African-American participants aged ≥80 in the National Alzheimer's Coordinating Center (NACC) dataset were analyzed. Using global Clinical Dementia Rating (CDR) scores, participants were first categorized as impaired (score ≥0.5) or non-impaired/normal cognition (NC) (score = 0). From the NC group, super-agers were identified using NACC-data-driven cutoffs. Participants were considered super-agers if their memory performance was similar to persons aged 50-60 with NC, and their performance on other domains was within one standard deviation of the mean for persons aged ≥80. We examined group characteristics (NC, super-ager, impaired) using chi-square and ANOVA with pairwise comparisons. Multinomial logistic regression, adjusted for sex and education, evaluated correlates of super-ager group assignment. RESULTS: Data for 1285 African-American participants aged ≥80 were analyzed. We identified 24.7% (n = 316) NC, 4.8% (n = 61) super-agers, and 70.6% (n = 905) impaired. Super-agers were mostly female and more educated, had similar vascular comorbidities as the other groups, and had less sleep disorders, depression, and alcohol use. After adjusting for sex and education, super-ager group assignment was associated with less sleep disorders, less depression, and moderate alcohol use. CONCLUSIONS: Participants with controlled vascular risk, mental health, alcohol use, and sleep disorders tended to be in the super-ager group. These factors may be important focus areas in clinical practice to support cognitive resilience with aging in older African-American adults.

Discrepancies between self- and informant-ratings of functional abilities and objective cognition: predictors of bias in mild cognitive impairment.

OBJECTIVE: Self- and informant-ratings of functional abilities are used to diagnose mild cognitive impairment (MCI) and are commonly measured in clinical trials. Ratings are assumed to be accurate, yet they are subject to biases. Biases in self-ratings have been found in individuals with dementia who are older and more depressed and in caregivers with higher distress, burden, and education. This study aimed to extend prior findings using an objective approach to identify determinants of bias in ratings. METHOD: Participants were 118 individuals with MCI and their informants. Three discrepancy variables were generated including the discrepancies between (1) self- and informant-rated functional status, (2) informant-rated functional status and objective cognition (in those with MCI), and (3) self-rated functional status and objective cognition. These variables served as dependent variables in forward linear regression models, with demographics, stress, burden, depression, and self-efficacy as predictors. RESULTS: Informants with higher stress rated individuals with MCI as having worse functional abilities relative to objective cognition. Individuals with MCI with worse self-efficacy rated their functional abilities as being worse compared to objective cognition. Informant-ratings were worse than self-ratings for informants with higher stress and individuals with MCI with higher self-efficacy. CONCLUSION: This study highlights biases in subjective ratings of functional abilities in MCI. The risk for relative underreporting of functional abilities by individuals with higher stress levels aligns with previous research. Bias in individuals with MCI with higher self-efficacy may be due to anosognosia. Findings have implications for the use of subjective ratings for diagnostic purposes and as outcome measures.

Comparison of performance on the oral versus written trail making test in patients with movement disorders.

The Oral Trail Making Test (O-TMT) was designed as a clinical analog of the written version (W-TMT). There is debate, however, about whether the measurement of processing speed and set shifting is equivalent between versions. Given the administration advantages of the O-TMT - especially for patients with motor impairments - we examined convergent validity with the W-TMT in patients with movement disorders. Fifty patients (n = 43 idiopathic Parkinson's disease [PD]) were evaluated in a movement disorders clinic. Patients averaged 71 years old (SD = 8.07 years), 16 years of education (SD = 2.30 years), and the majority were non-Hispanic White (n = 46) and male (n = 35). In addition to other neuropsychological measures, patients completed the O-TMT and the W-TMT, counterbalanced and separated by thirty-minutes. Part A scores on O-TMT and W-TMT were not significantly correlated. In contrast, Part B scores were strongly correlated, such that slower performances on O-TMT Part B corresponded with slower performances on W-TMT Part B. Discrepancy scores (Part B minus Part A completion times) were also strongly correlated, such that more time on O-TMT, indicative of slower set shifting speed, corresponded with more time on W-TMT. Better performances on both O-TMT B and W-TMT B were associated with better scores on measures of overall cognitive status, verbal learning, and both phonemic and semantic fluency. Part B of the O-TMT shows promise as an analog for Part B of the W-TMT when evaluating set shifting abilities in patients with movement disorders. Future research with diverse patient populations is recommended to establish generalizability.

Frequency and correlates of subjective cognitive complaints and objective cognitive screening results in African American adults following COVID-19 infection.

Background: Subjective cognitive complaints are frequent following COVID-19 infection, but assessment of whether these complaints map onto objective cognitive findings may not be routine in busy clinical settings. Consequently, opportunities to confirm these complaints and to provide follow-up referrals and appropriate care may be missed, thereby impacting patients' functional independence and quality of life. African Americans are vulnerable to poor outcomes from COVID-19, and thus represent a minority group in whom subjective concerns are especially important to investigate. Towards this end, we examined the frequency and correlates of subjective complaints and objective screening results of African American patients referred to the Post-Acute Sequelae of SARS-CoV-2 (PASC) Clinic at Grady Memorial Hospital, a large county teaching hospital in Atlanta, Georgia. Methods: Eighty seven African American patients (mean age = 52.5, SD = 10.5, range = 30-73) were evaluated between January 28, 2021-October 14, 2021 in the Grady PASC clinic. They ranged from 1 to 17 months post positive SARS-COV-2 antigen testing. Patients were administered a subjective cognitive complaint questionnaire (PROMIS Cognitive Function Scale Short Form 8a) as well as cognitive screening measures including the Mini-Cog (3 item recall, clock) and the Digit Symbol Substitution Test (timed visuomotor sequencing). Mood was assessed via the Patient Health Questionnaire-9, and anxiety via the Generalized Anxiety Disorders Scale. Published norms were used to identify clinically elevated scores. Results: Sixty six (76%) patients denied experiencing meaningful cognitive concerns, and of these, 25 (38%) had positive cognitive screens indicating impaired performance on objective testing. Of 21 patients with subjectively elevated cognitive concerns, 17 (81%) also had positive cognitive screens. There were no significant differences in sociodemographic factors (p values = .07-.71), days post-acute positive SARS-COV-2 Antigen Test (p = .99), disease severity (p values = .67-.75), or COVID-19 comorbidity indices (medical conditions (p values = .20-.77), substance abuse (p = .79), psychiatric history (p values = .11-.99) in those with or without subjective complaints and objective cognitive findings. However, patients with subjective complaints and objective cognitive findings reported more post-COVID-19 anxiety (p = .02) and depression (p = .001). Conclusions: Findings indicate a high concordance between subjective complaints on the PROMIS Cognitive Scale and objectively confirmed cognitive impairments in African Americans. Further, almost 40% who reported no cognitive complaints screened positive for cognitive impairment. Although depression and anxiety are associated with subjective complaints, they do not account for positive cognitive screening results, as those patients without depressive complaints also had similar rates of positive objective screens. The findings suggest that cognitive screening using assessment tools should be routinely performed in African Americans, especially those reporting cognitive symptoms on outcome scales. While future studies are needed to assess long-term outcomes, we highly recommend follow-ups in those with positive screens to characterize the specific domains that are impacted and that could affect activities of daily living and quality of life.

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.

Mild antecedent COVID-19 associated with symptom-specific post-acute sequelae.

BACKGROUND: The impact of COVID-19 severity on development of long-term sequelae remains unclear, and symptom courses are not well defined. METHODS: This ambidirectional cohort study recruited adults with new or worsening symptoms lasting ≥3 weeks from confirmed SARS-CoV-2 infection between August 2020-December 2021. COVID-19 severity was defined as severe for those requiring hospitalization and mild for those not. Symptoms were collected using standardized questionnaires. Multivariable logistical regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between clinical variables and symptoms. RESULTS: Of 332 participants enrolled, median age was 52 years (IQR 42-62), 233 (70%) were female, and 172 (52%) were African American. Antecedent COVID-19 was mild in 171 (52%) and severe in 161 (48%). In adjusted models relative to severe cases, mild COVID-19 was associated with greater odds of fatigue (OR:1.83, CI:1.01-3.31), subjective cognitive impairment (OR:2.76, CI:1.53-5.00), headaches (OR:2.15, CI:1.05-4.44), and dizziness (OR:2.41, CI:1.18-4.92). Remdesivir treatment was associated with less fatigue (OR:0.47, CI:0.26-0.86) and fewer participants scoring >1.5 SD on PROMIS Cognitive scales (OR:0.43, CI:0.20-0.92). Fatigue and subjective cognitive impairment prevalence was higher 3-6 months after COVID-19 and persisted (fatigue OR:3.29, CI:2.08-5.20; cognitive OR:2.62, CI:1.67-4.11). Headache was highest at 9-12 months (OR:5.80, CI:1.94-17.3). CONCLUSIONS: Mild antecedent COVID-19 was associated with highly prevalent symptoms, and those treated with remdesivir developed less fatigue and cognitive impairment. Sequelae had a delayed peak, ranging 3-12 months post infection, and many did not improve over time, underscoring the importance of targeted preventative measures.

Predictors of Cognitive Decline in Healthy Middle-Aged Individuals with Asymptomatic Alzheimer's Disease.

Alzheimer's disease (AD) progresses through a lengthy asymptomatic period during which pathological changes accumulate prior to development of clinical symptoms. As disease-modifying treatments are developed, tools to stratify risk of clinical disease will be required to guide their use. In this study, we examine the relationship of AD biomarkers in healthy middle-aged individuals to health history, family history, and neuropsychological measures and identify cerebrospinal fluid (CSF) biomarkers to stratify risk of progression from asymptomatic to symptomatic AD. CSF from cognitively normal (CN) individuals (N=1149) in the Emory Healthy Brain Study were assayed for Aß42, total Tau (tTau), and phospho181-Tau (pTau), and a subset of 134 cognitively normal, but biomarker-positive, individuals were identified with asymptomatic AD (AsymAD) based on a locally-determined cutoff value for ratio of tTau to Aß42. These AsymAD cases were matched for demographic features with 134 biomarker-negative controls (CN/BM-) and compared for differences in medical comorbidities and family history. Dyslipidemia emerged as a distinguishing feature between AsymAD and CN/BM-groups with significant association with personal and family history of dyslipidemia. A weaker relationship was seen with diabetes, but there was no association with hypertension. Examination of the full cohort by median regression revealed a significant relationship of CSF Aß42 (but not tTau or pTau) with dyslipidemia and diabetes. On neuropsychological tests, CSF Aß42 was not correlated with performance on any measures, but tTau and pTau were strongly correlated with visuospatial perception and visual episodic memory. In addition to traditional CSF AD biomarkers, a panel of AD biomarker peptides derived from integrating brain and CSF proteomes were evaluated using machine learning strategies to identify a set of 8 peptides that accurately classified CN/BM- and symptomatic AD CSF samples with AUC of 0.982. Using these 8 peptides in a low dimensional t-distributed Stochastic Neighbor Embedding analysis and k-Nearest Neighbor (k=5) algorithm, AsymAD cases were stratified into "Control-like" and "AD-like" subgroups based on their proximity to CN/BM- or AD CSF profiles. Independent analysis of these cases using a Joint Mutual Information algorithm selected a set of 5 peptides with 81% accuracy in stratifying cases into AD-like and Control-like subgroups. Performance of both sets of peptides was evaluated and validated in an independent data set from the Alzheimer's Disease Neuroimaging Initiative. Based on our findings, we conclude that there is an important role of lipid metabolism in asymptomatic stages of AD. Visuospatial perception and visual episodic memory may be more sensitive than language-based abilities to earliest stages of cognitive decline in AD. Finally, candidate CSF peptides show promise as next generation biomarkers for predicting progression from asymptomatic to symptomatic stages of AD.

Magnetic resonance evidence of increased iron content in subcortical brain regions in asymptomatic Alzheimer's disease.

While iron over-accumulation has been reported in late stage Alzheimer's disease (AD), whether this occurs early in the asymptomatic stage of AD remains unknown. We aimed to assess brain iron levels in asymptomatic AD using quantitative MR relaxometry of effective transverse relaxation rate (R2*) and longitudinal relaxation rate (R1), and recruited 118 participants comprised of three groups including healthy young participants, and cognitively normal older individuals without or with positive AD biomarkers based on cerebrospinal fluid (CSF) proteomics analysis. Compared with the healthy young group, increased R2* was found in widespread cortical and subcortical regions in the older groups. Further, significantly higher levels of R2* were found in the cognitively normal older subjects with positive CSF AD biomarker (i.e., asymptomatic AD) compared with those with negative AD biomarker in subcortical regions including the left and right caudate, left and right putamen, and left and right globus pallidus (p < .05 for all regions), suggesting increased iron content in these regions. Subcortical R2* of some regions was found to significantly correlate with CSF AD biomarkers and neuropsychological assessments of visuospatial functions. In conclusion, R2* could be a valuable biomarker for studying early pathophysiological changes in AD.

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.

Telehealth equivalence of the Montreal cognitive assessment (MoCA): Results from the Emory healthy brain study (EHBS).

BACKGROUND: We investigated potential differences between in-person cognitive testing and video telehealth administration of the Montreal Cognitive Assessment (MoCA). In addition to the MoCA, the Patient Health Questionnaire-8 (PHQ-8) and Generalized Anxiety Disorder-7 (GAD-7) were administered. METHODS: MoCA scores from participants in the Emory Health Brain Study (EHBS) were contrasted based upon whether they were administered the MoCA in the standard face-to-face (F2F) assessment setting (n = 1205) or using a video telehealth administration (n = 491). All EHBS participants were self-reported to be cognitively normal. RESULTS: MoCA scores did not differ across administration method (F2F MoCA = 26.6, SD = 2.4; telehealth MoCA = 26.5, SD = 2.4). The 95% confidence interval for difference in administration was small (CI = -0.16 to 0.34). When examining MoCA domain scores, administration differences were either associated with no statistically significant effect, or if present due to large sample sizes, were associated with small effects and differences <0.5 point. Telehealth patients reported slightly lower PHQ-8 scores (F2F PHQ-8 = 2.0, SD = 2.5; telehealth PHQ-8 = 1.6, SD = 2.1), although these scores are well within the normal range. No group difference in GAD-7 scores was present (F2F GAD-7 = 1.4, SD = 2.4; telehealth PHQ-8 = 1.4, SD = 2.4). DISCUSSION: This report with its large sample size and between subject cohort provides complementary evidence to smaller test-retest studies, further supporting equivalence of MoCA telehealth testing to F2F MoCA administration. These findings provide additional reassurance that administration mode does not introduce systematic performance differences for MoCA test administration, thereby permitting telehealth MoCA testing to be applied confidently for both clinical and research applications.

Levodopa responsive freezing of gait is associated with reduced norepinephrine transporter binding in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is a major cause of falling in Parkinson's disease (PD) and can be responsive or unresponsive to levodopa. Pathophysiology is poorly understood. OBJECTIVE: To examine the link between noradrenergic systems, the development of FOG in PD and its responsiveness to levodopa. METHODS: We examined norepinephrine transporter (NET) binding via brain positron emission tomography (PET) to evaluate changes in NET density associated with FOG using the high affinity selective NET antagonist radioligand [11C]MeNER (2S,3S)(2-[α-(2-methoxyphenoxy)benzyl]morpholine) in 52 parkinsonian patients. We used a rigorous levodopa challenge paradigm to characterize PD patients as non-freezing (NO-FOG, N = 16), levodopa responsive freezing (OFF-FOG, N = 10), and levodopa-unresponsive freezing (ONOFF-FOG, N = 21), and also included a non-PD FOG group, primary progressive freezing of gait (PP-FOG, N = 5). RESULTS: Linear mixed models identified significant reductions in whole brain NET binding in the OFF-FOG group compared to the NO-FOG group (-16.8%, P = 0.021) and regionally in the frontal lobe, left and right thalamus, temporal lobe, and locus coeruleus, with the strongest effect in right thalamus (P = 0.038). Additional regions examined in a post hoc secondary analysis including the left and right amygdalae confirmed the contrast between OFF-FOG and NO-FOG (P = 0.003). A linear regression analysis identified an association between reduced NET binding in the right thalamus and more severe New FOG Questionnaire (N-FOG-Q) score only in the OFF-FOG group (P = 0.022). CONCLUSION: This is the first study to examine brain noradrenergic innervation using NET-PET in PD patients with and without FOG. Based on the normal regional distribution of noradrenergic innervation and pathological studies in the thalamus of PD patients, the implications of our findings suggest that noradrenergic limbic pathways may play a key role in OFF-FOG in PD. This finding could have implications for clinical subtyping of FOG as well as development of therapies.

The Rey Auditory Verbal Learning Test: Cross-validation of Mayo Normative Studies (MNS) demographically corrected norms with confidence interval estimates.

OBJECTIVE: The Mayo Normative Studies (MNS) represents a robust dataset that provides demographically corrected norms for the Rey Auditory Verbal Learning Test. We report MNS application to an independent cohort to evaluate whether MNS norms accurately adjust for age, sex, and education differences in subjects from a different geographic region of the country. As secondary goals, we examined item-level patterns, recognition benefit compared to delayed free recall, and derived Auditory Verbal Learning Test (AVLT) confidence intervals (CIs) to facilitate clinical performance characterization. METHOD: Participants from the Emory Healthy Brain Study (463 women, 200 men) who were administered the AVLT were analyzed to demonstrate expected demographic group differences. AVLT scores were transformed using MNS normative correction to characterize the success of MNS demographic adjustment. RESULTS: Expected demographic effects were observed across all primary raw AVLT scores. Depending on sample size, MNS normative adjustment either eliminated or minimized all observed statistically significant AVLT differences. Estimated CIs yielded broad CI ranges exceeding the standard deviation of each measure. The recognition performance benefit across age ranged from 2.7 words (SD = 2.3) in the 50-54-year-old group to 4.7 words (SD = 2.7) in the 70-75-year-old group. CONCLUSIONS: These findings demonstrate generalizability of MNS normative correction to an independent sample from a different geographic region, with demographic adjusted performance differences close to overall performance levels near the expected value of T = 50. A large recognition performance benefit is commonly observed in the normal aging process and by itself does not necessarily suggest a pathological retrieval deficit.

Rationale and Design of the PARTNER Trial: Partnered Rhythmic Rehabilitation for Enhanced Motor-Cognition in Prodromal Alzheimer's Disease.

BACKGROUND: Functional decline in Alzheimer's disease (AD) is impacted by impaired ability to integrate and modulate complex cognitive and motor abilities, commonly known as motor-cognitive integration. Impaired motor-cognitive integration occurs in the early stages of AD, prodromal AD (pAD), and may precede other symptoms. Combined motor and cognitive training have been recommended for people with pAD and need to be better researched. Our data suggest that partnered rhythmic rehabilitation (PRR) improves motor-cognitive integration in older adults with cognitive impairment. PRR is an ideal intervention to simultaneously target cardiovascular, social, and motor-cognitive domains important to AD. OBJECTIVE/METHODS: We propose to conduct a 1-year Phase II, single-blind randomized controlled trial using PRR in 66 patients with pAD. Participants will be assigned to three months of biweekly sessions, followed by nine months of weekly sessions of PRR or group walking (WALK) with 1 : 1 allocation. Group walking in the control group will allow us to compare physical exercise alone versus the added benefit of the cognitively engaging elements of PRR. RESULTS/CONCLUSION: Using an intent-to-treat approach, this innovative pilot study will 1) Determine acceptability, safety, tolerability, and satisfaction with PRR; 2) Compare efficacy of PRR versus WALK for improving motor-cognitive integration and identify the most sensitive endpoint for a Phase III trial from a set of motor-cognitive, volumetric MRI, and cognitive measures. The study will additionally explore potential neural, vascular, and inflammatory mechanisms by which PRR affects pAD to derive effect size of these intermediary measures and aid us in estimating sample size for a future trial.

Clinical value of the Montreal Cognitive Assessment free recall condition alone versus cued recall and recognition conditions to detect true memory impairment.

The Montreal Cognitive Assessment (MoCA) is widely used as a screener to characterize cognition. Although only the delayed free recall condition is required for administration, performance on the optional cued recall and multiple-choice recognition conditions may improve diagnostic accuracy over free recall alone. Data on 719 individuals with MCI and 601 controls were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The Rey Auditory Verbal Learning Test (AVLT) delayed free recall condition was used as the gold standard of memory status. Participants with T-scores ≤30 (≤2 SDs below the mean) were classified as memory "impaired." Binary logistic regressions assessed if combined MoCA cued recall/recognition predicted impaired delayed recall on the AVLT beyond the contribution of MoCA free recall. Results showed that MoCA free recall predicted AVLT delayed recall, and that the addition of combined MoCA cued recall/recognition improved the ability to detect impaired AVLT recall, with a better overall model fit. The combined MoCA cued recall/recognition score also had higher specificity and likelihood ratios in detecting memory impairment than MoCA free recall, while higher sensitivity values were present for free recall. Thus, the additional administration of the MoCA cued recall and recognition is recommended.

Multidimensional Environmental Factors and Sleep Health for Aging Adults: A Focused Narrative Review.

The timing, amount, and quality of sleep are critical for an individual's health and quality of life. This paper provides a focused narrative review of the existing literature around multidimensional environments and sleep health for aging adults. Five electronic databases, Scopus, Web of Science, PubMed/Medline; EBSCOhost, PsycINFO (ProQuest), and Google Scholar yielded 54,502 total records. After removing duplicates, non-peer reviewed academic articles, and nonrelevant articles, 70 were included for review. We were able to categorize environmental factors into housing security, home environment, and neighborhood environment, and, within each environmental category, specific elements/aspects are discussed. This paper provides a comprehensive map connecting identified levels of influence (individual, home/house, and neighborhood-level) in which subfactors are listed under each level of influence/category with the related literature list. Our review highlights that multidimensional environmental factors can affect aging adults' sleep health and eventually their physical, mental, and cognitive health and that sleep disparities exist in racial minorities in socioeconomically disadvantaged communities in which cumulative environmental stressors coexist. Based on this focused narrative review on the multidimensional sleep environments for aging adults, knowledge gaps are identified, and future research directions are suggested.

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.

Knowledge About COVID-19 Symptoms, Transmission, and Prevention: The Relationship With Cognitive Status in Older Adults.

Objective: Advanced age poses an increased risk for cognitive impairment, and therefore, poor knowledge regarding the risks associated with COVID-19 may confer vulnerability. We administered a COVID-19 Knowledge Questionnaire to older persons to evaluate the association between knowledge regarding public health recommendations, and cognitive status as measured by the Montreal Cognitive Assessment (MoCA). Method: Ninety-nine participants completed a 22-item questionnaire about COVID-19 symptoms, risks, and protective strategies, and they also completed the MoCA. Associations between knowledge and cognitive status were examined via Spearman correlations. Results: The mean (SD) age of participants was 72.6 (7.6) years, and MoCA scores averaged 23.4 (4.5) points. Higher MoCA total scores were significantly (p < .001) correlated with a greater number of correct questionnaire responses. Higher Orientation and Memory Index scores were moderately associated with an increased number of correct responses (p < .001), with the Executive Index exhibiting a significant albeit weaker association. MoCA Index scores assessing attention, language, and visuospatial functioning were not significantly associated with COVID-19 knowledge. Conclusions: Given the rapid transmission rate of the SARS CoV-2 infections, COVID knowledge lapses will likely have deleterious repercussions. Public health messages should ensure effective acquisition and retention of COVID specific information, especially in cognitively compromised older adults.