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.

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.

A phase II study repurposing atomoxetine for neuroprotection in mild cognitive impairment.

The locus coeruleus is the initial site of Alzheimer's disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. Locus coeruleus dysfunction contributes to Alzheimer's pathobiology in experimental models, which can be rescued by increasing norepinephrine transmission. To test norepinephrine augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved norepinephrine transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer's disease. The design was a single-centre, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment and biomarker evidence of Alzheimer's disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of norepinephrine and metabolites. Prespecified primary outcomes were CSF levels of IL1α and TECK. Secondary/exploratory outcomes included clinical measures, CSF analyses of amyloid-ß42, Tau, and pTau181, mass spectrometry proteomics and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and fluorodeoxyglucose-PET. Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF norepinephrine levels. IL-1α and TECK were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in amyloid-ß42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK and osteoprotegerin proteins. Treatment was also associated with significantly increased brain-derived neurotrophic factor and reduced triglycerides in plasma. Resting state functional MRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. Fluorodeoxyglucose-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus and fusiform gyrus, with carry-over effects 6 months after treatment. In summary, atomoxetine treatment was safe, well tolerated and achieved target engagement in prodromal Alzheimer's disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer's disease progression.

An Exploration of Subgroups of Neuropsychiatric Symptoms in Mild Cognitive Impairment and Their Risks of Conversion to Dementia or Death.

OBJECTIVE: To explore the heterogeneity of neuropsychiatric symptom (NPS) complexes in individuals with mild cognitive impairment (MCI) and assess the relative risks of converting to dementia or dying. DESIGN: Latent class analysis using 7,971 participants with MCI. SETTING: Participants in the Uniform Data Set (UDS) from 39 NIH Alzheimer's Disease Centers. PARTICIPANTS: Persons with a diagnosis of MCI at initial visit from each center and with either a Mini-Mental State Examination (MMSE) score of 22 or greater or an equivalent education-adjusted Montreal Cognitive Assessment (MoCA) score of 16 or greater. MEASUREMENTS: Neuropsychiatric Inventory Questionnaire (NPI-Q) administered at initial visit. RESULTS: In addition to a subgroup with mild or no NPS (relative frequency, 50%), three empirically-based subgroups of NPS were identified: 1) an "affect" or "negative mood" subgroup (27%) with depression, anxiety, apathy, nighttime disturbance, and change in appetite; 2) a "hyperactive" subgroup (14%) with agitation, irritability, and disinhibition; and 3) a "psychotic with additional severe NPS" subgroup (9%) with the highest risk of delusions and hallucinations, as well as highest risk of all other NPS. Each of these three subgroups had significantly higher risk of converting to dementia than the "mild NPS" class, with the "psychotic with additional severe NPS" subgroup possessing a 64% greater risk. The subgroups did not differ in their risks of death without dementia. CONCLUSION: Our findings of three NPS subgroups in MCI characterized by affect, hyperactive, or psychotic features are largely consistent with a previous 3-factor model of NPS found in a demented population. The consistency of these findings across studies and samples, coupled with our results on the associated risks of converting to dementia, suggests that the NPS structure is robust, and warrants further consideration in classification models of MCI.

Exploratory evaluation of baseline cognition as a predictor of perceived benefit in a study of behavioral therapy for urinary incontinence in Parkinson disease.

AIMS: While behavior-based pelvic floor muscle exercise therapy is an effective treatment for overactive bladder in Parkinson's disease (PD) patients, cognitive function may be a predictor of rehabilitation outcomes. METHODS: In a planned exploratory analysis, participants who had a Montreal Cognitive Assessment (MoCA) with a score ≥18 who were randomized in a clinical trial to behavioral treatment were classified by perceived improvement (Benefit vs. No Benefit) as reported on a validated Satisfaction and Benefit Questionnaire. General cognition (MoCA), motor procedural learning (Serial reaction time task), verbal memory (Buschke delayed recall), spatial memory (Nonverbal/Spatial selective reminding test), and working memory (Wisconsin card sorting task) were compared between the two groups using Wilcoxon rank-sum test. RESULTS: Of the 26 participants randomized to behavioral treatment (70% male, mean age 71 ± 6.1 years), 22 participants (85%) reported Benefit and four reported No Benefit. General cognition, motor procedural learning, verbal memory, spatial memory, and working memory did not differ between these groups. While the difference between the time to complete the final practiced series and the random series of the Serial Reaction Time Task (SRTT) was statistically similar between the groups, the Benefit group performed the random sequence more quickly (567.0 ± 136.5 ms) compared to the No Benefit group (959.4 ± 443.0 ms; p = 0.03) and trended toward faster performance in the final practiced series. CONCLUSIONS: Perceived benefit from behavioral treatment for overactive bladder was not associated with measures of baseline cognition other than faster completion of the SRTT. This is noteworthy because many behavior-based therapy studies exclude participants with mild cognitive impairment. Additional studies may evaluate if domain-specific cognitive function, particularly the assessment of implicit memory, could lead to individualized behavioral therapy recommendations.

Expanded Demographic Norms for Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set.

BACKGROUND: Norms for the Uniform Data Set Version 3 Neuropsychological Battery are available for cognitively normal individuals based on age, education, and sex; however, these norms do not include race. We provide expanded norms for African Americans and whites. METHODS: Data from 32 Alzheimer's Disease Centers (ADCs) and ADC affiliated cohorts with global Clinical Dementia Rating Scale (CDR) Dementia Staging Instrument scores of 0 were included. Descriptive statistics for each test were calculated by age, sex, race, and education. Multiple linear regressions were conducted to estimate the effect of each demographic variable; squared semipartial correlation coefficients measured the relative importance of variables. RESULTS: There were 8313 participants (16% African American) with complete demographic information, ranging from 6600 to 7885 depending on the test. Lower scores were found for older and less educated groups, and African Americans versus whites. Education was the strongest predictor for most tests, followed in order by age, race, and sex. Quadratic terms were significant for age and education, indicating some nonlinearity, but did not substantially increase R. CONCLUSIONS: Although race-based norms represent incomplete proxies for other sociocultural variables, the appropriate application of these norms is important given the potential to improve diagnostic accuracy and to reduce misclassification bias in cognitive disorders of aging such as Alzheimer disease.

Subjective Memory Complaints in White and African American Participants.

OBJECTIVE: Subjective memory complaints (SMCs) are associated with mild cognitive impairment and dementia but are understudied in African Americans (AAs). We compared SMC endorsement in white and AA participants and evaluated predictors of diagnostic progression. METHODS: Initial visit variables, including SMC and memory performance, were compared within a cognitively normal race-matched sample of white and AA participants (Ntotal = 912; 456each race) to assess the presence and predictors of SMC, the predictors of future diagnostic progression, and the change in memory performance over time. RESULTS: More white (32.9%) than AA (24.3%) participants reported SMC (P < .01, ϕ = -.10). Subjective memory complaint was predicted by memory performance (B = -0.03, standard error [SE] = 0.013, odds ratio [OR] = .968, P < .05) and race (B = -0.99, SE = 0.080, OR = .373, P < .001). Subjective memory complaints and memory performance were associated with progression, χ2 (3, n = 912) = 102.37, P < .001. African American race (-2.05 ± 0.24 SE) and SMC (-0.45 ± 0.21 SE) were associated with worse memory performance at baseline and over time, χ2(3) = 13.54, P < .01. CONCLUSIONS: In contrast to previous research, our study found that SMC is associated with diagnostic progression and objective memory declines in both white and AA participants.

Latent classes of mild cognitive impairment are associated with clinical outcomes and neuropathology: Analysis of data from the National Alzheimer's Coordinating Center.

Given the importance of identifying prodromes of dementia with specific etiologies, we assessed whether seven latent classes of mild cognitive impairment (MCI), defined empirically based on cognitive, functional, and neuropsychiatric information at initial visit, are associated with distinct clinical outcomes and neuropathological features. We separated 6034 participants with a baseline diagnosis of MCI into seven latent classes using previously defined criteria. We found that these latent classes of MCI differed significantly in their clinical outcomes, survival time, and neuropathology. Two amnestic multi-domain subgroups, as well as two other subgroups with functional impairments and neuropsychiatric disturbances, were at higher risk of not only a 'pure' form of Alzheimer's disease (AD) pathology, but also a 'mixed' pathology consisting of both AD and vascular features. Moreover, the seven latent classes had different risks of Lewy bodies, hippocampal sclerosis, and frontotemporal lobar degeneration (FTLD). This study indicates that data-driven subgroups of MCI are clinicopathologically informative and, with refinement, could lead to targeted interventions focused on each etiology.

Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study.

BACKGROUND: Redox signaling, which can be assessed by circulating aminothiols, reflects oxidative stress (OS) status and has been linked to clinical cardiovascular disease and its risk factors. These, in turn, are related to executive function decline. OS may precede the pro-inflammatory state seen in vascular disease. The objective of this study is to investigate the association between aminothiol markers of OS and inflammation in cognitive decline, especially in the executive cognitive domain which is highly susceptible to cardiovascular risk factors and is an important predictor of cognitive disability. METHODS: The study design is that of a longitudinal cohort study within the setting of a large academic institution with participants being university employees (n = 511), mean age 49 years, 68% women, and 23% African-American. These participants were followed for four consecutive years with a yearly cognitive assessment conducted using computerized versions of 15 cognitive tests. Peripheral cystine, glutathione, their disulfide derivatives, and C-reactive protein (CRP) were measured. RESULTS: Lower levels of glutathione at baseline was associated with a decline in the executive domain over 4 years (covariate-adjusted relative risk (RR) for glutathione = 1.70 (95% CI = 1.02-2.85), p = 0.04). Furthermore, a longitudinal decline in glutathione level was associated with a faster decline in the executive domain (p = 0.03). None of the other OS markers or CRP were linked to cognitive decline over 4 years. CONCLUSION: Increased OS reflected by decreased glutathione was associated with a decline in executive function in a healthy population. In contrast, inflammation was not linked to cognitive decline. OS may be an earlier biomarker that precedes the inflammatory phase of executive decline with aging.

Incremental Validity of Montreal Cognitive Assessment Index Scores in Mild Cognitive Impairment and Alzheimer Disease.

BACKGROUND/AIMS: The aim of this paper was to evaluate the incremental validity of the Montreal Cognitive Assessment (MoCA) index scores and the MoCA total score in differentiating individuals with normal cognition versus mild cognitive impairment (MCI) or Alzheimer disease (AD). METHODS: Effect sizes were calculated for Alzheimer's Disease Neuroimaging Initiative research participants with normal cognition (n = 295), MCI (n = 471), or AD (n = 150). RESULTS: Effect sizes for the total score were large (> 0.80) and exceeded the index scores in differentiating those with MCI versus normal cognition, MCI versus AD, and AD versus normal cognition. A combined score incorporating the Memory, Executive, and Orientation indexes also improved incremental validity for all 3 group comparisons. CONCLUSION: Administration of the entire MoCA is more informative than the index scores, especially in distinguishing normal cognition versus MCI. A combined score has stronger incremental validity than the individual index scores.

Version 3 of the Alzheimer Disease Centers' Neuropsychological Test Battery in the Uniform Data Set (UDS).

INTRODUCTION: The neuropsychological battery of the Uniform Data Set (UDSNB) was implemented in 2005 by the National Institute on Aging (NIA) Alzheimer Disease Centers program to measure cognitive performance in dementia and mild cognitive impairment due to Alzheimer Disease. This paper describes a revision, the UDSNB 3.0. METHODS: The Neuropsychology Work Group of the NIA Clinical Task Force recommended revisions through a process of due diligence to address shortcomings of the original battery. The UDSNB 3.0 covers episodic memory, processing speed, executive function, language, and constructional ability. Data from 3602 cognitively normal participants in the National Alzheimer Coordinating Center database were analyzed. RESULTS: Descriptive statistics are presented. Multivariable linear regression analyses demonstrated score differences by age, sex, and education and were also used to create a normative calculator available online. DISCUSSION: The UDSNB 3.0 neuropsychological battery provides a valuable non proprietary resource for conducting research on cognitive aging and dementia.

Very early administration of progesterone for acute traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Progesterone has been shown to improve neurologic outcome in multiple experimental models and two early-phase trials involving patients with TBI. METHODS: We conducted a double-blind, multicenter clinical trial in which patients with severe, moderate-to-severe, or moderate acute TBI (Glasgow Coma Scale score of 4 to 12, on a scale from 3 to 15, with lower scores indicating a lower level of consciousness) were randomly assigned to intravenous progesterone or placebo, with the study treatment initiated within 4 hours after injury and administered for a total of 96 hours. Efficacy was defined as an increase of 10 percentage points in the proportion of patients with a favorable outcome, as determined with the use of the stratified dichotomy of the Extended Glasgow Outcome Scale score at 6 months after injury. Secondary outcomes included mortality and the Disability Rating Scale score. RESULTS: A total of 882 of the planned sample of 1140 patients underwent randomization before the trial was stopped for futility with respect to the primary outcome. The study groups were similar with regard to baseline characteristics; the median age of the patients was 35 years, 73.7% were men, 15.2% were black, and the mean Injury Severity Score was 24.4 (on a scale from 0 to 75, with higher scores indicating greater severity). The most frequent mechanism of injury was a motor vehicle accident. There was no significant difference between the progesterone group and the placebo group in the proportion of patients with a favorable outcome (relative benefit of progesterone, 0.95; 95% confidence interval [CI], 0.85 to 1.06; P=0.35). Phlebitis or thrombophlebitis was more frequent in the progesterone group than in the placebo group (relative risk, 3.03; CI, 1.96 to 4.66). There were no significant differences in the other prespecified safety outcomes. CONCLUSIONS: This clinical trial did not show a benefit of progesterone over placebo in the improvement of outcomes in patients with acute TBI. (Funded by the National Institute of Neurological Disorders and Stroke and others; PROTECT III ClinicalTrials.gov number, NCT00822900.).

Inflammation and cognitive functioning in African Americans and Caucasians.

OBJECTIVE: To examine associations between inflammation and cognitive performance in African Americans and Caucasians. METHODS: The sample included 59 African Americans and 219 Caucasians ≥ 50 years old who had a baseline visit at the Emory/Georgia Tech Center for Health Discovery and Well Being. Peripheral levels of inflammation (interleukin-6, interleukin-8, C-reactive protein, and tumor necrosis factor-α) were examined in relation to performance on tests of visual processing (Identify the Odd Pattern), attention (Digit Span Forward), visuomotor set shifting (Digit Symbol Substitution), verbal set shifting (Digit Span Backwards), and memory (Recall a Pattern). RESULTS: Multiple regression models adjusting for potential demographic and vascular/metabolic confounders were conducted, with markers of inflammation included as either continuous or categorical (quartiles) variables. There were significant interactions between IL-8 and race for the Recall a Pattern (p = .006) and the Digit Symbol Substitution (p = .014) tests. Race-specific analyses (using a continuous variable for IL-8) demonstrated slower response times on the Recall a Pattern and Digit Symbol Substitution tests for African Americans but not for Caucasians. Categorical analyses among African Americans indicated that all of the top three quartiles of IL-8 were associated with slower reaction times on the Recall a Pattern test compared to the lowest quartile, while for Digit Symbol, the highest quartile of IL-8 was associated with the slowest cognitive performance. CONCLUSIONS: These preliminary findings suggest a stronger association between IL-8 and cognitive performance in African Americans than Caucasians. This relationship should be further examined in larger samples that are followed over time.

Validity of the montreal cognitive assessment as a screen for mild cognitive impairment and dementia in African Americans.

The validity of the Montreal Cognitive Assessment (MoCA) as a screen for mild cognitive impairment (MCI) and dementia was evaluated in African Americans attending an urban outpatient memory disorders clinic. Eighty one patients ≥50 years old were administered the MoCA and neuropsychological tests. Clinicians, blinded to the MoCA scores, reviewed the neuropsychological findings and reports of instrumental activities of daily living and they assigned a diagnosis of normal cognition (NC; N = 16), MCI (N = 38), or dementia (N = 27). The MoCA scores of the 3 groups were significantly different (NC > MCI > dementia). Using cutoff scores of ≤24 points for MCI and ≤22 points for dementia, the MoCA had .95 sensitivity and .63 specificity for MCI and .96 sensitivity and .88 specificity for dementia. The MoCA is a valid and cost-effective screen for cognitive impairment in African Americans but with a higher likelihood of falsely classifying persons with NC as having MCI.

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.

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.

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.

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.