Predictors of Improvement after Cognitive Training in Mild Cognitive Impairment: Insights from the Cognitive Training and Neuroplasticity in Mild Cognitive Impairment Trial.

OBJECTIVE: Cognitive training may benefit older adults with mild cognitive impairment (MCI), but the prognostic factors are not well-established. METHODS: This study analyzed data from a 78-week trial with 107 participants with MCI, comparing computerized cognitive training (CCT) and computerized crossword puzzle training (CPT). Outcomes were changes in cognitive and functional measures from baseline. Linear mixed-effect models were used to identify prognostic factors for each intervention. RESULTS: Baseline neuropsychological composite z-score was positively associated with cognitive and functional improvements for both interventions in univariable models, retaining significance in the final multivariable model for functional outcome in CPT ( P < 0.001). Apolipoprotein E e4 carriers had worse cognitive ( P = 0.023) and functional ( P = 0.001) outcomes than noncarriers for CPT but not CCT. African Americans showed greater functional improvements than non-African Americans in both CPT ( P = 0.001) and CCT ( P = 0.010). Better baseline odor identification was correlated with cognitive improvements in CPT ( P = 0.006) and functional improvements in CCT ( P < 0.001). CONCLUSION: Baseline cognitive test performance, African American background, and odor identification ability are potential prognostic factors for improved outcomes with cognitive interventions in older adults with MCI. Apolipoprotein E e4 is associated with poor outcomes. Replication of these findings may improve the selection of cognitive interventions for individuals with MCI.

Subjective versus Psychophysical Measures of Chemosensory Alterations following COVID-19.

INTRODUCTION: Olfactory dysfunction is a common symptom of COVID-19. However, subjective perception of olfactory function does not always correlate well with more objective measures. This study seeks to clarify associations between subjective and psychophysical measures of olfaction and gustation in patients with subjective chemosensory dysfunction following COVID-19. METHODS: Adults with persistent COVID-19-associated chemosensory disturbance were recruited for a prospective, longitudinal cohort study at a tertiary care institution. Participants provided subjective measures of olfactory and gustatory function and underwent psychophysical assessment using Sniffin' Sticks olfactory and Monell gustatory tests. RESULTS: Data analysis (n = 65) showed a statistically significant association between subjective and psychophysical measures of olfaction (p < 0.001). For each one-point increase in subjectively-reported olfactory ability, there is, on average, a 0.11 (95% CI: 0.06, 0.16; p < 0.001) point increase in TDI score while adjusting for age at baseline assessment, sex, and follow-up time. For each one-point increase in subjectively-reported olfactory ability, there is, on average, a 0.04 (95% CI: 0.02, 0.06; p < 0.001) point and 0.05 (95% CI: 0.03, 0.07; p < 0.001) point increase in discrimination and identification scores, respectively, when adjusting for age at baseline assessment, sex, and follow-up time. CONCLUSION: Subjective olfaction shows a mild to moderate association with psychophysical measures, but it fails to comprehensively assess persistent COVID-19-associated chemosensory deficits. The lack of significant association between subjective olfaction and threshold limits the utility of subjective olfaction in tracking recovery. These findings support the push for more widespread psychophysical chemosensory testing.

Life-Course Brain Health as a Determinant of Late-Life Mental Health: American Association for Geriatric Psychiatry Expert Panel Recommendations.

This position statement of the Expert Panel on Brain Health of the American Association for Geriatric Psychiatry (AAGP) emphasizes the critical role of life course brain health in shaping mental well-being during the later stages of life. Evidence posits that maintaining optimal brain health earlier in life is crucial for preventing and managing brain aging-related disorders such as dementia/cognitive decline, depression, stroke, and anxiety. We advocate for a holistic approach that integrates medical, psychological, and social frameworks with culturally tailored interventions across the lifespan to promote brain health and overall mental well-being in aging adults across all communities. Furthermore, our statement underscores the significance of prevention, early detection, and intervention in identifying cognitive decline, mood changes, and related mental illness. Action should also be taken to understand and address the needs of communities that traditionally have unequal access to preventive health information and services. By implementing culturally relevant and tailored evidence-based practices and advancing research in geriatric psychiatry, behavioral neurology, and geroscience, we can enhance the quality of life for older adults facing the unique challenges of aging. This position statement emphasizes the intrinsic link between brain health and mental health in aging, urging healthcare professionals, policymakers, and a broader society to prioritize comprehensive strategies that safeguard and promote brain health from birth through later years across all communities. The AAGP Expert Panel has the goal of launching further activities in the coming months and years.

R- and S-citalopram concentrations have differential effects on neuropsychiatric scores in elders with dementia and agitation.

AIMS: The aim was to determine the relationship between (R) and (S)-citalopram enantiomer exposure (AUC(0,24 h)) and therapeutic response in agitated individuals greater than 60 years old with Alzheimer's dementia (AD). METHODS: Citalopram enantiomer exposures (AUC(0,24 h)) derived from an established population pharmacokinetic analysis were utilized to explore the relationship between (R)- and (S)-citalopram area under the curve (AUC(0,24 )) and Mini-Mental State Examination (MMSE), Neurobehavioural Rating Scale-Agitation Subscale (NBRS-A), modified Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (mADCS-CGIC) and Neuropsychiatric Inventory Agitation subscale (NPIA) scores. Time dependent changes in these scores (disease progression) were accounted for prior to exploring the exposure effect relationship for each enantiomer. These relationships were evaluated using a non-linear-mixed effects modelling approach as implemented in nonmem v7.3. RESULTS: (S)-AUC(0,24 h) and (R)-AUC(0,24 h) each contributed to improvement in NBRS-A scores (k3(R) -0.502; k4(S) -0.712) as did time in treatment. However, increasing (R)-AUC(0,24 h) decreased the probability of patient response (maximum Δ -0.182%/AUC(0,24 h)) based on the CGIC while (S)-AUC(0,24 h) improved the probability of response (maximum Δ 0.112%/AUC(0,24 h)). (R)-AUC(0,24 h) was also associated with worsening in MMSE scores (-0.5 points). CONCLUSIONS: Our results suggest that citalopram enantiomers contributed differentially to treatment outcomes. (R)-citalopram accounted for a greater proportion of the adverse consequences associated with racemic citalopram treatment in patients with AD including a decreased probability of treatment response as measured by the CGIC and a reduction in MMSE scores. The S-enantiomer was associated with increased probability of response based on the CGIC.

Time to Response to Citalopram Treatment for Agitation in Alzheimer Disease.

OBJECTIVE: Agitation is a common and significant problem in Alzheimer disease (AD). In the recent Citalopram for Agitation in Alzheimer's Disease (CitAD) study, citalopram was efficacious for the treatment of AD agitation. Here we examined the time course and predictors of response to treatment. METHODS: Response in CitAD was defined as a modified Alzheimer Disease Cooperative Study Clinical Global Impression of Change (CGIC) score of 1 or 2 or a Neurobehavioral Rating Scale agitation subscale (NBRS-A) score reduction ≥ 50% from baseline. "Stable early response" was defined as meeting the aforementioned criteria at both weeks 3 and 9, "late response" was response at week 9 but not at week 3, and "unstable response" was response at week 3 but not at week 9. RESULTS: In the primary analyses, citalopram was superior to placebo on both the CGIC and the NBRS-A response measures. Little between-group differences were found in response rates in the first 3 weeks of the study (21% versus 19% on the CGIC). Citalopram patients were more likely than placebo patients to be a late responder (18% versus 8% on CGIC, Fisher's exact p = 0.09; 31% versus 15% on NBRS-A, Fisher's exact p = 0.02). Approximately half of citalopram responders (45%-56%) at end of study achieved response later in the study compared with 30%-44% of placebo responders. CONCLUSION: Treatment with citalopram for agitation in AD needs to be at least 9 weeks in duration to allow sufficient time for full response. Study duration is an important factor to consider in the design of clinical trials for agitation in AD.

Deep learning improves utility of tau PET in the study of Alzheimer's disease.

INTRODUCTION: Positron emission tomography (PET) imaging targeting neurofibrillary tau tangles is increasingly used in the study of Alzheimer's disease (AD), but its utility may be limited by conventional quantitative or qualitative evaluation techniques in earlier disease states. Convolutional neural networks (CNNs) are effective in learning spatial patterns for image classification. METHODS: 18F-MK6240 (n = 320) and AV-1451 (n = 446) PET images were pooled from multiple studies. We performed iterations with differing permutations of radioligands, heuristics, and architectures. Performance was compared to a standard region of interest (ROI)-based approach on prediction of memory impairment. We visualized attention of the network to illustrate decision making. RESULTS: Overall, models had high accuracy (> 80%) with good average sensitivity and specificity (75% and 82%, respectively), and had comparable or higher accuracy to the ROI standard. Visualizations of model attention highlight known characteristics of tau radioligand binding. DISCUSSION: CNNs could improve tau PET's role in early disease and extend the utility of tau PET across generations of radioligands.

Mild Parkinsonian signs are associated with lower olfactory test scores in the community-dwelling elderly.

Mild Parkinsonian signs (MPS, impaired gait, rigidity, bradykinesia, rest tremor) are commonly found during the clinical examination of older people and may be a precursor to Parkinson's disease (PD) or Alzheimer's disease (AD). Marked deficits in olfaction occur in PD and AD. The objective of this study was to determine whether University of Pennsylvania Smell Test (UPSIT) scores were lower in nondemented community-dwelling elderly with versus without MPS. Nondemented persons age >or=65 years without PD in Washington Heights-Inwood, NY were evaluated with an abbreviated motor Unified PD Rating Scale and a 40-item UPSIT. Lower UPSIT and higher transformed UPSIT score (square root [UPSIT - 41]) indicated greater olfactory dysfunction. One-hundred-seventy-seven (16.4%) of 1,078 participants had MPS. Mean UPSIT scores (MPS vs. without MPS) were 24.3 +/- 7.1 versus 26.4 +/- 6.8, P < 0.001. In a logistic regression analysis adjusting for age and education, transformed UPSIT score was associated with MPS (OR 1.25, 95% CI 1.04-1.52, P = 0.02). In an adjusted logistic regression analysis, participants with higher transformed UPSIT scores (based on a median split) were 1.55 times more likely to have MPS than were those with lower scores (P = 0.01). Within transformed UPSIT score quartiles, the odds of having MPS were 1.0 (reference), 1.35, 2.02, and 2.20 (P < 0.05). The association with transformed UPSIT scores was similar across MPS subtypes (axial dysfunction, rigidity, tremor).MPS were associated with a mild reduction in olfactory function. These observations further support the view of MPS as a marker of emerging degenerative brain pathologies.

Stroke, depression, and functional health outcomes among adults in the community.

The objective was to determine the association between stroke and depression, the co-occurrence of stroke and depression, and functional health outcomes among adults in the US population. Data were drawn from the Midlife Development in the United States Study (MIDUS) (N = 3032), a nationally representative sample of adults age 25 to 74. Multiple logistic regression analyses were used to determine the association between stroke (past 12-month prevalence), depression (past 12-month prevalence), and functional health outcomes (past 12 months) and to determine whether there is an interaction between depression and stroke in predicting impairment in functioning. Almost one third (29.2%) of adults with stroke in the past year also had depression in the past year (odds ratio 3.5, 95% confidence interval 1.4, 8.9). The co-occurrence of stroke and depression was associated with significantly greater limitations in walking and climbing stairs and poorer general physical functioning than that associated with either without the other. There was evidence of interaction between depression and stroke in predicting limitations, specifically with a statistically significant effect in walking short distances (P = .045). These findings are consistent with previous clinical data and extend those data by suggesting that the co-occurrence of depression and stroke is associated with even poorer functional health outcomes, compared with each alone, and that there may be synergism between the two disorders related to this effect.

Depressive symptoms, vascular risk factors, and Alzheimer's disease.

BACKGROUND: Depressive symptoms in the elderly are associated with an increased Alzheimer's disease (AD) risk. We sought to determine whether the association between depressive symptoms and AD is explained by a history of vascular risk factors and stroke. METHODS: Five hundred and twenty-six elderly persons from New York City without dementia at baseline were followed for a mean of 5 years. Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HAM). Incident AD was ascertained using standard criteria. Diabetes, hypertension, heart disease, current smoking and stroke were ascertained by self-report. Proportional hazards regression was used to relate HAM scores to incident AD. RESULTS: HAM scores were higher in persons with hypertension, heart disease, and stroke, which in turn were related to higher AD risk. AD risk increased with increasing HAM scores as a continuous logarithmically transformed variable (HR for one point increase=1.4; 95% CI=1.1,1.8) and as a categorical variable (HR for HAM >or= 10=3.4; 95% CI=1.5,8.1; p for trend=0.004 with HAM=0 as the reference). These results were virtually unchanged after adjustment for vascular risk factors and stroke, individually (HR for HAM >or= 10=3.4; 95% CI=1.5,8.1; p for trend = 0.004), and in a composite measure (HR for HAM >or= 10=3.0; 95% CI=1.2,7.8; p for trend=0.02). CONCLUSION: The prospective relation between depressive symptoms and AD is not explained by a history of vascular risk factors and stroke, suggesting that other mechanisms may account for this association.

Usefulness of plasma haloperidol levels for monitoring clinical efficacy and side effects in Alzheimer patients with psychosis and behavioral dyscontrol.

OBJECTIVE: This study investigated whether measurement of plasma levels may be useful in monitoring clinical efficacy and side effects during oral haloperidol (HL) treatment of psychosis and behavioral dyscontrol in patients with Alzheimer disease (AD). METHODS: After a single-blind placebo period of 1 week, 71 outpatients with AD were randomized to a 6-week, double-blind, placebo-controlled trial of HL 2 mg-3 mg/day (standard dose), HL 0.5 mg-0.75 mg/day (low dose), or placebo, with plasma levels for HL drawn at the end of 6 weeks. RESULTS: Of the 40 patients who received active HL for 6 weeks, 35 had plasma levels drawn. Plasma levels were all below the lower limit of the postulated therapeutic range in schizophrenia. Nonetheless, HL plasma level significantly correlated with clinical efficacy as measured by reduction in Brief Psychiatric Rating Scale Total score, Psychosis factor, and Hostile-Suspiciousness factor, the Behavioral Syndromes Scale for Dementia Psychomotor Agitation scale, and with the severity of extrapyramidal side effects (EPS). Oral dose did not significantly correlate with any of these efficacy or side-effect measures. Plasma levels significantly correlated with HL dose. When both HL dose and HL plasma level were included as independent variables in linear-regression analyses, only HL plasma level was a significant predictor of efficacy and EPS. CONCLUSION: Measurement of HL plasma levels may have potential usefulness as an adjunct in monitoring treatment response to oral HL in AD patients with psychosis or disruptive behavior.