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.

A systematic review of music interventions for the cognitive and behavioural symptoms of mild cognitive impairment (non-dementia).

Music interventions may represent an effective approach to improving symptoms and delaying progression of MCI to dementia. This review identified nine studies (8 RCT's, 1 observational study) that explored the benefits of music interventions to those with MCI. Studies included five music-playing interventions (sample size (n) ranged from 35 to 201, age ranged from 62 to 94), one music listening intervention (n = 100, mean age = 77 (music intervention) mean age = 76 (dance intervention), one music with movement intervention (n = 16, age range 65-84 years) and two music reminiscence interventions (n = 68; 72, age range = 60-85 years). Only individuals with a clinical diagnosis of MCI were included, no individuals with a diagnosis of dementia were included. Studies were limited due to their sample size, failure to consider confounding variables (i.e. socialization), inconsistency with therapist led sessions, failure to match conditions across interventions, limited follow-up period post-intervention and the tendency to focus on depression exclusively as a measure of behavioural symptoms. Different types of music interventions have differential results on cognitive and behavioural symptoms. The different pattern of brain activation and cognitive abilities which support each type of music activity (e.g. listening vs playing music) may offer some explanation towards these differences. A standardised protocol is needed for each type of music intervention to address how music interventions are studied, taking these limitations into consideration.

Blood Pressure Variability and Progression of Clinical Alzheimer Disease.

Blood pressure variability (BPV) has been shown to have predictive value over blood pressure (BP) levels alone in stroke patients. We assessed whether BPV predicts cognitive and functional decline in Alzheimer disease, using data from a randomized trial (NILVAD [A European Multicentre Double-blind Placebo-controlled Phase III Trial of Nilvadipine in Mild to Moderate Alzheimer's Disease]). Patients with mild-to-moderate Alzheimer disease were included if they had ≥3 office BP measurements available to determine visit-to-visit BPV. Day-to-day BPV was assessed using home BP measurements in a subsample. The variation independent of mean was used to calculate BPV. Outcomes were change in Alzheimer's Disease Assessment Scale-cognitive subscale-12 and Disability Assessment for Dementia after 1 and 1.5 years. A total of 460 patients aged 72.1 (SD=8.1) years, with mean BP of 134.0/75.1 (10.9/6.3) mm Hg were included. After 1 year, patients in the highest quartile of BPV had deteriorated more on Alzheimer's Disease Assessment Scale-cognitive subscale compared with patients in the lowest quartile (systolic: ß, 2.24 [95% CI, 0.11-4.38], P=0.040; diastolic: ß, 2.54 [95% CI, 0.33-4.75] P=0.024). This association was still present after 1.5 years (systolic: ß, 2.86 [95% CI, 0.35-5.36], P=0.026; diastolic: ß, 3.30 [95% CI, 0.67-5.93], P=0.014). There was no effect of visit-to-visit BPV on Disability Assessment for Dementia. Day-to-day BPV was available for 46 patients. Significant associations were observed between day-to-day BPV and deterioration on Alzheimer's Disease Assessment Scale-cognitive subscale (systolic: P=0.036) and Disability Assessment for Dementia (systolic: P=0.020; diastolic: P=0.007) after 1 year, but not after 1.5 years. All associations were adjusted for potential confounders, including intervention group. In conclusion, this post hoc analysis indicates that higher visit-to-visit and day-to-day BPV might be associated with progression of Alzheimer disease. Targeting BPV may be a future target to slow decline in patients with Alzheimer disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02017340.

The Prevalence and Determinants of Vitamin D Status in Community-Dwelling Older Adults: Results from the English Longitudinal Study of Ageing (ELSA).

Vitamin D deficiency is often associated with adverse health outcomes in older adults. The circulating 25-hydroxyvitamin D (25(OH)D) status predominately relies on UV exposure. However, the extent of which northerly latitude exasperates deficiency is less explored in ageing. We aimed to investigate vitamin D deficiency in community-dwelling, older adults, residing at latitudes 50-55° north. This study was comprised of 6004 adults, aged >50 years from wave 6 (2012-2013) of the English Longitudinal Study of Ageing (ELSA). Deficiency was categorised by two criteria: Institute of Medicine (IOM) (<30 nmol/L) and Endocrine Society (ES) (<50 nmol/L). The overall prevalence of Institute of Medicine (IOM) and Endocrine Society (ES) definitions of deficiency were 26.4% and 58.7%, respectively. Females (odds ratio (OR) 1.23; CI: 1.04-1.44), those aged 80+ (OR: 1.42; CI: 1.01-1.93), smoking (OR: 1.88; CI: 1.51-2.34); of non-white ethnicity (OR: 3.8; CI:2.39-6.05); being obese (OR: 1.32; CI:1.09-1.58), and of poor self-reported health (OR:1.99; CI:1.33, 2.96), were more likely to be vitamin D deficient (by IOM). Residents in the south of England had a reduced risk of deficiency (OR: 0.78; CI:0.64-0.95), even after adjustment for socioeconomic and traditional predictors (obesity, age, lifestyle, etc.) of vitamin D status. Other factors, such as being retired, having a normal BMI, engaging in regular vigorous physical activity, vitamin D supplement use, sun travel, and summer season were also significantly positive correlates of deficiency. Similar results were observed for the ES cut-off definition. Importantly, more than half of adults aged >50 years had 25(OH)D concentrations <50 nmol/L. These findings demonstrate that low vitamin D status is highly prevalent in older English adults and the crucial importance of public health strategies throughout midlife and older age to achieve optimal vitamin D status.

Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease.

Cerebrovascular changes, including reduced cerebral blood flow (CBF), occur early in the development of Alzheimer disease and may accelerate disease progression. This randomized, double-blind, placebo-controlled study investigated how 6 months of treatment with the calcium antagonist nilvadipine would affect CBF in patients with mild-to-moderate Alzheimer disease. CBF was measured with magnetic resonance arterial spin labeling in whole-brain gray matter and in a priori defined regions of interest including the hippocampus. Fifty-eight patients were randomly assigned (29 in each group), of whom 22 in both groups had no magnetic resonance exclusion criteria and were medication compliant over 6 months. Mean age was 72.8±6.2 years, mean mini-mental state examination was 20.4±3.4. Nilvadipine treatment lowered systolic blood pressure (Δ=-11.5 [95% CI, -19.7 to -3.2] mm Hg; P<0.01), while whole-brain gray-matter CBF remained stable (Δ=5.4 [95% CI, -6.4 to 17.2] mL/100 g per minute; P=0.36). CBF in the hippocampus increased (left: Δ=24.4 [95% CI, 4.3-44.5] mL/100 g per minute; P=0.02; right: Δ=20.1 [95% CI, -0.6 to 40.8] mL/100 g per minute; P=0.06). There was no significant change in CBF in the posterior cingulate cortex (Δ=5.2 [95% CI, -16.5 to 27.0] mL/100 g per minute; P=0.63) or other regions of interest. In conclusion, nilvadipine reduced blood pressure and increased CBF in the hippocampus, whereas other regions showed stable or small nonsignificant increases in CBF. These findings not only indicate preserved cerebral autoregulation in Alzheimer disease but also point toward beneficial cerebrovascular effects of antihypertensive treatment. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT02017340.

Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension.

Background Hypertension is common among patients with Alzheimer disease. Because this group has been excluded from hypertension trials, evidence regarding safety of treatment is lacking. This secondary analysis of a randomized controlled trial assessed whether antihypertensive treatment increases the prevalence of orthostatic hypotension (OH) in patients with Alzheimer disease. Methods and Results Four hundred seventy-seven patients with mild-to-moderate Alzheimer disease were randomized to the calcium-channel blocker nilvadipine 8 mg/day or placebo for 78 weeks. Presence of OH (blood pressure drop ≥20/≥10 mm Hg after 1 minute of standing) and OH-related adverse events (dizziness, syncope, falls, and fractures) was determined at 7 follow-up visits. Mean age of the study population was 72.2±8.2 years and mean Mini-Mental State Examination score was 20.4±3.8. Baseline blood pressure was 137.8±14.0/77.0±8.6 mm Hg. Grade I hypertension was present in 53.4% (n=255). After 13 weeks, blood pressure had fallen by -7.8/-3.9 mm Hg for nilvadipine and by -0.4/-0.8 mm Hg for placebo ( P<0.001). Across the 78-week intervention period, there was no difference between groups in the proportion of patients with OH at a study visit (odds ratio [95% CI]=1.1 [0.8-1.5], P=0.62), nor in the proportion of visits where a patient met criteria for OH, corrected for number of visits (7.7±13.8% versus 7.3±11.6%). OH-related adverse events were not more often reported in the intervention group compared with placebo. Results were similar for those with baseline hypertension. Conclusions This study suggests that initiation of a low dose of antihypertensive treatment does not significantly increase the risk of OH in patients with mild-to-moderate Alzheimer disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02017340.

Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.

BACKGROUND: This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS: NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease-specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADAS-Cog 12 on placebo was 0.79 (95% CI, -0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. CONCLUSIONS: The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. TRIAL REGISTRATION: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.

Cognitive Impairment Is Reflected by an Increased Difference between Real and Imagined Timed Up and Go Test Performance.

BACKGROUND: Recent research suggests using an imaginary version of the Timed Up and Go test (TUG) for a first assessment of cognitive impairment. By using the time difference between a real (TUGr) and an imagined (TUGi) TUG task, the objective of this study was to examine the effect of cognitive impairment on motor imagery ability. METHODS: Fifty-two participants (mean age 69.3 ± 4.0 years) with mild cognitive impairment or subjective cognitive impairment were included in this study. The time difference between the TUGr and the TUGi was used as the main outcome. The Trail Making Test part B (TMT B), the ratio between TMT A and TMT B, and the Montreal Cognitive Assessment (MoCA) battery were the main independent variables. RESULTS: The difference between TUGr and TUGi performance time and the TMT B performance time increased with decreasing cognitive function (p < 0.01). There was no relationship between TUGr and TUGi performance time and TMT B/A ratio. There were significant correlations between TUG time differences and the MoCA score (r = -0.489, p < 0.01), the TMT B (r = 0.364, p < 0.01), and the TMT B/A ratio (r = 0.377, p < 0.01). CONCLUSION: The combination of TUGr and TUGi may have added value in assessing cognitive impairment, which is a possible pre-stage of dementia.

NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer's disease.

INTRODUCTION: This study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild-to-moderate Alzheimer's disease (AD) in a phase III study that will run for a period of 82 weeks with a treatment period of 78 weeks. METHODS AND ANALYSIS: Adult patients, males and females over 50 years with mild-to-moderate AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) criteria, will be included in the study. It aims to recruit a total of 500 patients with AD; 250 in the nilvadipine group and 250 in the placebo group. Participants will be randomised to receive nilvadipine, an 8 mg overencapsulated, sustained release capsule, or a matching overencapsulated placebo (sugar pill) for a period of 78 weeks of treatment. The primary efficacy outcome measure in this study is the change in cognitive function as assessed by the Alzheimer's disease Assessment Scale (ADAS-Cog 12) from baseline to the end of treatment duration (78 weeks). There are two key secondary outcome measures, the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) and the Disability Assessment for Dementia (DAD). If a statistically significant effect is seen in the primary outcome, CDR-sb will be considered to be a coprimary end point and only the DAD will contribute to the secondary outcome analysis. ETHICS AND DISSEMINATION: The study and all subsequent amendments have received ethical approval within each participating country according to national regulations. Each participant will provide written consent to participate in the study. All participants will remain anonymised throughout and the results of the study will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: EUDRACT Reference Number: 2012-002764-27.

The impact of exercise on the cognitive functioning of healthy older adults: a systematic review and meta-analysis.

Data from epidemiological, cross-sectional, and neuroimaging research show a relationship between higher levels of exercise and reduced risk of cognitive decline but evidence from randomised controlled trials (RCTs) is less consistent. This review examines the impact of aerobic exercise, resistance training, and Tai Chi on the cognitive function of older adults without known cognitive impairment. We investigate explanations for inconsistent results across trials and discrepancies between evidence from RCTs and other research data. Twenty-five RCTs were included in the review. Meta-analysis results revealed significant improvements for resistance training compared to stretching/toning on measures of reasoning (p<0.005); and for Tai Chi compared to 'no exercise' controls on measures of attention (p<0.001) and processing speed (p<0.00001). There were no significant differences between exercise and controls on any of the remaining 26 comparisons. Results should be interpreted with caution however as differences in participant profiles, study design, exercise programmes, adherence rates, and outcome measures contribute to both discrepancies within the exercise research literature and inconsistent results across trials.

Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer's patients--an open-label trial.

BACKGROUND: Evidence suggests that dihydropyridine calcium channel blockers may be useful in preventing and treating Alzheimer's disease (AD). OBJECTIVE: In an open-label trial of safety and tolerability of nilvadipine in patients with AD, we examined cognition and executive function over a short time period to determine an influence of nilvadipine on these outcomes. METHOD: We investigated change in cognition using the Mini mental state examination and in executive function using the EXIT25 in 55 patients with AD who received nilvadipine 8 mg daily for 6 weeks compared with 30 non-treated subjects with AD. Apolipoprotein E genotyping was performed, and the study team and caregivers were kept blinded to APOE ε4 status during the trial. RESULTS: Aside from differences in gender and education, both the treatment and the control groups were similar in general demographics and on baseline cognition status. After correction for potential confounders, APOE ε4 status, and use of other antihypertensive medications, a significant impact of study intervention was observed on MMSE (F = 8.67, p < 0.01) and EXIT (F = 8.77, p < 0.03) scores. An interaction between APOE ε4 carrier status and treatment (p ≤ 0.05) was observed for both outcome measures. CONCLUSION: In this open-label trial, among APOE ε4 non-carriers, we observed stabilization of cognition and improvement in executive function among treated individuals compared with non-treated individuals. Among APOE ε4 carriers, cognitive stabilization was evident for treated individuals whereas a cognitive decline was observed in non-treated individuals. These findings provide additional evidence for potential therapeutic efficacy of nilvadipine in treating AD and warrant further investigation.

Impaired capacity for autonoetic reliving during autobiographical event recall in mild Alzheimer's disease.

The capacity to mentally travel back in time and relive past events via autonoetic consciousness has been shown to be compromised even in the early stages of Alzheimer's disease (AD). To further understand the unravelling of the recollective experience in pathological ageing, we investigated autobiographical memory (ABM) using the Episodic Autobiographical Memory Interview (EAMI) in thirty middle-aged and thirty healthy elderly controls, and twenty patients with mild AD. Of key interest was the recall of contextual details and the behavioural markers predictive of autonoetic reliving. AD patients exhibited significant difficulties in recalling contextual details across all life epochs on the EAMI manifesting in a negative temporal gradient from the Early Adulthood epoch onwards. Overall there was a low incidence of autonoetic consciousness during ABM recall across all participant groups and life epochs when compared with previous studies. AD patients showed a compromised capacity to mentally relive past memories (AD

Exploring the recollective experience during autobiographical memory retrieval in amnestic mild cognitive impairment.

Autonoetic consciousness refers to the ability to mentally transport oneself back in subjective time to relive elements of, or all, of a past event, and is compromised in the early stages of Alzheimer's disease (AD). Here, we investigate autobiographical memory (ABM) and the recollective experience in amnestic mild cognitive impairment (aMCI). aMCI participants exhibited significant deficits compared with healthy elderly controls for both personal semantic and event detail components of ABM. These decrements were evident across all life epochs for episodic recall. Recall of an event that occurred 1 week previously, was tested in the same spatiotemporal context, and provided the greatest group dissociation, with elderly controls benefitting from a context-dependent memory effect. This reinstantiation of context did not ameliorate the anterograde deficits in the aMCI cohort, nor did it facilitate the mental reliving of these memories for either participant group. Whereas reliving judgments were comparable in both groups, aMCI participants exhibited a compromised capacity to generate vivid, self-referential visual imagery and to re-experience the original emotion of events. These contextual and experiential deficits extended beyond recently encountered events into remote epochs, and suggest a greater level of ABM impairment in aMCI than previously assumed.

Investigating the enhancing effect of music on autobiographical memory in mild Alzheimer's disease.

The enhancing effect of music on autobiographical memory recall in mild Alzheimer's disease individuals (n = 10; Mini-Mental State Examination score >17/30) and healthy elderly matched individuals (n = 10; Mini-Mental State Examination score 25-30) was investigated. Using a repeated-measures design, each participant was seen on two occasions: once in music condition (Vivaldi's 'Spring' movement from 'The Four Seasons') and once in silence condition, with order counterbalanced. Considerable improvement was found for Alzheimer individuals' recall on the Autobiographical Memory Interview in the music condition, with an interaction for condition by group (p < 0.005). There were no differences in terms of overall arousal using galvanic skin response recordings or attentional errors during the Sustained Attention to Response Task. A significant reduction in state anxiety was found on the State Trait Anxiety Inventory in the music condition (p < 0.001), suggesting anxiety reduction as a potential mechanism underlying the enhancing effect of music on autobiographical memory recall.