Randomised controlled decentralised feasibility trial of a fixed low-dose combination antihypertensive drug strategy to attenuate cognitive decline in high-risk adults.

OBJECTIVES: The Action To promote brain HEalth iN Adults study aimed to determine the feasibility and applicability of recruitment using home blood pressure (BP) monitoring, routine blood biochemistry and videoconference measures of cognition, in adults at high risk of dementia. DESIGN: A decentralised double-blind, placebo-controlled, randomised feasibility trial with a four-stage screening process. SETTING: Conducted with participants online in the state of New South Wales, Australia. PARTICIPANTS: Participants were aged 50-70 years with moderately elevated BP (systolic >120 and <160 mm Hg or diastolic >80 and <95 mm Hg) and ≥1 additional enrichment risk factor of monotherapy treatment of hypertension, diabetes mellitus, elevated low-density lipoprotein cholesterol, obesity, current smoking or a first degree relative with dementia, which indicated an elevated risk for future cognitive decline. INTERVENTION: Triple Pill (active antihypertensive treatment of telmisartan 20 mg, amlodipine 2.5 mg and indapamide 1.25 mg) or placebo Triple Pill (blinded study capsules). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was feasibility of the study expressed as the percentage of participants randomised from those who were screened. Secondary outcomes were the applicability of videoconference measures of cognition and the overall trial, tolerability of the Triple Pill, safety outcomes and medication adherence. RESULTS: The proportion (95% CI) of patients randomised to those screened was 5% (2%-10%). The applicability of the trial expressed as percentage of those who completed all remote assessments over the number of randomised participants was 67% (95% CI 05 to 22%). There were no serious adverse events or withdrawals from treatment. All participants adhered to study medication, except for one person who had two capsules left at the end of the study period. CONCLUSIONS: The feasibility of this decentralised trial on BP lowering in patients at high risk for dementia is low. However, the applicability of remote assessments of cognitive function is acceptable. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000121864.

Obesity and Oxidative Stress in Older Adults At Risk for Dementia: A Magnetic Resonance Spectroscopy Study.

OBJECTIVE: This study aimed to investigate the relationship between obesity and oxidative stress in older adults at risk for dementia. It also aimed to explore the influence of physical activity on the relationship between obesity and oxidative stress in this at risk cohort. METHODS: Older adults at risk for dementia underwent comprehensive medical, neuropsychological, and psychiatric assessment. At risk was defined as participants with subjective or mild cognitive impairment. Glutathione was assessed by magnetic resonance spectroscopy in the left hippocampus and the anterior and posterior cingulate cortex. Body mass index (BMI) was calculated and classified as healthy (BMI <25 kg/m2) or overweight/obese (BMI ≥25 kg/m2). RESULTS: Sixty-five older adults (mean age=66.2 y) were included for analysis. The overweight/obese group had significantly greater glutathione in the hippocampus compared with the healthy weight group (t=-2.76, P=0.008). No significant difference in glutathione was observed between groups in the anterior or posterior cingulate. In the overweight/obese group, a higher BMI was associated with a diabetes diagnosis and lower total time engaging in physical activity (r=-0.36, P=0.025), however, glutathione did not correlate with activity levels across groups. CONCLUSION: This study demonstrates that changes in in vivo markers of oxidative stress are present in overweight/obese older adults at risk for dementia. Future research should explore the relationship with diabetes and the longitudinal relationship between BMI and oxidative stress, and response to therapeutic interventions.

Prevalence and patterns of cognitive impairment in acute coronary syndrome patients: A systematic review.

BACKGROUND: Minimising risk factors through secondary prevention behaviour is challenging for patients following an acute coronary syndrome. Cognitive impairment can potentially make these changes more difficult. However, cognitive impairment prevalence in acute coronary syndrome patients is poorly understood. DESIGN: This study was based on a systematic review. METHODS: A systematic review was conducted of PubMed, Medline, PsycINFO and Cochrane databases up to March 2019, to identify studies reporting the prevalence of cognitive impairment in acute coronary syndrome patients. Predefined inclusion criteria were specified, including use of a validated cognitive impairment screening tool. Studies were excluded if patients had diagnosed dementia or coronary artery bypass graft surgery. Strengthening The Reporting of Observational Studies in Epidemiology and Cochrane Risk of Bias tools were used to assess quality. RESULTS: From 747 potential studies, nine were included. The total sample size was 6457 (range 53-2174), mean age range was 51.3-77.4 years, and range of proportions of males was 57-100%. Reported cognitive impairment prevalence rates varied substantially (9-85%) with no clear pattern over time. From the two studies which examined domains, verbal fluency, memory and language were affected the most. Meta-analysis could not be undertaken due to diverse screening tools (n = 9), cut-off scores and screening timepoints. CONCLUSIONS: Cognitive impairment in acute coronary syndrome patients is currently poorly described, and likely affects a substantial number of acute coronary syndrome patients who remain undetected and have the potential to develop to dementia in the future. As domains are most affected, this could impact understanding and retention of health education. Research is needed to accurately determine the prevalence of cognitive impairment in acute coronary syndrome patients and create suitable standardised measures and thresholds.

Reducing risk factors for cognitive decline through psychological interventions: a pilot randomized controlled trial.

OBJECTIVES: Modifiable factors associated with increased risk of cognitive decline include emotional (anxiety, depression), cognitive (low social and mental stimulation), and health factors (smoking, alcohol use, sedentary lifestyle, obesity). Older adults with anxiety and depression may be at heightened risk due to direct and indirect impacts of emotional distress on cognitive decline. DESIGN: Randomized controlled trial. SETTING: Community sample attending a university clinic. Participants: 27 participants (female = 20) aged over 65 years (M = 72.56, SD = 6.74) with an anxiety and/or mood disorder. Interventions: two cognitive behavioral therapy (CBT) interventions (face-to-face or low intensity) that targeted emotional, health, and cognitive risks for cognitive decline. MEASUREMENTS: Participants completed diagnostic interviews; self-report measures of anxiety, depression, quality of life, and lifestyle factors at baseline; post-treatment; and 3-month follow-up. RESULTS: Both interventions resulted in significant and sustained improvements in depression, anxiety, quality of life, and physical and social activity. At post-treatment, face-to-face CBT demonstrated significantly greater improvements in emotional symptoms, alcohol use, and memory (exercise approached significance). At 3-month follow-up, gains were maintained and there were significantly greater increases in mental activity for face-to-face CBT, with social activity approaching significance. Conclusions: This study demonstrates the feasibility of CBT interventions to reduce emotional as well as lifestyle risk factors associated with cognitive decline in at-risk older participants. Large studies are needed to evaluate the long-term impact on cognitive decline. The trial was registered with the Australian and New Zealand Clinical Trials Registry (Trial Registration No. ACTRN12618000939291).

Impaired Neurobehavioural Performance in Untreated Obstructive Sleep Apnea Patients Using a Novel Standardised Test Battery.

OBJECTIVE/BACKGROUND: Although polysomnography (PSG) is the gold-standard measure for assessing disease severity in obstructive sleep apnea (OSA), it has limited value in identifying individuals experiencing significant neurobehavioural dysfunction. This study used a brief and novel computerised test battery to examine neurobehavioural function in adults with and without OSA. PATIENTS/METHODS: 204 patients with untreated OSA [age 49.3 (12.5) years; body mass index, [BMI] 33.6 (8.0) kg/m2; Epworth sleepiness scale 12 (4.9)/24; apnea hypopnea index 33.6 (25.8)/h] and 50 non-OSA participants [age 39.2 (14.0) years; BMI 25.8 (4.2) kg/m2, ESS 3.6 (2.3)/24]. All participants completed a computerised neurobehavioural battery during the daytime in the sleep clinic. The OSA group subsequently underwent an overnight PSG. The 30 min test battery assessed cognitive domains of visual spatial scanning and selective attention (Letter Cancellation Test), executive function (Stroop task) and working memory (2- and 3-Back tasks), and a validated sustained attention task (psychomotor vigilance task, PVT). Group differences in performance were compared. Associations between disease severity and performance were examined in the OSA group. RESULTS: After controlling for age, gender and education, OSA patients demonstrated impaired performance on the Stroop-Text, 2 and 3-Back tasks, and the PVT compared with the non-OSA group. OSA patients had worse performance on the LCT with fewer average hits albeit with better accuracy. Some OSA polysomnographic disease severity measures were weakly correlated with performance. CONCLUSIONS: This brief test battery may provide a sensitive, standardised method of assessing daytime dysfunction in OSA.

Cognitive Training in Parkinson's Disease.

Cognitive impairment is now widely accepted as a fundamental aspect of Parkinson's disease (PD). Given the prevalence of cognitive impairment and the associated impact on well-being, evidence-based interventions are needed. However, while research is continually accumulating in order to better understand the pathology and trajectory of cognitive changes, treatment options lag behind. Nonpharmacological approaches are of particular interest in this group, given the typical polypharmacy already present in PD patients. In this regard, cognitive training (CT) is a relatively new and prominent therapeutic option with accumulating scientific support and increasing public awareness. Research has now established benefits across many different populations, and trials investigating the use of CT specifically in PD are becoming more common. We offer a brief summary of CT and its efficacy in PD samples to date, as well as discuss areas requiring further exploration in this group. Crucially, we suggest that CT should be supported as a research priority in PD, given both proven and potential benefits as a noninvasive and well-tolerated behavioral intervention for cognitive impairment.

Association of Anterior Cingulate Glutathione with Sleep Apnea in Older Adults At-Risk for Dementia.

STUDY OBJECTIVES: Sleep disordered breathing (SDB) is common in older adults and is strongly associated with cognitive decline, with increasing evidence suggesting that it may represent a risk factor for dementia. Given that SDB is characterized by intermittent episodes of hypoxemia during sleep, it is possible that cognitive impairment may relate to cerebral oxidative stress. This study aimed to examine the relationship between nocturnal markers of hypoxemia and proton magnetic resonance spectroscopy ((1)H-MRS) markers of oxidative stress within the anterior cingulate cortex (ACC) of the brain. METHODS: Twenty-four older adults (mean age = 67.9 y) at-risk for dementia were recruited from our Healthy Brain Ageing Research Clinic. At-risk was defined as participants seeking help for assessment and/or intervention for cognitive decline, including those with subjective and/or objective cognitive complaints. This could occur in the context of prior depression or risk factors (e.g., vascular) for dementia. All participants underwent psychiatric, medical and neuropsychological assessment followed by overnight polysomnography. In addition, participants underwent (1)H-MRS to derive levels of ACC metabolite glutathione (GSH) reported as a ratio to creatine (GSH/Cr). RESULTS: Increased levels of GSH/Cr were associated with lower oxygen desaturation (r = -0.54, P = 0.007) and more severe apnea-hypopnea index scores during rapid eye movement sleep (r = 0.42, P = 0.050). In addition, ACC GSH/Cr correlated with poorer executive functioning (i.e., response inhibition: r = -0.49, P = 0.015; set shifting: r = -0.43, P = 0.037). CONCLUSIONS: Markers of nocturnal hypoxemia and SDB are associated with cerebral oxidative stress in older people at-risk for dementia, suggesting a potential mechanism by which SDB may contribute to brain degeneration, cognitive decline, and dementia. Further work focused on utilizing this biomarker for the early identification and treatment of this possible modifiable risk factor in older persons is now warranted.

Antisaccade errors reveal cognitive control deficits in Parkinson's disease with freezing of gait.

Freezing of gait is a poorly understood symptom of Parkinson's disease (PD) that is commonly accompanied by executive dysfunction. This study employed an antisaccade task to measure deficits in inhibitory control in patients with freezing, and to determine if these are associated with a specific pattern of grey matter loss using voxel-based morphometry. PD patients with (n = 15) and without (n = 11) freezing along with 10 age-matched controls were included. A simple prosaccade task was administered, followed by a second antisaccade task that required subjects to either look towards or away from a peripheral target. Behavioral results from the antisaccade task were entered as covariates in the voxel-based morphometry analysis. Patient and control groups performed equally well on the first task. However, patients with freezing were significantly worse on the second, which was driven by a specific impairment in suppressing their responses toward the target on the antisaccade trials. Impaired antisaccade performance was associated with grey matter loss across bilateral visual and fronto-parietal regions. These results suggest that patients with freezing have a significant deficit of inhibitory control that is associated with volume reductions in regions crucial for orchestrating both complex motor behaviors and cognitive control. These findings highlight the inter-relationship between freezing of gait and cognition and confirm that dysfunction along common neural pathways is likely to mediate the widespread cognitive dysfunction that emerges with this symptom.

The effect of 12-wk ω-3 fatty acid supplementation on in vivo thalamus glutathione concentration in patients "at risk" for major depression.

OBJECTIVES: As life expectancy increases, the need to prevent major health disorders is clear. Depressive symptoms are common in older adults and are associated with cognitive decline and greater risk for transitioning to major depression. Oxidative stress may be implicated in the pathophysiology of major depression and can be measured in vivo using proton magnetic resonance spectroscopy via the neurometabolite glutathione (GSH). Evidence suggests ω-3 fatty acid (FA) supplementation may prevent depression and directly affect GSH concentration. The aim of this study was to examine the effect of ω-3 FA supplementation on in vivo GSH concentration in older adults at risk for depression. METHODS: Fifty-one older adults at risk for depression were randomized to receive either four 1000-mg ω-3 FA supplements daily (containing eicosapentaenoic acid 1200 mg plus docosahexaenoic acid 800 mg) or placebo (four 1000-mg paraffin oil placebo capsules daily) for 12 wk. Participants underwent magnetic resonance spectroscopy, as well as medical, neuropsychological, and self-report assessments at baseline and after 12 wk of supplementation. GSH was measured in the thalamus and calculated as a ratio to creatine. Depressive symptoms were measured using the Patient Health Questionnaire. RESULTS: Compared with the group given the ω-3 FA supplements, the placebo group had greater change in the GSH-to-creatine ratio in the thalamus (t = 2.00; P = 0.049) after the 12 wk intervention. This increase was in turn associated with a worsening of depressive symptoms (r = 0.43; P = 0.043). CONCLUSIONS: Depressive symptom severity in older adults appears to be associated with increased brain levels of GSH, a key marker of oxidative stress. Importantly, ω-3 FA supplementation may attenuate oxidative stress mechanisms, thereby offering benefits for depression prevention.

Oxidative stress and depressive symptoms in older adults: A magnetic resonance spectroscopy study.

Major depression is common in older adults and associated with greater health care utilisation and increased risk of poor health outcomes. Oxidative stress may be implicated in the pathophysiology of depression and can be measured via the neurometabolite glutathione using proton magnetic resonance spectroscopy ((1)H-MRS). This study aimed to examine the relationship between glutathione concentration and depressive symptom severity in older adults 'at-risk' of depression. In total, fifty-eight older adults considered 'at-risk' of depression (DEP) and 12 controls underwent (1)H-MRS, medical and neuropsychological assessments. Glutathione was measured in the anterior cingulate cortex (ACC), and calculated as a ratio to creatine. Depressive and anxiety symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS). Compared to controls, DEP patients had increased glutathione/creatine ratios in the ACC (t=2.7, p=0.012). In turn, these increased ratios were associated with greater depressive symptoms (r=0.28, p=0.038), and poorer performance on a verbal learning task (r=-0.28, p=0.040). In conclusion, depressive symptoms in older people are associated with increased glutathione in the ACC. Oxidative stress may be pathophysiologically linked to illness development and may represent an early compensatory response. Further research examining the utility of glutathione as a marker for depressive symptoms and cognitive decline is now required.

Body mass, cardiovascular risk and metabolic characteristics of young persons presenting for mental healthcare in Sydney, Australia.

OBJECTIVES: To determine the body mass, cardiovascular and metabolic characteristics of young people presenting for mental healthcare. DESIGN: Cross-sectional assessments of body mass, cardiovascular and metabolic risk factors. SETTING: Two primary-care based sites in Sydney, Australia for young people in the early stages of mental disorders. PARTICIPANTS: A clinical sample of young people (12-30 years) with mental health problems. OUTCOME MEASURES: Daily smoking rates, body mass index (BMI), blood glucose and lipids, blood pressure (BP) and pulse rate. RESULTS: Of 1005 young people who had their BMI determined (62% female; 19.0±3.5 years), three quarters (739/1005) also had BP recordings and one-third (298/1005) had blood sampling. Clinically, 775 were assigned to one of three diagnostic categories (anxious-depression: n=541; mania-fatigue, n=104; developmental-psychotic n=130). The profile of BMI categories approximated that of the comparable segments of the Australian population. Older age, lower levels of social functioning and higher systolic BP were all associated with high BMI. In a subset (n=129), current use of any psychotropic medication was associated (p<0.05) with increased BMI. Almost one-third of cases were current daily smokers (compared to population rate of 11%). Males had a higher proportion of raised glucose and high-density lipoprotein (HDL) compared to females (9.3% and 34.1% vs 2.1% and 5.9%, respectively). Overall, there was no relationship between BMI and fasting glucose but significant relationships with triglycerides and HDL were noted. Furthermore, there were no significant relationships between diagnostic subgroup and metabolic profiles. CONCLUSIONS: Daily smoking rates are increased among young people presenting for mental healthcare. However, these young people do not demonstrate adverse cardiometabolic profiles. The high levels of smoking, and association of BMI with adverse social circumstances, suggest that risk factors for chronic disease are already present and likely to be compounded by medication and social disadvantage.

Delayed circadian phase is linked to glutamatergic functions in young people with affective disorders: a proton magnetic resonance spectroscopy study.

BACKGROUND: While the association between affective disorders and sleep and circadian disturbance is well established, little is known about the neurobiology underpinning these relationships. In this study, we sought to determine the relationship between a marker of circadian rhythm and neuronal integrity (N-Acetyl Aspartate, NAA), oxidative stress (glutathione, GSH) and neuronal-glial dysfunction (Glutamate + Glutamine, Glx). METHODS: Fifty-three young adults (age range 15-33 years, mean = 21.8, sd = 4.3) with emerging affective disorders were recruited from a specialized tertiary referral service. Participants underwent clinical assessment and actigraphy monitoring, from which sleep midpoint was calculated as a marker of circadian rhythm. Proton magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC). The metabolites NAA, GSH and Glx were obtained, and expressed as a ratio to Creatine. RESULTS: Neither NAA or GSH were associated with sleep midpoint. However, higher levels of ACC Glx were associated with later sleep midpoints (rho = 0.35, p = 0.013). This relationship appeared to be independent of age and depression severity. CONCLUSIONS: This study is the first to demonstrate that delayed circadian phase is related to altered glutamatergic processes. It is aligned with animal research linking circadian rhythms with glutamatergic neurotransmission as well as clinical studies showing changes in glutamate with sleep interventions. Further studies may seek to examine the role of glutamate modulators for circadian misalignment.

Cognitive impairment with and without depression history: an analysis of white matter microstructure.

BACKGROUND: Mild cognitive impairment (MCI) and late-life depression are clinical syndromes that often co-occur and may represent an early manifestation of neurodegenerative disease. The present study examined white matter microstructure in patients with MCI with and without a history of major depression compared with healthy controls. METHODS: Older adults with MCI and no history of major depression (MCI), adults with MCI and euthymic major depression (MCI-MD) and healthy controls underwent comprehensive medical, psychiatric and neuropsychological assessments. Participants also underwent diffusion tensor imaging, which was analyzed using tract-based spatial statistics. White matter hyperintensity (WMH) burden and medical burden were also quantified. RESULTS: We enrolled 30 participants in the MCI group, 36 in the MCI-MD group and 22 in the control group. Compared with controls, participants in the MCI group had significantly reduced fractional anisotropy (FA) in the corpus callosum, superior longitudinal fasciculus (SLF), corona radiata and posterior thalamic radiation. Participants in the MCI-MD group had significantly reduced FA in the corpus callosum, internal capsule, external capsule, corona radiata, posterior thalamic radiation, sagittal striatum, fornix, SLF, uncinate fasciculus and right cingulum compared with controls. No significant differences in FA were observed between the MCI and MCI-MD groups. Participants in the MCI-MD group had greater medical burden (p = 0.020) and WMH burden than controls (p = 0.013). LIMITATIONS: Study limitations include the cross-sectional design and antidepressant medication use. CONCLUSION: To our knowledge, this study is the first to compare white matter microstructure in patients with MCI with and without a history of major depression and suggests that a common underlying structural white matter change may underpin cognitive impairment in both MCI groups. Further research is needed to delineate the pathophysiological mechanisms underlying these microstructural changes.

Glutathione relates to neuropsychological functioning in mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) represents an at-risk state for Alzheimer's disease in which underlying pathophysiological mechanisms could be delineated. Oxidative stress has been implicated in Alzheimer's disease and can be measured by levels of the antioxidant glutathione. This study aims to assess in vivo levels of glutathione via proton magnetic resonance spectroscopy in patients with MCI and to determine how glutathione relates to cognitive decline. METHODS: Fifty-four patients with MCI and 41 healthy control subjects underwent proton magnetic resonance spectroscopy in conjunction with medical, psychiatric, and neuropsychological assessments. The concentration of glutathione was measured in the anterior and posterior cingulate, and ratios of glutathione were calculated relative to creatine. Neuropsychological performance was assessed across the domains of processing speed, learning, memory, and executive functions. RESULTS: In comparison with control subjects, patients with MCI had significantly elevated ratios of glutathione in the anterior (t = -2.2, P = .03) and posterior (t = -2.9, P = .005) cingulate. Higher levels of anterior cingulate glutathione were related to neuropsychological decrements on tests of executive functions. Elevated posterior cingulate glutathione was associated with poorer memory consolidation. CONCLUSION: This study has shown for the first time that MCI is associated with increased glutathione in the cingulate, which in turn relates to neuropsychological performance. This finding may be indicative of an early compensatory or neuroprotective response, and the role of glial cells and glutathione enzymes requires delineation. Longitudinal studies examining the utility of glutathione as a marker for cognitive decline are now required.

Subjective memory complaints, vascular risk factors and psychological distress in the middle-aged: a cross-sectional study.

BACKGROUND: Subjective memory complaints (SMC) are common but their significance is still unclear. It has been suggested they are a precursor of mild cognitive impairment (MCI) or dementia and an early indicator of cognitive decline. Vascular risk factors have an important role in the development of dementia and possibly MCI. We therefore aimed to test the hypothesis that vascular risk factors were associated with SMC, independent of psychological distress, in a middle-aged community-dwelling population. METHODS: A cross-sectional analysis of baseline data from the 45 and Up Study was performed. This is a cohort study of people living in New South Wales (Australia), and we explored the sample of 45, 532 participants aged between 45 and 64 years. SMC were defined as 'fair' or 'poor' on a self-reported five-point Likert scale of memory function. Vascular risk factors of obesity, diabetes, hypertension, hypercholesterolemia and smoking were identified by self-report. Psychological distress was measured by the Kessler Psychological Distress Scale. We tested the model generated from a randomly selected exploratory sample (n = 22, 766) with a confirmatory sample of equal size. RESULTS: 5, 479/45, 532 (12%) of respondents reported SMC. Using multivariate logistic regression, only two vascular risk factors: smoking (OR 1.18; 95% CI = 1.03 - 1.35) and hypercholesterolaemia (OR 1.19; 95% CI = 1.04 - 1.36) showed a small independent association with SMC. In contrast psychological distress was strongly associated with SMC. Those with the highest levels of psychological distress were 7.00 (95% CI = 5.41 - 9.07) times more likely to have SMC than the non-distressed. The confirmatory sample also demonstrated the strong association of SMC with psychological distress rather than vascular risk factors. CONCLUSIONS: In a large sample of middle-aged people without any history of major affective illness or stroke, psychological distress was strongly, and vascular risk factors only weakly, associated with SMC, although we cannot discount psychological distress acting as a mediator in any association between vascular risk factors and SMC. Given this, clinicians should be vigilant regarding the presence of an affective illness when assessing middle-aged patients presenting with memory problems.