A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol.

BACKGROUND: Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer's Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60-79 years) at increased risk of dementia. METHODS: MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. CONCLUSION: MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05109169).

Computerized cognitive training in people with depression: a protocol for a systematic review and meta-analysis.

BACKGROUND: People with depression often present with concurrent cognitive impairment. Computerized cognitive training (CCT) is a safe and efficacious strategy to maintain or enhance cognitive performance in a range of clinical populations. However, its efficacy in people with depression and how it varies across populations and design factors are currently unclear. METHODS: We searched MEDLINE, EMBASE, and PsycINFO from inception to 13 July 2021 for randomised controlled trials examining the efficacy of CCT vs any control condition on cognitive, mood, psychiatric symptoms, psychosocial, and daily functioning in adults with depression. Eligible samples include studies specifically targeting people with major depressive disorder as well as those with other diagnoses where at least 50% of the sample meets the clinical criteria for depression, with the exception of major psychiatric disorders or dementia. The primary outcome is change in the overall cognitive performance. Multivariate analyses will be used to examine the effect sizes on each outcome category as well as possible effect modifiers and correlations between categories. The risk of bias will be assessed using the Cochrane risk of bias tool version 2. DISCUSSION: To the best of our knowledge, this will be the first systematic review and meta-analysis of narrowly defined CCT across clinical populations with depression. We aim to investigate not only whether CCT is efficacious for cognition, but also how such effects vary across design factors, what other clinically relevant outcomes might respond to CCT, and the extent to which they differ across populations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020204209.

Subjective cognitive complaints in patients with stress-related exhaustion disorder: a cross sectional study.

BACKGROUND: Stress-related exhaustion is associated with cognitive impairment as measured by both subjective cognitive complaints (SCCs) and objective cognitive test performance. This study aimed to examine how patients diagnosed with exhaustion disorder differ from healthy control participants in regard to levels and type of SCCs, and if SCCs are associated with cognitive test performance and psychological distress. METHODS: We compared a group of patients with stress-related exhaustion disorder (n = 103, female = 88) with matched healthy controls (n = 58, female = 47) cross-sectionally, concerning the type and magnitude of self-reported SCCs. We furthermore explored the association between SCCs and cognitive test performance as well as with self-reported depression, anxiety and burnout levels, in the patient and the control group, respectively. RESULTS: Patients reported considerably more cognitive failures and were more likely than controls to express memory failures in situations providing few external cues and reminders in the environment. In both groups, SCCs were associated with demographic and psychological factors, and not with cognitive test performance. CONCLUSION: Our findings underline the high burden of cognitive problems experienced by patients with exhaustion disorder, particularly in executively demanding tasks without external cognitive support. From a clinical perspective, SCCs and objective cognitive test performance may measure different aspects of cognitive functioning, and external cognitive aids could be of value in stress rehabilitation. TRIAL REGISTRATION: Participants were recruited as part of the Rehabilitation for Improved Cognition (RECO) study (ClinicalTrials.gov: NCT03073772). Date of registration: 8 March 2017.

Combined physical and cognitive training for older adults with and without cognitive impairment: A systematic review and network meta-analysis of randomized controlled trials.

Combining physical exercise with cognitive training is a popular intervention in dementia prevention trials and guidelines. However, it remains unclear what combination strategies are most beneficial for cognitive and physical outcomes. We aimed to compare the efficacy of the three main types of combination strategies (simultaneous, sequential or exergaming) to either intervention alone or control in older adults. Randomized controlled trials of combined cognitive and physical training were included in multivariate and network meta-analyses. In cognitively healthy older adults and mild cognitive impairment, the effect of any combined intervention relative to control was small and statistically significant for overall cognitive (k = 41, Hedges' g = 0.22, 95 % CI 0.14 to 0.30) and physical function (k = 32, g = 0.25, 95 % CI 0.13 to 0.37). Simultaneous training was the most efficacious approach for cognition, followed by sequential combinations and cognitive training alone, and significantly better than physical exercise. For physical outcomes, simultaneous and sequential training showed comparable efficacy as exercise alone and significantly exceeded all other control conditions. Exergaming ranked low for both outcomes. Our findings suggest that simultaneously and sequentially combined interventions are efficacious for promoting cognitive alongside physical health in older adults, and therefore should be preferred over implementation of single-domain training.

Computerised cognitive training in Parkinson's disease: a protocol for a systematic review and updated meta-analysis.

INTRODUCTION: Cognitive impairment is recognised as an important non-motor symptom in Parkinson's disease (PD) and there is a need for evidence-based non-pharmacological interventions that may prevent or slow cognitive decline in this patient group. One such intervention is computerised cognitive training (CCT), which has shown efficacious for cognition across older adult populations. This systematic review aims to investigate the efficacy of CCT across cognitive, psychosocial and functional domains for people with PD and examine study and intervention design factors that could moderate CCT effects on cognition. METHODS AND ANALYSIS: Randomised controlled trials investigating the effects of CCT in patients with PD without dementia, on cognitive, psychosocial or functional outcomes, will be included. The primary outcome is overall cognitive function. Secondary outcomes are domain-specific cognitive function, psychosocial functioning and functional abilities. We systematically searched MEDLINE, Embase and PsycINFO through 14 May 2020 to identify relevant literature. Risk of bias will be assessed using the revised Cochrane Risk of Bias tool. Effect sizes will be calculated as standardised mean difference of baseline to postintervention change (Hedges' g) with 95% CI for each eligible outcome measure. Pooling of outcomes across studies will be conducted using random-effects models, accounting for dependency structure of effect sizes within studies. Heterogeneity will be assessed using τ2 and I2 statistic. Potential moderators, based on key study and intervention design factors, will be investigated using mixed-effects meta-regression models. ETHICS AND DISSEMINATION: No ethical approval is required. The findings will be disseminated in a peer-reviewed scientific journal. PROSPERO REGISTRATION NUMBER: CRD42020185386.

Mental fatigue in stress-related exhaustion disorder: Structural brain correlates, clinical characteristics and relations with cognitive functioning.

Emerging evidence suggests that mental fatigue is a central component of the cognitive and clinical characteristics of stress-related exhaustion disorder (ED). Yet, the underlying mechanisms of mental fatigue in this patient group are poorly understood. The aim of this study was to investigate cortical and subcortical structural neural correlates of mental fatigue in patients with ED, and to explore the association between mental fatigue and cognitive functioning. Fifty-five patients with clinical ED diagnosis underwent magnetic resonance imaging. Mental fatigue was assessed using the Concentration subscale from the Checklist Individual Strength. Patients with high levels of mental fatigue (n = 30) had smaller caudate and putamen volumes compared to patients with low-moderate levels of mental fatigue (n = 25). No statistically significant differences in cortical thickness were observed between the groups. Mediation analysis showed that mental fatigue mediated the relationship between caudate volume and working memory; specifically, smaller caudate volume was associated with higher level of mental fatigue and mental fatigue was positively associated with working memory performance. Our findings demonstrate that the structural integrity of the striatum is of relevance for the subjective perception of mental fatigue in ED, while also highlighting the complex relationship between mental fatigue, cognitive performance and its neural underpinnings.

Cognition-Oriented Treatments for Older Adults: a Systematic Overview of Systematic Reviews.

Cognition-oriented treatments - commonly categorized as cognitive training, cognitive rehabilitation and cognitive stimulation - are promising approaches for the prevention of cognitive and functional decline in older adults. We conducted a systematic overview of meta-analyses investigating the efficacy of cognition-oriented treatments on cognitive and non-cognitive outcomes in older adults with or without cognitive impairment. Review quality was assessed by A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR). We identified 51 eligible reviews, 46 of which were included in the quantitative synthesis. The confidence ratings were "moderate" for 9 (20%), "low" for 13 (28%) and "critically low" for 24 (52%) of the 46 reviews. While most reviews provided pooled effect estimates for objective cognition, non-cognitive outcomes of potential relevance were more sparsely reported. The mean effect estimate on cognition was small for cognitive training in healthy older adults (mean Hedges' g = 0.32, range 0.13-0.64, 19 reviews), mild cognitive impairment (mean Hedges' g = 0.40, range 0.32-0.60, five reviews), and dementia (mean Hedges' g = 0.38, range 0.09-1.16, seven reviews), and small for cognitive stimulation in dementia (mean Hedges' g = 0.36, range 0.26-0.44, five reviews). Meta-regression revealed that higher AMSTAR score was associated with larger effect estimates for cognitive outcomes. The available evidence supports the efficacy of cognition-oriented treatments improving cognitive performance in older adults. The extent to which such effects are of clinical value remains unclear, due to the scarcity of high-quality evidence and heterogeneity in reported findings. An important avenue for future trials is to include relevant non-cognitive outcomes in a more consistent way and, for meta-analyses in the field, there is a need for better adherence to methodological standards. PROSPERO registration number: CRD42018084490.

Neural activation in stress-related exhaustion: Cross-sectional observations and interventional effects.

The primary purpose of this study was to investigate the association between burnout and neural activation during working memory processing in patients with stress-related exhaustion. Additionally, we investigated the neural effects of cognitive training as part of stress rehabilitation. Fifty-five patients with clinical diagnosis of exhaustion disorder were administered the n-back task during fMRI scanning at baseline. Ten patients completed a 12-week cognitive training intervention, as an addition to stress rehabilitation. Eleven patients served as a treatment-as-usual control group. At baseline, burnout level was positively associated with neural activation in the rostral prefrontal cortex, the posterior parietal cortex and the striatum, primarily in the 2-back condition. Following stress rehabilitation, the striatal activity decreased as a function of improved levels of burnout. No significant association between burnout level and working memory performance was found, however, our findings indicate that frontostriatal neural responses related to working memory were modulated by burnout severity. We suggest that patients with high levels of burnout need to recruit additional cognitive resources to uphold task performance. Following cognitive training, increased neural activation was observed during 3-back in working memory-related regions, including the striatum, however, low sample size limits any firm conclusions.

Effects of a process-based cognitive training intervention for patients with stress-related exhaustion.

Stress-related exhaustion has been linked to a pattern of selective cognitive impairments, mainly affecting executive functioning, attention and episodic memory. Little is known about potential treatments of these cognitive deficits. The purpose of this study was to evaluate the effects of a process-based cognitive training intervention, designed to target the specific cognitive impairments associated with stress-related exhaustion. To this end, patients diagnosed with exhaustion disorder (ED) were randomized to either a multimodal stress rehabilitation program with the addition of a process-based cognitive training intervention (training group, n = 27) or a treatment-as-usual control condition, consisting of multimodal stress rehabilitation with no additional training (control group, n = 32). Treatment effects were evaluated through an extensive cognitive test battery, assessing both near and far transfer effects, as well as self-report forms regarding subjective cognitive complaints and burnout levels. Results showed pronounced training-related improvements on the criterion updating task (p < 0.001). Further, evidence was found of selective near transfer effects to updating (p = 0.01) and episodic memory (p = 0.04). Also, the trained group reported less subjective memory complaints (p = 0.02) and levels of burnout decreased for both groups, but more so for the trained group (p = 0.04), following the intervention. These findings suggest that process-based cognitive training may be a viable method to address the cognitive impairments associated with ED.

Effects of a process-based cognitive training intervention for patients with stress-related exhaustion.

Stress-related exhaustion has been linked to a pattern of selective cognitive impairments, mainly affecting executive functioning, attention and episodic memory. Little is known about potential treatments of these cognitive deficits. The purpose of this study was to evaluate the effects of a process-based cognitive training intervention, designed to target the specific cognitive impairments associated with stress-related exhaustion. To this end, patients diagnosed with exhaustion disorder (ED) were randomized to either a multimodal stress rehabilitation program with the addition of a process-based cognitive training intervention (training group, n = 27) or a treatment-as-usual control condition, consisting of multimodal stress rehabilitation with no additional training (control group, n = 32). Treatment effects were evaluated through an extensive cognitive test battery, assessing both near and far transfer effects, as well as self-report forms regarding subjective cognitive complaints and burnout levels. Results showed pronounced training-related improvements on the criterion updating task (p < 0.001). Further, evidence was found of selective near transfer effects to updating (p = 0.01) and episodic memory (p = 0.04). Also, the trained group reported less subjective memory complaints (p = 0.02) and levels of burnout decreased for both groups, but more so for the trained group (p = 0.04), following the intervention. These findings suggest that process-based cognitive training may be a viable method to address the cognitive impairments associated with ED.