Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial

Background: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer’s disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. Methods: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. Discussion: The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer’s disease

The feasibility of a cognitive behavioural therapy group for men with mild/moderate cognitive impairment

Memory aid groups have often been used as a method for teaching mnemonic strategies to older adults in early stages of dementia. This study describes the use of CBT to address unhelpful memory-related beliefs in three older men with mild/moderate dementia and associated low mood or anxiety. The members were able to participate and engage in the sessions, and changes in behaviour, cognition and affect were monitored over the course of a 7 week group intervention. Recommendations are made for further research

REMCARE : pragmatic multi-centre randomised trial of reminiscence groups for people with dementia and their family carers : effectiveness and economic analysis

Background Joint reminiscence groups, involving people with dementia and family carers together, are popular, but the evidence-base is limited. This study aimed to assess the effectiveness and cost-effectiveness of joint reminiscence groups as compared to usual care. Methods This multi-centre, pragmatic randomised controlled trial had two parallel arms: intervention group and usual-care control group. A restricted dynamic method of randomisation was used, with an overall allocation ratio of 1:1, restricted to ensure viable sized intervention groups. Assessments, blind to treatment allocation, were carried out at baseline, three months and ten months (primary end-point), usually in the person's home. Participants were recruited in eight centres, mainly through NHS Memory Clinics and NHS community mental health teams. Included participants were community resident people with mild to moderate dementia (DSM-IV), who had a relative or other care-giver in regular contact, to act as informant and willing and able to participate in intervention. 71% carers were spouses. 488 people with dementia (mean age 77.5) were randomised: 268 intervention, 220 control; 350 dyads completed the study (206 intervention, 144 control). The intervention evaluated was joint reminiscence groups (with up to 12 dyads) weekly for twelve weeks; monthly maintenance sessions for further seven months. Sessions followed a published treatment manual and were held in a variety of community settings. Two trained facilitators in each centre were supported by volunteers. Primary outcome measures were self-reported quality of life for the person with dementia (QoL-AD), psychological distress for the carer (General Health Questionnaire, GHQ-28). Secondary outcome measures included: autobiographical memory and activities of daily living for the person with dementia; carer stress for the carer; mood, relationship quality and service use and costs for both. Results The intention to treat analysis (ANCOVA) identified no differences in outcome between the intervention and control conditions on primary or secondary outcomes (self-reported QoL-AD mean difference 0.07 (-1.21 to 1.35), F = 0.48, p = 0.53). Carers of people with dementia allocated to the reminiscence intervention reported a significant increase in anxiety on a General Health Questionnaire-28 sub-scale at the ten month end-point (mean difference 1.25 (0.25 to 2.26), F = 8.28, p = 0.04). Compliance analyses suggested improved autobiographical memory, quality of life and relationship quality for people with dementia attending more reminiscence sessions, however carers attending more groups showed increased care-giving stress. Economic analyses from a public sector perspective indicated that joint reminiscence groups are unlikely to be cost-effective. There were no significant adverse effects attributed to the intervention. Potential limitations of the study include less than optimal attendance at the group sessions—only 57% of participants attended at least half of the intervention sessions over the 10 month period, and a higher rate of study withdrawal in the control group. Conclusions This trial does not support the clinical effectiveness or cost-effectiveness of joint reminiscence groups. Possible beneficial effects for people with dementia who attend sessions as planned are offset by raised anxiety and stress in their carers. The reasons for these discrepant outcomes need to be explored further, and may necessitate reappraisal of the movement towards joint interventions

Study protocol for a randomised, controlled platform trial estimating the effect of autobiographical Memory Flexibility training (MemFlex) on relapse of recurrent major depressive disorder.

INTRODUCTION: Major depressive disorder (MDD) is a chronic condition. Although current treatment approaches are effective in reducing acute depressive symptoms, rates of relapse are high. Chronic and inflexible retrieval of autobiographical memories, and in particular a bias towards negative and overgeneral memories, is a reliable predictor of relapse. This randomised controlled single-blind trial will determine whether a therapist-guided self-help intervention to ameliorate autobiographical memory biases using Memory Flexibility training (MemFlex) will increase the experience of depression-free days, relative to a psychoeducation control condition, in the 12 months following intervention. METHODS AND ANALYSIS: Individuals (aged 18 and above) with a diagnosis of recurrent MDD will be recruited when remitted from a major depressive episode. Participants will be randomly allocated to complete 4 weeks of a workbook providing either MemFlex training, or psychoeducation on factors that increase risk of relapse. Assessment of diagnostic status, self-report depressive symptoms, depression-free days and cognitive risk factors for depression will be completed post-intervention, and at 6 and 12 months follow-up. The cognitive target of MemFlex will be change in memory flexibility on the Autobiographical Memory Test- Alternating Instructions. The primary clinical endpoints will be the number of depression-free days in the 12 months following workbook completion, and time to depressive relapse. ETHICS AND DISSEMINATION: Ethics approval has been granted by the NHS National Research Ethics Committee (East of England, 11/H0305/1). Results from this study will provide a point-estimate of the effect of MemFlex on depressive relapse, which will be used to inform a fully powered trial evaluating the potential of MemFlex as an effective, low-cost and low-intensity option for reducing relapse of MDD. TRIAL REGISTRATION NUMBER: NCT02614326

Positive and Negative Sources of Emotional Arousal Enhance Long-Term Word-List Retention When Induced as Long as 30 Min After Learning

The consolidation of newly formed memories occurs slowly, allowing memories to be altered by experience for some time after their formation. Various treatments, including arousal, can modulate memory consolidation when given soon after learning, but the degree of time-dependency of these treatments in humans has not been studied. Thus, 212 participants learned a word list, which was followed by either a positively or negatively valenced arousing video clip (i.e., comedy or surgery, respectively) after delays of 0, 10, 30 or 45 min. Arousal of either valence induced up to 30 min after learning, but not after 45 min, significantly enhanced one-week retrieval. The findings support (1) the time-dependency of memory modulation in humans and (2) other studies that suggest that it is the degree of arousal, rather than valence that modulates memory. Important implications for developing memory intervention strategies and for preserving and validating witness testimony are discussed

Moderators, mediators and nonspecific predictors of outcome after cognitive rehabilitation of executive functions in a randomised controlled trial

Moderators, mediators and nonspecific predictors of treatment after cognitive rehabilitation of executive functions in a randomised controlled trial Objective: To explore moderators, mediators and nonspecific predictors of executive functioning after cognitive rehabilitation in a randomised controlled trial, comparing Goal Management Training (GMT) with an active psycho-educative control-intervention, in patients with chronic acquired brain injury. Methods: Seventy patients with executive dysfunction were randomly allocated to GMT (n = 33) or control (n = 37). Outcome measures were established by factor-analysis and included cognitive executive complaints, emotional dysregulation and psychological distress. Results: Higher age and IQ emerged as nonspecific predictors. Verbal memory and planning ability at baseline moderated cognitive executive complaints, while planning ability at six-month follow-up mediated all three outcome measures. Inhibitory cognitive control emerged as a unique GMT specific mediator. A general pattern regardless of intervention was identified; higher levels of self-reported cognitive—and executive–symptoms of emotional dysregulation and psychological distress at six-month follow-up mediated less improvement across outcome factors. Conclusions: The majority of treatment effects were nonspecific to intervention, probably underscoring the variables’ general contribution to outcome of cognitive rehabilitation interventions. Interventions targeting specific cognitive domains, such as attention or working memory, need to take into account the patients’ overall cognitive and emotional self-perceived functioning. Future studies should investigate the identified predictors further, and also consider other predictor candidates

Pushing the Limits: Cognitive, Affective, and Neural Plasticity Revealed by an Intensive Multifaceted Intervention.

Scientific understanding of how much the adult brain can be shaped by experience requires examination of how multiple influences combine to elicit cognitive, affective, and neural plasticity. Using an intensive multifaceted intervention, we discovered that substantial and enduring improvements can occur in parallel across multiple cognitive and neuroimaging measures in healthy young adults. The intervention elicited substantial improvements in physical health, working memory, standardized test performance, mood, self-esteem, self-efficacy, mindfulness, and life satisfaction. Improvements in mindfulness were associated with increased degree centrality of the insula, greater functional connectivity between insula and somatosensory cortex, and reduced functional connectivity between posterior cingulate cortex (PCC) and somatosensory cortex. Improvements in working memory and reading comprehension were associated with increased degree centrality of a region within the middle temporal gyrus (MTG) that was extensively and predominately integrated with the executive control network. The scope and magnitude of the observed improvements represent the most extensive demonstration to date of the considerable human capacity for change. These findings point to higher limits for rapid and concurrent cognitive, affective, and neural plasticity than is widely assumed

A systematic review of recommended modifications of CBT for people with cognitive impairments following brain injury

Due to diverse cognitive, emotional and interpersonal changes that can follow brain injury, psychological therapies often need to be adapted to suit the complex needs of this population. The aims of the study were to synthesise published recommendations for therapy modifications following brain injury from non-progressive traumatic, vascular, or metabolic causes and to determine how often such modifications have been applied to cognitive behavioural therapy (CBT) for post-injury emotional adjustment problems. A systematic review and narrative synthesis of therapy modifications recommended in review articles and reported in intervention studies was undertaken. Database and manual searches identified 688 unique papers of which eight review articles and 16 intervention studies met inclusion criteria. The review articles were thematically analysed and a checklist of commonly recommended modifications composed. The checklist items clustered under themes of: therapeutic education and formulation; attention; communication; memory; and executive functioning. When this checklist was applied to the intervention studies, memory aids and an emphasis on socialising patients to the CBT model were most frequently reported as adaptations. It was concluded that the inconsistent reporting of psychological therapy adaptations for people with brain injury is a barrier to developing effective and replicable therapies. We present a comprehensive account of potential modifications that should be used to guide future research and practice