Cognitive training for people with mild to moderate dementia (protocol)

This is the final version of the article. Available from Cochrane Collaboration / Wiley via the DOI in this record.The review version is in ORE at: http://hdl.handle.net/10871/36870This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the effects of cognitive training on cognitive and non-cognitive outcomes for people with mild to moderate dementia and their caregivers. To compare the effects of cognitive training with those of other non-pharmacological interventions, including cognitive stimulation or rehabilitation. To identify and explore factors related to intervention and trial design that may be associated with the efficacy of cognitive training.Internal sources • Cochrane Incentive Award, UK. External sources • NIHR, UK. This protocol was supported by the National Institute for Health Research (NIHR), via Cochrane Incentive funding Cochrane to the Cochrane Dementia and Cognitive Improvement group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, National Health Service or the Department of Health • National Health and Medical Research Council of Australia, Australi

Behavioral Effects of Inhibition of Cyclic Nucleotide Phosphodiesterase 2 (PDE2) in Mice

Cyclic nucleotide phosphodiesterases (PDEs) are a super-family of enzymes that regulate intracellular levels of the second messengers, cyclic AMP and cyclic GMP. Multiple PDEs have been shown to play vital roles in the central nervous system, with involvement in mood, reward mechanisms, and learning and memory. PDE2 is of special interest due to its high level of expression in forebrain regions, which are specifically implicated in mood and memory processes. In the first set of experiments, the potential role of PDE2 in depression- and anxiety-like behaviors was investigated using the forced swim test, tail suspension test, elevated plus maze, hole-board and step-through passive avoidance tests, as well as the object recognition test (ORT). The PDE2-selective inhibitor, Bay 60-7550 (3 mg/kg) did not significantly alter any of the depression- or anxiety-like behaviors, but did significantly enhance memory in the ORT. In the next set of experiments, the ORT was used to investigate the effect of PDE2 inhibition on various stages of learning and memory. Bay 60-7550 was administered 30-120 min prior to training, 0, 1, or 3 hrs after training, or 30 min prior to recall testing. Next, inhibitors of the cAMP or cGMP signaling pathways were administered 30 min prior to the PDE2 inhibitors Bay 60-7550 or ND7001, to assess the role cyclic nucleotide signaling on PDE2 inhibitor-enhanced memory. Finally, changes in the phosphorylation of CREB at Ser-133 and VASP at Ser-239 were determined to confirm activation of cAMP and cGMP signaling by PDE2 inhibition at behaviorally relevant doses. Bay 60-7550 (3 mg/kg) significantly enhanced memory of mice in the ORT when given 30 min prior to training, immediately after training, or 30 min prior to recall. Inhibitors of the cGMP pathway blocked the memory-enhancing effects of both Bay 60-7550 (3 mg/kg) and ND7001 (3 mg/kg). Bay 60-7550 (3 mg/kg) significantly enhanced the phosphorylation of CREB and VASP, both targets of PKG. While PDE2 inhibition did not appear to play a major role in depression- and anxiety-like behaviors in these tests, future research will further elucidate the role of PDE2 in other mood-related behavior tests. Additionally, PDE2 does appear to play a major role in learning and memory, as seen in the ORT. Developing a greater understanding of the role of PDE-2 in these memory processes will allow for potential drug development for the intervention of a variety of human diseases related to cognitive decline and memory impairment, which plague millions of individuals each year

Investigating the Correspondence of Clinical Diagnostic Grouping With Underlying Neurobiological and Phenotypic Clusters Using Unsupervised Machine Learning

Many brain-based disorders are traditionally diagnosed based on clinical interviews and behavioral assessments, which are recognized to be largely imperfect. Therefore, it is necessary to establish neuroimaging-based biomarkers to improve diagnostic precision. Resting-state functional magnetic resonance imaging (rs-fMRI) is a promising technique for the characterization and classification of varying disorders. However, most of these classification methods are supervised, i.e., they require a priori clinical labels to guide classification. In this study, we adopted various unsupervised clustering methods using static and dynamic rs-fMRI connectivity measures to investigate whether the clinical diagnostic grouping of different disorders is grounded in underlying neurobiological and phenotypic clusters. In order to do so, we derived a general analysis pipeline for identifying different brain-based disorders using genetic algorithm-based feature selection, and unsupervised clustering methods on four different datasets; three of them—ADNI, ADHD-200, and ABIDE—which are publicly available, and a fourth one—PTSD and PCS—which was acquired in-house. Using these datasets, the effectiveness of the proposed pipeline was verified on different disorders: Attention Deficit Hyperactivity Disorder (ADHD), Alzheimer's Disease (AD), Autism Spectrum Disorder (ASD), Post-Traumatic Stress Disorder (PTSD), and Post-Concussion Syndrome (PCS). For ADHD and AD, highest similarity was achieved between connectivity and phenotypic clusters, whereas for ASD and PTSD/PCS, highest similarity was achieved between connectivity and clinical diagnostic clusters. For multi-site data (ABIDE and ADHD-200), we report site-specific results. We also reported the effect of elimination of outlier subjects for all four datasets. Overall, our results suggest that neurobiological and phenotypic biomarkers could potentially be used as an aid by the clinician, in additional to currently available clinical diagnostic standards, to improve diagnostic precision. Data and source code used in this work is publicly available at https://github.com/xinyuzhao/identification-of-brain-based-disorders.git

Cognitive training for people with mild to moderate dementia (review)

This is the final version. Available from Cochrane Collaboration / Wiley via the DOI in this recordThe protocol version is in ORE at: http://hdl.handle.net/10871/33809Background Cognitive impairment, a defining feature of dementia, plays an important role in the compromised functional independence that characterises the condition. Cognitive training (CT) is an approach that uses guided practice on structured tasks with the direct aim of improving or maintaining cognitive abilities. Objectives To assess effects of CT on cognitive and non-cognitive outcomes for people with mild to moderate dementia and their caregivers. To compare effects of CT with those of other non-pharmacological interventions, including cognitive stimulation or rehabilitation, for people with mild to moderate dementia and their caregivers. To identify and explore factors related to intervention and trial design that may be associated with the efficacy of CT for people with mild to moderate dementia and their caregivers. Search methods We searched ALOIS, the Cochrane Dementia and Cognitive ImprovementGroup Specialised Register, on 5 July 2018. ALOIS contains records of clinical trials identified through monthly searches of several major healthcare databases and numerous trial registries and grey literature sources. In addition to this, we searched MEDLINE, Embase, PsycINFO, CINAHL, LILACS, Web of Science Core Collection, ClinicalTrials.gov, and the World Health Organization's trials portal, ICTRP, to ensure that searches were comprehensive and up-to-date. Selection criteria We included randomised controlled trials (RCTs) that described interventions for peoplewithmild tomoderate dementia and compared CT versus a control or alternative intervention. Data collection and analysis We extracted relevant data from published manuscripts and through contact with trial authors if required.We assessed risk of bias using the Cochrane 'Risk of bias' tool.We divided comparison conditions into active or passive control conditions and alternative treatments. We used a large number of measures and data to evaluate 19 outcomes at end of treatment, as well as 16 outcomes at follow-up in the medium term; we pooled this information in meta-analyses. We calculated pooled estimates of treatment effect using a random-effects model, and we estimated statistical heterogeneity using a standard Chi statistic. We graded the evidence using GradePro. Main results The 33 included trials were published between 1988 and 2018 and were conducted in 12 countries; most were unregistered, parallelgroup, single-site RCTs, with samples ranging from 12 to 653 participants. Interventions were between two and 104 weeks long. We classified most experimental interventions as 'straight CT', but we classified some as 'augmented CT', and about two-thirds as multi-domain interventions. Researchers investigated 18 passive and 13 active control conditions, along with 15 alternative treatment conditions, including occupational therapy, mindfulness, reminiscence therapy, and others. The methodological quality of studies varied, but we rated nearly all studies as having high or unclear risk of selection bias due to lack of allocation concealment, and high or unclear risk of performance bias due to lack of blinding of participants and personnel. We used data from 32 studies in the meta-analysis of at least one outcome. Relative to a control condition, we found moderate-quality evidence showing a small to moderate effect of CT on our first primary outcome, composite measure of global cognition at end of treatment (standardised mean difference (SMD) 0.42, 95% confidence interval (CI) 0.23 to 0.62), and high-quality evidence showing a moderate effect on the secondary outcome of verbal semantic fluency (SMD 0.52, 95% CI 0.23 to 0.81) at end of treatment, with these gains retained in the medium term (3 to 12 months post treatment). In relation to many other outcomes, including our second primary outcome of clinical disease severity in the medium term, the quality of evidence was very low, so we were unable to determine whether CT was associated with any meaningful gains. When compared with an alternative treatment, we found that CT may have little to no effect on our first primary outcome of global cognition at end of treatment (SMD 0.21, 95% CI-0.23 to 0.64), but the quality of evidence was low. No evidence was available to assess our second primary outcome of clinical disease severity in the medium term.We found moderate-quality evidence showing that CT was associated with improved mood of the caregiver at end of treatment, but this was based on a single trial. The quality of evidence in relation to many other outcomes at end of treatment and in the medium term was too low for us to determine whether CT was associated with any gains, but we are moderately confident that CT did not lead to any gains in mood, behavioural and psychological symptoms, or capacity to perform activities of daily living. Authors' conclusions Relative to a control intervention, but not to a variety of alternative treatments, CT is probably associated with small to moderate positive effects on global cognition and verbal semantic fluency at end of treatment, and these benefits appear to be maintained in the medium term. Our certainty in relation to many of these findings is low or very low. Future studies should take stronger measures to mitigate well-established risks of bias, and should provide long-term follow-up to improve our understanding of the extent to which observed gains are retained. Future trials should also focus on direct comparison of CT versus alternative treatments rather than passive or active control conditions.National Institute for Health Research (NIHR)National Health and Medical Research Council of Australi

Neurophysiology of prospective memory in typical and atypical ageing

The ability to delay an intention is known as ‘prospective memory’ (PM) and underpins many day-to-day activities. The ubiquity of PM makes it essential for independent living in older adults. Research suggests that PM function declines as we age and may be further exacerbated with the development of mild cognitive impairment (MCI). To date, there has been no research examining the neurophysiology of PM in older adults with MCI. This thesis addresses a series of questions to help understand the neurophysiology of PM and how it may be affected by ageing and MCI: 1) Are there neurophysiological differences between highly salient PM cues and less salient PM cues? 2) Can the neurophysiological reorientation of attention be identified in PM tasks? 3) Are there behavioural and neurophysiological differences between young adults, older adults and older adults with MCI during PM tasks? 4) Are there behavioural and neurophysiological differences when maintaining a PM intention between young adults, older adults and older adults with MCI? 5) Can machine learning be used to understand spatiotemporal patterns of brain activity in response to PM between young adults, older adults and older adults with MCI? To answer these questions behavioural and time-locked electroencephalographic (EEG) responses were examined during PM tasks and were modelled with a machine learning method known as Spiking Neural Networks (SNN). Results suggest that: there are behavioural and neurophysiological differences between the PM cues and the neurophysiological reorientation of attention can be detected in PM tasks; older adults are not impaired in PM tasks possibly due to compensatory neural mechanisms; older adults with MCI may be impaired in some PM tasks, which may be due to deficits in attention and feelings of knowing; modelling PM with SNNs may offer useful ways of understanding spatiotemporal connectivity in PM and MCI