Multidomain interventions: state-of-the-art and future directions for protocols to implement precision dementia risk reduction. A user manual for Brain Health Services-part 4 of 6.

Although prevention of dementia and late-life cognitive decline is a major public health priority, there are currently no generally established prevention strategies or operational models for implementing such strategies into practice. This article is a narrative review of available evidence from multidomain dementia prevention trials targeting several risk factors and disease mechanisms simultaneously, in individuals without dementia at baseline. Based on the findings, we formulate recommendations for implementing precision risk reduction strategies into new services called Brain Health Services. A literature search was conducted using medical databases (MEDLINE via PubMed and SCOPUS) to select relevant studies: non-pharmacological multidomain interventions (i.e., combining two or more intervention domains), target population including individuals without dementia, and primary outcomes including cognitive/functional performance changes and/or incident cognitive impairment or dementia. Further literature searches covered the following topics: sub-group analyses assessing potential modifiers for the intervention effect on cognition in the multidomain prevention trials, dementia risk scores used as surrogate outcomes in multidomain prevention trials, dementia risk scores in relation to brain pathology markers, and cardiovascular risk scores in relation to dementia. Multidomain intervention studies conducted so far appear to have mixed results and substantial variability in target populations, format and intensity of interventions, choice of control conditions, and outcome measures. Most trials were conducted in high-income countries. The differences in design between the larger, longer-term trials that met vs. did not meet their primary outcomes suggest that multidomain intervention effectiveness may be dependent on a precision prevention approach, i.e., successfully identifying the at-risk groups who are most likely to benefit. One such successful trial has already developed an operational model for implementing the intervention into practice. Evidence on the efficacy of risk reduction interventions is promising, but not yet conclusive. More long-term multidomain randomized controlled trials are needed to fill the current evidence gaps, especially concerning low- and middle-income countries and integration of dementia prevention with existing cerebrovascular prevention programs. A precision risk reduction approach may be most effective for dementia prevention. Such an approach could be implemented in Brain Health Services

Exploring the impact of Cognitive Health Enhancing Behaviours, Subjective Cognitive Complaints, Fear of Dementia and Generalised Anxiety on Cognitive Function

There has been much interest recently in health behaviours that might reduce the risk of neurodegenerative illnesses that cause dementia. Examples of behaviours that potentially enhance (neuro)cognitive health include exercising, maintaining social connections, cognitive activity, and diet. This thesis explores how anxiety mediates the relationship between cognitive health enhancing behaviours and cognitive functioning in healthy adults. Part I is a systematic literature review examining the impact of psychosocial, cognitive training, and multidomain interventions on cognitive functioning. In total, 31 randomised controlled trials (RCTs) were included in this review. Part II presents a secondary analysis of data collected from a charity called Food for the Brain (FFB). Structural Equation Modelling (SEM) was used to analyse whether different types of anxiety mediate the relationship between cognitive health enhancing behaviours and cognitive functioning. Exploratory analysis of longitudinal data collected at six, 12 and 24 months after baseline, investigated predictors of change in cognitive health enhancing behaviours over time. Part III is a critical appraisal that reflects on my experience of co-production and completing the systematic review for the APPLE-Tree project, methodological problems with the measures in the empirical study and the role that clinical psychology has in public health

Modifiable risk factors for dementia and dementia risk profiling. A user manual for Brain Health Services-part 2 of 6.

We envisage the development of new Brain Health Services to achieve primary and secondary dementia prevention. These services will complement existing memory clinics by targeting cognitively unimpaired individuals, where the focus is on risk profiling and personalized risk reduction interventions rather than diagnosing and treating late-stage disease. In this article, we review key potentially modifiable risk factors and genetic risk factors and discuss assessment of risk factors as well as additional fluid and imaging biomarkers that may enhance risk profiling. We then outline multidomain measures and risk profiling and provide practical guidelines for Brain Health Services, with consideration of outstanding uncertainties and challenges. Users of Brain Health Services should undergo risk profiling tailored to their age, level of risk, and availability of local resources. Initial risk assessment should incorporate a multidomain risk profiling measure. For users aged 39-64, we recommend the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) Dementia Risk Score, whereas for users aged 65 and older, we recommend the Brief Dementia Screening Indicator (BDSI) and the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI). The initial assessment should also include potentially modifiable risk factors including sociodemographic, lifestyle, and health factors. If resources allow, apolipoprotein E ɛ4 status testing and structural magnetic resonance imaging should be conducted. If this initial assessment indicates a low dementia risk, then low intensity interventions can be implemented. If the user has a high dementia risk, additional investigations should be considered if local resources allow. Common variant polygenic risk of late-onset AD can be tested in middle-aged or older adults. Rare variants should only be investigated in users with a family history of early-onset dementia in a first degree relative. Advanced imaging with 18-fluorodeoxyglucose positron emission tomography (FDG-PET) or amyloid PET may be informative in high risk users to clarify the nature and burden of their underlying pathologies. Cerebrospinal fluid biomarkers are not recommended for this setting, and blood-based biomarkers need further validation before clinical use. As new technologies become available, advances in artificial intelligence are likely to improve our ability to combine diverse data to further enhance risk profiling. Ultimately, Brain Health Services have the potential to reduce the future burden of dementia through risk profiling, risk communication, personalized risk reduction, and cognitive enhancement interventions

Modifiable risk factors for dementia and dementia risk profiling. A user manual for Brain Health Services-part 2 of 6

We envisage the development of new Brain Health Services to achieve primary and secondary dementia prevention. These services will complement existing memory clinics by targeting cognitively unimpaired individuals, where the focus is on risk profiling and personalized risk reduction interventions rather than diagnosing and treating late-stage disease. In this article, we review key potentially modifiable risk factors and genetic risk factors and discuss assessment of risk factors as well as additional fluid and imaging biomarkers that may enhance risk profiling. We then outline multidomain measures and risk profiling and provide practical guidelines for Brain Health Services, with consideration of outstanding uncertainties and challenges. Users of Brain Health Services should undergo risk profiling tailored to their age, level of risk, and availability of local resources. Initial risk assessment should incorporate a multidomain risk profiling measure. For users aged 39-64, we recommend the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) Dementia Risk Score, whereas for users aged 65 and older, we recommend the Brief Dementia Screening Indicator (BDSI) and the Australian National University Alzheimer's Disease Risk Index (ANU-ADRI). The initial assessment should also include potentially modifiable risk factors including sociodemographic, lifestyle, and health factors. If resources allow, apolipoprotein E ɛ4 status testing and structural magnetic resonance imaging should be conducted. If this initial assessment indicates a low dementia risk, then low intensity interventions can be implemented. If the user has a high dementia risk, additional investigations should be considered if local resources allow. Common variant polygenic risk of late-onset AD can be tested in middle-aged or older adults. Rare variants should only be investigated in users with a family history of early-onset dementia in a first degree relative. Advanced imaging with 18-fluorodeoxyglucose positron emission tomography (FDG-PET) or amyloid PET may be informative in high risk users to clarify the nature and burden of their underlying pathologies. Cerebrospinal fluid biomarkers are not recommended for this setting, and blood-based biomarkers need further validation before clinical use. As new technologies become available, advances in artificial intelligence are likely to improve our ability to combine diverse data to further enhance risk profiling. Ultimately, Brain Health Services have the potential to reduce the future burden of dementia through risk profiling, risk communication, personalized risk reduction, and cognitive enhancement interventions

Perceived Alzheimer\u27s Disease Threat as a Predictor of Behavior Change to Lower Disease Risk: The Gray Matters Study

Alzheimer’s disease is a growing public health concern with the current number afflicted of 5 million in the US expected to triple by 2050. Since there is currently no cure or preventive pharmacological treatment, AD prevention research is now recognized as an important enterprise, with a goal to identify modifiable lifestyle factors that can reduce AD risk or delay its onset. Among these, increased physical activity, healthier food choices, more cognitive stimulation, better sleep quality, stress management, and social engagement have been identified as reasonable targets for behavioral intervention. A smartphone application-based behavioral intervention targeting these six behavioral domains was recently developed and a six-month randomized controlled trial was conducted, both to determine feasibility and compliance with technology usage and to test its efficacy. This study, titled the Gray Matters Study, was conducted in Cache County, Utah, enrolling a sample of 146 middle-aged participants (aged 40 to 64 years) randomized to treatment or control condition. Under the Health Belief Model, individuals who perceive a greater susceptibility to a particular health condition are hypothesized to be more likely to engage in more positive behaviors to reduce disease risk. Following this model, perceived threat of AD (operationalized by fear of AD, family history of AD, and metacognitive concerns) was examined for prediction of behavioral change over the six-month Gray Matters intervention period in these same six behavioral domains. Persons with a moderate level of fear of AD made significantly greater improvements in physical activity than those with low or high levels of fear. Family history was not a significant predictor of health-related behavioral change. However, persons with a moderate level of metacognitive concerns made significantly greater improvements in both physical activity and food quality than those with low or high levels of concerns. This is the first study to examine these psychological constructs related to AD risk and the extent to which they predict health-related behavior change. Future studies should extend the length of follow-up to at least one full year, include a more diverse sample of participants to expand generalizability, and build upon these findings to personalize supportive behavioral change interventions in order to be sensitive to these psychological factors

Timecourse of Cognitive and Brain Adaptation to Cognitive Training in At-risk Elderly

Maintaining cognitive ability in the elderly is a global priority. Computerised cognitive training (CCT) is among the few effective interventions but the boundaries and mechanisms underlying its effectiveness are largely unknown. Chapter 2 is the first systematic review and meta-analysis of 37 randomised controlled trials (RCTs) of CCT in healthy elderly, encompassing a total of 4,310 participants. CCT was effective on all the cognitive domains except for executive functions. Type of training program, mode of delivery, session length and training frequency were found to moderate CCT efficacy. The Timecourse Trial (Chapter 3) was a randomized, double-blind, active controlled longitudinal trial of CCT in 80 healthy elderly. Significant effects were found on global cognition, memory and processing speed, and dose-response curves differed across domains. These domain-specific gains also followed different decay curves after training cessation throughout the 12 months follow-up period. Chapter 4 investigates the neural underpinnings of gains in global cognition. Modification of resting-state functional connectivity was found to predict subsequent cognitive gains, gains that were also correlated to structural cortical plasticity. CCT is an effective intervention in the elderly. The field may do well to now focus on improving standards, large-scale trials and a further understanding of biological mechanisms

AI and Non AI Assessments for Dementia

Current progress in the artificial intelligence domain has led to the development of various types of AI-powered dementia assessments, which can be employed to identify patients at the early stage of dementia. It can revolutionize the dementia care settings. It is essential that the medical community be aware of various AI assessments and choose them considering their degrees of validity, efficiency, practicality, reliability, and accuracy concerning the early identification of patients with dementia (PwD). On the other hand, AI developers should be informed about various non-AI assessments as well as recently developed AI assessments. Thus, this paper, which can be readable by both clinicians and AI engineers, fills the gap in the literature in explaining the existing solutions for the recognition of dementia to clinicians, as well as the techniques used and the most widespread dementia datasets to AI engineers. It follows a review of papers on AI and non-AI assessments for dementia to provide valuable information about various dementia assessments for both the AI and medical communities. The discussion and conclusion highlight the most prominent research directions and the maturity of existing solutions.Comment: 49 page

Mental stimulation and multimodal trials to prevent cognitive impairment and Alzheimer ́s disease

Theoretical models of dynamic biomarkers underlying the development of Alzheimer´s Disease (AD) acknowledge that there is inter-individual variability in the cognitive performance associated with any level of AD pathology. Mentally stimulating activities such as schooling, occupation, and leisure activities, may contribute to this variability, but it is yet unclear how this can be best assessed, and how such effects can vary across AD severity and among individuals at-risk for cognitive impairment. The association between mental stimulation and cognitive performance also suggests that it is important to account for mental stimulation levels in randomized clinical trials (RCTs) comparing rates of cognitive change between interventions (i.e., drugs, lifestyle interventions) and controls. The aim of this thesis was to investigate a) how pre-existing levels of occupational complexity affect the cognitive outcomes of a multimodal lifestyle-based RCT among older adults at increased risk for dementia based on a validated risk score b) if occupational complexity is associated to cognitive performance among individuals at-risk for dementia, including individuals in the early stages of symptomatic AD (prodromal AD) and c) if occupational complexity is associated with resilience to AD pathology, measured with validated biomarkers and neuroimaging among individuals at-risk for cognitive impairment and with prodromal AD. The four studies in this thesis were based on data from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), the Karolinska University Hospital electronic database and biobank for clinical research (GEDOC) and The Multimodal Prevention Trial for Alzheimer´s Disease (MIND-ADmini). Study I. This study used data from the FINGER study (N=1026) to investigate if preexisting levels of occupational complexity were associated with cognitive function at baseline, and if occupational complexity was associated with the rate of change in cognition during the 2-year intervention period. For all measures of occupational complexity, higher levels of complexity were associated with better cognitive outcomes at baseline. Occupational complexity was not associated with the rate of cognitive change during the intervention, except for the executive function outcome, for which higher levels of complexity with data predicted increased improvement ((ß[SE]: .028[.014], p=.044). Study II. This study used data from the FINGER neuroimaging cohort, to investigate if the association between occupational complexity and cognition was moderated by measures of brain integrity, both in terms of magnetic resonance imaging (MRI, N=126) and Pittsburgh-B Compound – Positron Emission Tomography (PiB-PET, N=41). The results showed that higher levels of occupational complexity were associated with better cognitive performance for some outcomes after adjusting for Alzheimer’s Disease Signature (ADS) and medial temporal atrophy (MTA). However, for most types of neuropathology and cognitive outcomes, moderation effects indicated that higher occupational complexity levels were associated with better cognitive performance only in people with higher brain integrity, suggesting lack of occupational complexity-related resilience mechanisms. Study III. This study investigated the association between mental stimulation (occupational complexity and education) and validated AD biomarkers, Aβ1–42, p-tau and t-tau measured in cerebrospinal fluid (CSF). Using data from the GEDOC database, 174 individuals with prodromal AD were included, and analyses were adjusted for cognitive function. The results indicated that both higher occupational complexity and education were associated with higher levels of p-tau and t-tau. For education the association with tau pathology was age dependent. No association was found with Aβ1– 42. This suggests that higher education and occupational complexity may provide resilience against tau-related pathology in prodromal AD. Study IV. This study used data from FINGER, GEDOC, and MIND-ADmini, thus including a total of 1410 individuals, 1207 at-risk for dementia and 203 with Prodromal AD. The aim was to to compare the two most common rating systems for occupational complexity, the Occupation Information Network (O*NET) and the Dictionary of Occupational Titles (DOT) and assess if there was an association between occupational complexity and episodic memory performance among individuals at-risk for dementia. The study found that higher occupational complexity was only associated with memory performance in the FINGER cohort but not the two prodromal AD cohorts. The correlation between the two rating systems was moderate to strong, and highly significant (Spearman’s rho = 0.5-0.6, p <.001). Conclusions. Higher levels of Occupational complexity are associated with better cognitive performance among older individuals at-risk for dementia (and with no substantial cognitive impairment), but does not affect the intervention effect in the FINGER multidomain lifestyle-based RCT, apart from the effect on executive function. Occupational complexity does not seem to provide strong resilience against neuropathology among individuals at-risk for cognitive impairment. Among individuals with prodromal AD, higher levels of occupational complexity do seem to provide resilience to tau-related pathology measured with CSF markers but is not associated with better episodic memory performance. Measuring occupational complexity with the DOT or O*NET system seems to yield similar results, as the two systems scores are correlated

Remote Monitor System for Alzheimer disease

Health Remote Monitoring Systems (HRMS) offer the ability to address health-care human resource concerns. In developing nations, where pervasive mobile networks and device access are linking people like never before, HRMS are of special relevance. A fundamental aim of this research work is the realization of technological-based solution to triage and follow-up people living with dementias so as to reduce pressure on busy staff while doing this from home so as to avoid all unnecessary visits to hospital facilities, increasingly perceived as dangerous due to COVID-19 but also raising nosocomial infections, raising alerts for abnormal values. Sensing approaches are complemented by advanced predictive models based on Machine Learning (ML) and Artificial Intelligence (AI), thus being able to explore novel ways of demonstrating patient-centered predictive measures. Low-cost IoT devices composing a network of sensors and actuators aggregated to create a digital experience that will be used and exposure to people to simultaneously conduct several tests and obtain health data that can allow screening of early onset dementia and to aid in the follow-up of selected cases. The best ML for predicting AD was logistic regression with an accuracy of 86.9%. This application as demonstrated to be essential for caregivers once they can monitor multiple patients in real-time and actuate when abnormal values occur.info:eu-repo/semantics/acceptedVersio

The role of physical activity and bilingualism in the development of neurodegenerative disorders: Cross-sectional and neuroimaging evidence

Delaying Alzheimer’s disease (AD), the most common form of dementia, by five years could decrease the global prevalence of AD by 57% and halve the annual economic impact which is currently estimated to surpass US$2 trillion by 2030. Since no treatment or cure for dementia exist, identifying modifiable factors to reduce the incidence of dementia has become a public health priority. Increased physical activity (PA) has been associated with a lower risk of developing dementia in observational studies. Observational studies have also linked bilingualism (the ability to speak two languages) with a delayed onset of dementia but no risk-reduction in dementia in bilinguals relative to monolinguals. Differences in study outcomes in the fields of PA- and bilingualism- related research to methodological limitations including poor measurement of the exposure (PA and language profiles), small sample sizes, and recruitment of participants with different dementia etiologies. The purpose of this thesis was twofold: i) to explore the roles of PA and bilingualism in dementia risk and ii) to inform the development of a randomized controlled trial (RCT) to test whether studying a foreign language combined with increasing PA can improve cognitive performance in seniors who are at a higher risk of developing AD. The aim of Chapter two was to review the available evidence linking PA with the risk of developing dementia as well as to explore the effects of increasing PA on cognition in individuals with dementia. Results showed that aerobic, and high-intensity, habitual PA was associated with improved cognition-related biomarkers and lower dementia risk in epidemiological studies. Experimental evidence showed increasing PA improved cognition-related biomarkers and cognition in preclinical phases of dementia, but not in clinical phases. The findings showed that PA is linked with a lower risk of dementia in epidemiological studies, but experimental studies showed little to no improvements in cognition in participants with dementia following a structured PA program. There was evidence indicating that increasing PA levels in the preclinical phase of AD may result in greater translation impact than in participants at the more advanced clinical stage of AD. Most studies assessed PA with self-report measures questioning the accuracy and precision of exposure and recruited participants with dementia irrespective of aetiology, which makes it problematic to discern whether PA is differentially related to varying dementia aetiologies. The aim of Chapter three was to systematically review the association between bilingualism and the delay in the diagnosis of dementia and AD. Here, we retrieved a total of 20 studies, 15 of which were meta-analysed. Results showed that bilinguals were on average 3.2 (95% CI: 1.5, 4.9) years older than monolinguals at the time of dementia. Moreover, at the time of dementia diagnosis, bilinguals and monolinguals demonstrated a similar level of global cognitive impairment (Hedges’ g = 0.05 95% CI: -0.10, 0.21). Prediction intervals however showed a large dispersion of effect sizes in the meta-analysis comparing monolinguals to bilinguals on the age of dementia diagnosis. To explore possible reasons for the observed dispersion in effect sizes, we conducted subgroup analyses. In one subgroup meta-analysis comparing studies that had recruited participants with dementia to studies that had recruited participants with AD, bilinguals were 4.2 (95% CI: 2.0, 6.2) and 1.7 (95% CI: -1.4, 4.7) years older than monolinguals at dementia and AD diagnosis, respectively. Meta-analytic results combining prospective longitudinal studies showed no risk reduction in dementia among bilinguals compared to monolinguals (Odds Ratio: 0.85; 95% CI: 0.69-1.05). Risk of bias assessment revealed that most studies carried several methodological limitations including poor measurement of participants’ language profiles and small sample sizes. The aim of Chapter four was to explore the underlying mechanisms in the brain that may be responsible for the observed findings in the first systematic review (Chapter three). In this study, we observed that bilinguals compared to monolinguals had greater brain volume in the frontostriatal and frontoparietal circuits. Also, functional neuroimaging studies showed that bilinguals made use of relevant brain areas more efficiently than monolinguals when completing interference cognitive tasks. Results from the cross-sectional studies showed that higher levels of language acculturation were associated with significantly greater verbal and psychomotor speed performance than lower levels of language acculturation. The aim of the Chapter five was to explore the link between language acculturation and cognition in older individuals from ethnic minorities (Hispanic and Asian) living in the United States of America using an epidemiological dataset. In this cross-sectional epidemiological study, we analyzed data from the National Health and Nutrition Examination Survey using a larger sample size than previous studies. We found that higher levels of language acculturation (i.e. speaking the native language and that of the recipient’s country at home) was associated with greater psychomotor speed processing than lower levels of language acculturation (mostly speaking the native language at home) and some, but not all, measures of verbal fluency. Overall, the findings suggest that higher levels of language acculturation are associated with greater cognitive performance in older individuals from ethnic minorities. Overall, the evidence gathered in the previous chapters indicate that i) increasing PA in individuals who are at a higher risk of developing AD might be more useful in improving cognitive performance than in individuals who already have developed AD and ii) bilingualism might render the brain areas typically affected by AD such as the frontostriatal and frontoparietal brain circuits more resilient against neurodegeneration and in turn, delay the onset of AD symptoms and diagnosis. Therefore, because no randomized-controlled trial (RCT) testing the combined effects of increased PA with studying a foreign language currently exist, Chapter five presents a detailed study protocol for an RCT addressing this gap in the literature while addressing the limitations of previous studies in the fields of PA- and bilingualism-based research. The purpose of this thesis was to explore the roles of PA and bilingualism in dementia onset and risk and to inform the development of a randomized controlled trial (RCT) testing the effects of studying a foreign language with increased PA in individuals at a higher risk of dementia. Increasing PA levels are associated with greater cognition in individuals at the preclinical phase of AD rather than in participants with a diagnosis of dementia or AD. Bilingualism was also associated with later age of AD diagnosis on average by 4.7 years. This finding is clinically relevant because a five-year delay in the onset of AD could lower the number of individuals with AD worldwide by 57% and as a consequence, halving the associated economic costs. Moreover, we also showed that bilingualism may be responsible for rendering brain areas typically affected by AD more resilient against neuropathology. Moreover, this thesis revealed that studies in the field of exercise science and bilingualism research in dementia carry important methodological limitations that question the internal validity of these two lines of research. Consequently, the evidence gathered within this thesis led us to propose a novel RCT exploring the effects of increasing PA levels and studying a foreign language in monolingual individuals at a higher risk of AD while addressing the most important limitations of previous research