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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). [ABSTRACT FROM AUTHOR]

Background and purpose: The complex aetiology of Alzheimer's disease suggests prevention potential. Risk scores have potential as risk stratification tools and surrogate outcomes in multimodal interventions targeting specific at‐risk populations. The Australian National University Alzheimer's Disease Risk Index (ANU‐ADRI) was tested in relation to cognition and its suitability as a surrogate outcome in a multidomain lifestyle randomized controlled trial, in older adults at risk of dementia. Methods: In this post hoc analysis of the Finnish Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), ANU‐ADRI was calculated at baseline, 12, and 24 months (n = 1174). The association between ANU‐ADRI and cognition (at baseline and over time), the intervention effect on changes in ANU‐ADRI, and the potential impact of baseline ANU‐ADRI on the intervention effect on changes in cognition were assessed using linear mixed models with maximum likelihood estimation. Results: A higher ANU‐ADRI was significantly related to worse cognition, at baseline (e.g., estimate for global cognition [95% confidence interval] was −0.028 [−0.032 to −0.025]) and over the 2‐year study (e.g., estimate for 2‐year changes in ANU‐ADRI and per‐year changes in global cognition [95% confidence interval] was −0.068 [−0.026 to −0.108]). No significant beneficial intervention effect was reported for ANU‐ADRI, and baseline ANU‐ADRI did not significantly affect the response to the intervention on changes in cognition. Conclusions: The ANU‐ADRI was effective for the risk prediction of cognitive decline. Risk scores may be crucial for the success of novel dementia prevention strategies, but their algorithm, the target population, and the intervention design should be carefully considered when choosing the appropriate tool for each context. [ABSTRACT FROM AUTHOR]

Background Modifiable vascular and lifestyle-related risk factors have been associated with dementia risk in observational studies. In the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), a proof-of-concept randomised controlled trial, we aimed to assess a multidomain approach to prevent cognitive decline in at-risk elderly people from the general population. Methods In a double-blind randomised controlled trial we enrolled individuals aged 60–77 years recruited from previous national surveys. Inclusion criteria were CAIDE (Cardiovascular Risk Factors, Aging and Dementia) Dementia Risk Score of at least 6 points and cognition at mean level or slightly lower than expected for age. We randomly assigned participants in a 1:1 ratio to a 2 year multidomain intervention (diet, exercise, cognitive training, vascular risk monitoring), or a control group (general health advice). Computer-generated allocation was done in blocks of four (two individuals randomly allocated to each group) at each site. Group allocation was not actively disclosed to participants and outcome assessors were masked to group allocation. The primary outcome was change in cognition as measured through comprehensive neuropsychological test battery (NTB) Z score. Analysis was by modified intention to treat (all participants with at least one post-baseline observation). This trial is registered at ClinicalTrials.gov, number NCT01041989. Findings Between Sept 7, 2009, and Nov 24, 2011, we screened 2654 individuals and randomly assigned 1260 to the intervention group (n=631) or control group (n=629). 591 (94%) participants in the intervention group and 599 (95%) in the control group had at least one post-baseline assessment and were included in the modified intention-to-treat analysis. Estimated mean change in NTB total Z score at 2 years was 0·20 (SE 0·02, SD 0·51) in the intervention group and 0·16 (0·01, 0·51) in the control group. Between-group difference in the change of NTB total score per year was 0·022 (95% CI 0·002–0·042, p=0·030). 153 (12%) individuals dropped out overall. Adverse events occurred in 46 (7%) participants in the intervention group compared with six (1%) participants in the control group; the most common adverse event was musculoskeletal pain (32 [5%] individuals for intervention vs no individuals for control). Interpretation Findings from this large, long-term, randomised controlled trial suggest that a multidomain intervention could improve or maintain cognitive functioning in at-risk elderly people from the general population. INSET: Research in context.. [ABSTRACT FROM AUTHOR]

Depression and cognition are associated, but the role of depressive symptoms in lifestyle interventions to prevent dementia needs further study. We investigated the intervention effect on depressive symptoms and their associations with cognition in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER; NCT01041989), a two-year multidomain lifestyle trial. One thousand two-hundred and sixty individuals (60–77 years) at risk for dementia were randomised into a multidomain intervention (diet, exercise, cognitive training, and vascular/metabolic risk monitoring) or control group (regular health advice). Depressive symptoms (Zung scale) and cognition (modified Neuropsychological Test Battery) were evaluated at baseline, 12, and 24 months. One thousand one-hundred and twenty-five participants had baseline Zung data. Mean Zung score decreased 0.73 (SD 5.6) points in the intervention and 0.36 (5.6) points in the control group, with nonsignificant between-group difference (group × time coefficient −0.006, 95% CI −0.019 to 0.007). Overall, higher baseline Zung score was associated with less improvement in global cognition (−0.140, p = 0.005) and memory (−0.231, p = 0.005). Participants with clinically significant baseline depressive symptoms (Zung ≥ 40 points) had less intervention benefit to executive functioning (group × time × Zung −0.096, 95% CI −0.163 to −0.028). Change in Zung score was not associated with change in cognition. Clinically significant depressive symptoms warrant more attention when designing dementia-prevention interventions. [ABSTRACT FROM AUTHOR]

Objective: To assess and compare the food consumption and nutrient intake between 3-year-old children cared for at home full-time and those attending day care outside the home. Nutrient intake on weekdays and weekends was also studied. Design: Cross-sectional sample of children invited to the nutrition study within the Type 1 Diabetes Prediction and Prevention (DIPP) birth cohort born in 2001. Families returned 3-d food record completed close to the child's third birthday. Subjects: A total of 471 pre-school children aged 3 years of whom 285 had only been cared for at home during the recording time and 186 had attended day care outside the home. Results: Among the children cared for outside the home, there were more consumers of recommendable foods as fresh vegetables, fruits, berries, rye bread, fish, skimmed milk and vegetable margarines, than among those cared for at home. The day-care group had higher intake of protein, dietary fibre, thiamine, potassium and magnesium, and lower intake of sucrose compared with the group cared for at home. Adjustment for sociodemographic factors did not change the results. In all children, food consumption was more varied on weekdays compared with weekends. On weekdays, children had higher intake of dietary fibre and protein and lower intake of sucrose compared to weekends. Conclusions: The type of day care was associated with food consumption and nutrient intake among pre-school children and hence might have an impact on their nutrition and health. The diet of the children attending day care outside the home was more balanced and closer to the national recommendations. [ABSTRACT FROM AUTHOR]

Objective: To decrease the intake of sucrose, increase the intake of fibre and the consumption of fruit and vegetables among secondary-school pupils. Design: Intervention study among eighth grade pupils during one school year. Data were collected by questionnaires and from a subgroup of pupils by 48 h dietary recall at baseline in spring 2007 and after the intervention in 2008. Setting: Twelve secondary schools were randomly allocated to intervention (IS) and control schools (CS) within three cities. Intervention included nutrition education and improvement of the food environment focusing particularly on the quality of snacks at school. Subjects: A total of 659 pupils completed the questionnaires and the dietary recall was obtained from 287 pupils both at baseline and follow-up. Results: The frequency of consumption of rye bread increased (P = 0·03) and that of sweets decreased (P = 0·006) among girls in the IS. The intake of sucrose fell among IS pupils, from 12·8% to 10·5% of the total energy intake (P = 0·01). Intake of fruit (g/MJ) remained the same in IS, whereas it decreased in CS (P = 0·04). Conclusions: Sugar intake can be lowered by improving the quality of snacks, but it is more difficult to increase fibre intake and fruit and vegetable consumption unless the content of school lunches can be modified. It is the responsibility of the adults working in schools to create a healthy environment and to make healthy choices easy for pupils. [ABSTRACT FROM AUTHOR]

Objective: To evaluate food and nutrient intake and especially eating during the school day among Finnish secondary-school pupils. Design: Cross-sectional study. Data were collected using a structured questionnaire mailed to home and by 48 h dietary recall interviews performed at schools in 2007. Setting: Twelve schools in three cities in Finland. Subjects: The seventh grade pupils (a total of 1469 at the mean age of 13?8 years). Questionnaire data were available from 726 pupils and dietary data from a subgroup of 40% (n 306). Results: According to the questionnaire data, 40% of the girls and 28% of the boys reported eating fresh vegetables daily and the respective figures for fruit were 32% and 23 %. Altogether, 71% of the adolescents reported having school lunch every day. The average intake of sucrose was higher and the average intakes of fibre, iron, folate and vitamin D were lower than recommended. School lunch provided around 20% of daily energy intake, while the recommended daily energy intake level is one-third. However, the school lunch as consumed was nutritionally superior to the other daily meals. Snacks provided 41% of the daily energy. The most common sources of sucrose were sugary drinks. Conclusions: Low consumption of fruit and vegetables and abundant consumption of sucrose-rich drinks and snacks are the main problems in the diet of Finnish adolescents. The nutritional quality of the school lunch is good, but the supply of healthy snacks must be improved in schools. Schools can promote healthy eating habits by making healthy choices easy during the school day. [ABSTRACT FROM AUTHOR]

Background: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) showed cognitive benefits from a multidomain lifestyle intervention in at-risk older people. The LipiDiDiet trial highlighted benefits of medical food in prodromal Alzheimer's disease (AD). However, the feasibility and impact of multimodal interventions combining lifestyle with medical food in prodromal AD is unclear. Methods: MIND-ADmini was a 6-month multinational (Sweden, Finland, Germany, France) proof-of-concept randomized controlled trial (RCT). Participants were 60–85 years old, had prodromal AD (International Working Group-1 criteria), and vascular/lifestyle risk factors. The parallel-group RCT had three arms: multimodal lifestyle intervention (nutritional guidance, exercise, cognitive training, vascular/metabolic risk management and social stimulation); multimodal lifestyle intervention + medical food (Fortasyn Connect); and regular health advice/care (control). Participants were randomized 1:1:1 (computer-generated allocation at each site). Outcome evaluators were blinded to randomization. Primary outcome was feasibility of the multimodal intervention, evaluated by recruitment rate during a 6-month recruitment phase, overall adherence in each intervention arm, and 6-month retention rate. Successful adherence was pre-specified as attending ≥ 40% of sessions/domain in ≥ 2/4 domains (lifestyle intervention), and consuming ≥ 60% of the medical food (lifestyle intervention + medical food). The secondary outcomes included adherence/participation to each intervention component and overall adherence to healthy lifestyle changes, measured using a composite score for healthy lifestyle. Cognitive assessments were included as exploratory outcomes, e.g. Clinical Dementia Rating scale. Results: During September 2017-May 2019, 93 individuals were randomized (32 lifestyle intervention, 31 lifestyle + medical food, and 30 control group). Overall recruitment rate was 76.2% (64.8% during the first 6 months). Overall 6-month retention rate was 91.4% (lifestyle intervention 87.5%; lifestyle + medical food 90.3%; control 96.7%). Domain-specific adherence in the lifestyle intervention group was 71.9% to cognitive training, 78.1% exercise, 68.8% nutritional guidance, and 81.3% vascular risk management; and in the lifestyle + medical food group, 90.3% to cognitive training, 87.1% exercise, 80.7% nutritional guidance, 87.1% vascular risk management, and 87.1% medical food. Compared with control, both intervention arms showed healthy diet improvements (βLifestyle×Time = 1.11, P = 0.038; βLifestyle+medical food×Time = 1.43, P = 0.007); the lifestyle + medical food group also showed vascular risk reduction (P = 0.043) and less cognitive-functional decline (P < 0.05, exploratory analysis). There were 5 serious adverse events (control group: 1; lifestyle intervention: 3; lifestyle + medical food: 1) unrelated to interventions. Conclusions: The multidomain lifestyle intervention, alone or combined with medical food, had good feasibility and adherence in prodromal AD. Longer-term cognitive and other health benefits should be further investigated in a larger-scale trial. Trial registration: ClinicalTrials.gov NCT03249688. [ABSTRACT FROM AUTHOR]

Introduction: Mechanisms underlying the positive association between occupational mental demands and late-life cognition are poorly understood. The objective of this study was to assess whether the association between occupational complexity and cognition is related to and moderated by brain integrity in individuals at risk for dementia. Brain integrity was appraised throughout structural measures (magnetic resonance imaging, MRI) and amyloid accumulation (Pittsburgh compound B (PiB)-positron emission tomography, PiB-PET). Methods: Participants from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) neuroimaging sample – MRI (N = 126), PiB-PET (N = 41) – were included in a post hoc cross-sectional analysis. Neuroimaging parameters comprised the Alzheimer's disease signature (ADS) cortical thickness (FreeSurfer 5.3), medial temporal atrophy (MTA), and amyloid accumulation (PiB-PET). Cognition was assessed using the neuropsychological test battery. Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles. Linear regression models included cognition as dependent variable, and occupational complexity, measures of brain integrity, and their interaction terms as predictors. Results: Occupational complexity with data and substantive complexity were associated with better cognition (overall cognition, executive function) when adjusting for ADS and MTA (independent association). Significant interaction effects between occupational complexity and brain integrity were also found, indicating that, for some indicators of brain integrity and cognition (e.g., overall cognition, processing speed), the positive association between occupational complexity and cognition occurred only among persons with higher brain integrity (moderated association). Conclusions: Among individuals at risk for dementia, occupational complexity does not seem to contribute toward resilience against neuropathology. These exploratory findings require validation in larger populations. [ABSTRACT FROM AUTHOR]

We studied cognition in the Finnish Diabetes Prevention Study (DPS), a trial of lifestyle intervention that prevented diabetes in persons with impaired glucose tolerance. Cognition was similar in the randomization arms 9 years after the intervention in 364 participants, suggesting that the intervention did not benefit cognition. [ABSTRACT FROM AUTHOR]

Naloxone as emergency treatment for opioid overdosing can be administered via several routes. However, the available administration methods are invasive or may be associated with incomplete or slow naloxone absorption. We evaluated pharmacokinetics and local tolerance of naloxone ocular drops in healthy beagle dogs. Naloxone administration as eye drops produced fast absorption with time to maximum plasma concentration (tmax) achieved in 14 to 28 min, high plasma exposure (Cmax 10.3 ng/mL to 12.7 ng/mL), and good bioavailability (41% to 56%). No signs of ocular irritability were observed in the scored ocular tolerability parameters, and the reactions of dogs suggesting immediate ocular discomfort after the dosing were sporadic and short lasting. Slight and transient increase in the intraocular pressure and transient decrease in the tear production were recorded. The results suggest that eye drops may provide a fast and an effective non-invasive route for naloxone administration to reverse opioid overdosing, and clinical studies in the human are warranted. [ABSTRACT FROM AUTHOR]

Background: Shorter leukocyte telomere length (LTL) is associated with aging and dementia. Impact of lifestyle changes on LTL, and relation to cognition and genetic susceptibility for dementia, has not been investigated in randomized controlled trials (RCTs).Methods: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability is a 2-year RCT enrolling 1260 participants at risk for dementia from the general population, aged 60-77 years, randomly assigned (1:1) to multidomain lifestyle intervention or control group. The primary outcome was cognitive change (Neuropsychological Test Battery z-score). Relative LTL was measured using quantitative real-time polymerase chain reaction (trial registration: NCT01041989).Results: This exploratory LTL substudy included 756 participants (377 intervention, 379 control) with baseline and 24-month LTL measurements. The mean annual LTL change (SD) was -0.016 (0.19) in the intervention group and -0.023 (0.17) in the control group. Between-group difference was nonsignificant (unstandardized β-coefficient 0.007, 95% CI -0.015 to 0.030). Interaction analyses indicated better LTL maintenance among apolipoprotein E (APOE)-ε4 carriers versus noncarriers: 0.054 (95% CI 0.007 to 0.102); younger versus older participants: -0.005 (95% CI -0.010 to -0.001); and those with more versus less healthy lifestyle changes: 0.047 (95% CI 0.005 to 0.089). Cognitive intervention benefits were more pronounced among participants with better LTL maintenance for executive functioning (0.227, 95% CI 0.057 to 0.396) and long-term memory (0.257, 95% CI 0.024 to 0.489), with a similar trend for Neuropsychological Test Battery total score (0.127, 95% CI -0.011 to 0.264).Conclusions: This is the first large RCT showing that a multidomain lifestyle intervention facilitated LTL maintenance among subgroups of older people at risk for dementia, including APOE-ε4 carriers. LTL maintenance was associated with more pronounced cognitive intervention benefits.Clinical Trials Registration Number: NCT01041989. [ABSTRACT FROM AUTHOR]

Background frailty syndrome is common amongst older people. Low physical activity is part of frailty, but long-term prospective studies investigating leisure-time physical activity (LTPA) during the life course as a predictor of frailty are still warranted. The aim of this study is to investigate whether earlier life LTPA predicts frailty in older age. Methods the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) included older adults (aged 60–77 years) from the general population who were at increased risk of cognitive decline. Frailty was assessed for 1,137 participants at a baseline visit using a modified version of Fried's phenotype, including five criteria: weight loss, exhaustion, weakness, slowness and low physical activity. Self-reported data on earlier life LTPA were available from previous population-based studies (average follow-up time 13.6 years). A binomial logistic regression analysis was used to investigate the association between earlier life LTPA and pre-frailty/frailty in older age. Results the prevalence of frailty and pre-frailty was 0.8% and 27.3%, respectively. In the analyses, pre-frail and frail groups were combined. People who had been physically very active (OR 0.37, 95% CI 0.23–0.60) or moderately active (OR 0.45, 95% CI 0.32–0.65) earlier in life had lower odds of becoming pre-frail/frail than individuals who had been sedentary. Conclusions frailty was rare in this relatively healthy study population, but almost a third of the participants were pre-frail. Earlier life LTPA was associated with lower levels of pre-frailty/frailty. The results highlight the importance of physical activity when aiming to promote healthy old age. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the effect of a 2‐year multidomain lifestyle intervention on daily functioning of older people. DESIGN: A 2‐year randomized controlled trial (ClinicalTrials.gov, NCT01041989). SETTING: Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability. PARTICIPANTS: A total of 1260 older adults, with a mean age of 69 years at the baseline, who were at risk of cognitive decline. INTERVENTION: A multidomain intervention, including simultaneous physical activity intervention, nutritional counseling, vascular risk monitoring and management, and cognitive training and social activity. MEASUREMENTS: The ability to perform daily activities (activities of daily living [ADLs] and instrumental ADLs) and physical performance (Short Physical Performance Battery). RESULTS: The mean baseline ADL score was 18.1 (SD = 2.6) points; the scale ranges from 17 (no difficulties) to 85 (total ADL dependence). During the 2‐year intervention, the ADL disability score slightly increased in the control group, while in the intervention group, it remained relatively stable. Based on the latent growth curve model, the difference in the change between the intervention and control groups was −0.95 (95% confidence interval [CI] = −1.61 to −0.28) after 1 year and −1.20 (95% CI = −2.02 to −0.38) after 2 years. In terms of physical performance, the intervention group had a slightly higher probability of improvement (from score 3 to score 4; P = .041) and a lower probability of decline (from score 3 to scores 0‐2; P = .043) for chair rise compared to the control group. CONCLUSION: A 2‐year lifestyle intervention was able to maintain the daily functioning of the at‐risk older population. The clinical significance of these results in this fairly well‐functioning population remains uncertain, but the study results hold promise that healthy eating, exercise, and cognitive and social activity may have favorable effects on functional independence in older people. [ABSTRACT FROM AUTHOR]

Objective To verify whether a multidomain intervention lowers the risk of developing new chronic diseases in older adults. Methods Multicenter, double-blind randomized controlled trial started in October 2009, with 2-year follow-up. A total of 1260 people aged 60 to 77 years were enrolled in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Participants were randomly assigned in a 1:1 ratio to a 2-year multidomain intervention (n = 631) (nutritional guidance, exercise, cognitive training, and management of metabolic and vascular risk factors) or a control group (n = 629) (general health advice). Data on most common chronic diseases were collected by a physician at baseline and 2 years later. Results At 2-year follow-up, the average number of new chronic diseases was 0.47 [standard deviation (SD) 0.7] in the intervention group and 0.58 (SD 0.8) in the control group ( P  < .01). The incidence rate per 100 person-years for developing 1+ new disease(s) was 17.4 [95% confidence interval (CI) = 15.1-20.1] in the intervention group and 20.5 (95% CI = 18.0-23.4) in the control group; for developing 2+ new diseases, 4.9 (95% CI = 3.7-6.4) and 6.1 (95% CI = 4.8-7.8); and for 3+ new diseases, 0.7 (95% CI = 0.4-1.5) and 1.8 (95% CI = 1.1-2.8), respectively. After adjustment for age, sex, education, current smoking, alcohol intake, and the number of chronic diseases at baseline, the intervention group had a hazard ratio ranging from 0.80 (0.66-0.98) for developing 1+ new chronic disease(s) to 0.38 (0.16-0.88) for developing 3+ new chronic diseases compared to the control group. Conclusions Findings from this randomized controlled trial suggest that a multidomain intervention could reduce the risk of developing new chronic diseases in older people. [ABSTRACT FROM AUTHOR]