Esko Levälahti

A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial

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. FUNDING Academy of Finland, La Carita Foundation, Alzheimer Association, Alzheimers Research and Prevention Foundation, Juho Vainio Foundation, Novo Nordisk Foundation, Finnish Social Insurance Institution, Ministry of Education and Culture, Salama bint Hamdan Al Nahyan Foundation, Axa Research Fund, EVO funding for University Hospitals of Kuopio, Oulu, and Turku and for Seinäjoki Central Hospital and Oulu City Hospital, Swedish Research Council, Swedish Research Council for Health, Working Life and Welfare, and af Jochnick Foundation.

Heritability of low back pain and the role of disc degeneration.

Abstract Twin studies suggest that both disc degeneration and back pain have a genetic component. We were interested in estimating the heritability of low back pain in men and examining whether genetic influences on back pain are mediated through genetic influences on disc degeneration. Thus, we conducted a classic twin study with multivariate quantitative genetic models to estimate the degree to which genetic (or environmental) effects on back pain were correlated with genetic (or environmental) effects on disc degeneration. Subjects included 147 monozygotic and 153 dizygotic male twin pairs (N = 600 subjects) from the population‐based Finnish Twin Cohort. All subjects underwent lumbar magnetic resonance imaging and completed an extensive interview, including back pain history and exposure to suspected risk factors. Disc height narrowing was the degenerative finding most associated with pain history, and was used to index disc degeneration in the models. Statistically significant genetic correlations were found for disc height narrowing and different definitions of back pain, such as duration of the worst back pain episode (rg = 0.46) and hospitalization for back problems (rg = 0.49), as well as disability in the previous year from back pain (rg = 0.33). The heritability estimates for these back pain variables ranged from 30% to 46%. There also were statistically significant, but weaker, environmental correlations for disc height narrowing with back symptoms over the prior year. A substantial minority of the genetic influences on pain was due to the same genetic influences affecting disc degeneration. This suggests that disc degeneration is one pathway through which genes influence back pain.

Associations of 25 structural, degradative, and inflammatory candidate genes with lumbar disc desiccation, bulging, and height narrowing

OBJECTIVE To examine the allelic diversity of structural, inflammatory, and matrix-modifying gene candidates and their association with disc degeneration. METHODS Subjects were 588 men ages 35-70 years. We investigated associations of single-nucleotide polymorphisms in AGC1 and in 12 collagen, 8 interleukin, and 4 matrix metalloproteinase genes with quantitative magnetic resonance imaging measurements of disc desiccation and disc bulging and height narrowing scores, after controlling for age and suspected risk factors. Analyses were performed using QTDT software. P values were derived from 1,000 permutations, and empirical P values for global significance also were applied. RESULTS Twelve of the 99 variants in 25 selected candidate genes provided evidence of association (P < 0.05) with disc signal intensity in the upper and/or lower lumbar regions. Allelic variants of AGC1 (rs1042631; P = 0.001), COL1A1 (rs2075555; P = 0.005), COL9A1 (rs696990; P = 0.00008), and COL11A2 (rs2076311; P = 0.018) genes provided the most significant evidence of association with disc signal intensity. The same variants of AGC1 (P = 0.010) and COL9A1 (P = 0.014), as well as variants in the COL11A1 gene (rs1463035 [P = 0.004]; rs1337185 [P = 0.015]) were also associated with disc bulging, as was AGC1 with disc height narrowing (rs1516797; P = 0.005). In addition, 4 allelic variants in the immunologic candidate genes (rs2071375 in IL1A [P = 0.027]; rs1420100 in IL18RAP [P = 0.005]) were associated with disc signal intensity. CONCLUSION Genetic variants account for interindividual differences in disc matrix synthesis and degradation. The accuracy of the quantitative disc signal intensity measurements we used likely enhanced our ability to observe these associations. Our findings shed light on possible mechanisms of degeneration and support the view that disc degeneration is a polygenetic condition.

Genetic and environmental effects on disc degeneration by phenotype and spinal level: a multivariate twin study.

Study Design. A classic twin study with multivariate analyses was conducted. Objective. We aimed to further clarify the presence and magnitude of genetic influences on disc degeneration, and to better understand the phenomenon of disc degeneration through comparisons of genetic and environmental influences on specific degenerative signs and different lumbar levels. Summary of Background Data. Previous studies suggest a substantial genetic influence on disc degeneration, but raise important questions about which disc phenotypes are or are not largely genetically influenced and differential effects on spinal levels. Methods. The study sample consisted of 152 monozygotic and 148 dizygotic male twin pairs, 35 to 70 years of age, from the population-based Finnish Twin Cohort. Lumbar magnetic resonance imaging was conducted with quantitative or qualitative assessments of disc signal, bulging, and height narrowing at each lumbar level. Data on possible confounding factors were obtained from an extensive, structured interview. Quantitative genetic modeling was conducted using MPlus. Results. Heritability estimates varied from 29% to 54%, depending on the particular disc degeneration phenotype and lumbar level. The same genetic influences affected signal intensity and disc height (genetic correlations of −0.60– −0.66) or bulging (−0.71– −0.72) to a great degree at either the lower or upper lumbar levels and genetic influences on disc height narrowing and bulging were virtually the same. (0.92–0.97). Conversely, genetic correlations (and environmental correlations)were substantially lower for upper and lower lumbar levels, implying largely independent effects. Conclusion. Genetic and environmental influences on disc degeneration seem to be of similar importance. Disc signal, narrowing, and bulging had a primarily common genetic pathway, suggesting a common genetic etiopathogenesis. Conversely, genetic and environmental influences differed substantially for upper versus lower lumbar levels, emphasizing the importance of examining these levels separately in studies of associated genes, other constitutional factors, and environmental influences.

The Effects of Anthropometrics, Lifting Strength, and Physical Activities in Disc Degeneration

Study Design. A cross-sectional study design was used. Objective. The objective was to examine the influences of body anthropometrics, axial disc area, and lifting strength on disc degeneration and to compare these with the effects of lifetime physical demands and age. Summary of Background Data. Although recent studies have shown that heredity is a dominant factor in disc degeneration, the common notion that occupational physical loading is the major risk factor persists. However, substantial variations in disc degeneration, particularly at the lowest lumbar levels, remain unexplained by heredity or occupational physical demands. Methods. Univariate methods and stepwise multiple regression modeling were used to estimate associations of body height, weight, fat content, axial disc area, isokinetic lifting performance, and lifetime routine physical activities at work and leisure with disc height narrowing and disc signal (in T2 images) based on lumbar MRIs. These data were available from a population sample of 600 men, 35 to 70 years of age. Results. Lower disc signal, representing disc desiccation, was associated with higher age, lower body mass and lifting strength, and larger axial disc area. Of the variance in disc signal, age explained 8.0% (P < 0.001) and body weight/axial disc area, isokinetic lifting strength, and occupational lifting history added 3.9%, 2.3%, and 1.3%, respectively. Greater disc narrowing was associated with higher age, larger axial disc area, and higher occupational physical loading. Of the variance in disc narrowing, age accounted for 3.8% (P < 0.001); axial disc area and occupational loading added 1.9% (P < 0.004) and 1.3% (P < 0.007), respectively. Conclusions. Body weight, lifting strength, and axial disc area were more highly associated with disc degeneration than occupational and leisure physical activity histories, although all had modest influences. Furthermore, higher body mass, greater lifting strength, and heavier work were all associated with more disc height narrowing but less disc desiccation contrary to current views. Smaller discs appeared to have beneficial effects.

The Genetic Liability to Disability Retirement: A 30-Year Follow-Up Study of 24,000 Finnish Twins

Background No previous studies on the effect of genetic factors on the liability to disability retirement have been carried out. The main aim of this study was to investigate the contribution of genetic factors on disability retirement due to the most common medical causes, including depressive disorders. Methods The study sample consisted of 24 043 participants (49.7% women) consisting of 11 186 complete same-sex twin pairs including 3519 monozygotic (MZ) and 7667dizygotic (DZ) pairs. Information on retirement events during 1.1.1975–31.12.2004, including disability pensions (DPs) with diagnoses, was obtained from the Finnish nationwide official pension registers. Correlations in liability for MZ and DZ twins and discrete time correlated frailty model were used to investigate the genetic liability to age at disability retirement. Results The 30 year cumulative incidence of disability retirement was 20%. Under the best fitting genetic models, the heritability estimate for DPs due to any medical cause was 0.36 (95% CI 0.32–0.40), due to musculoskeletal disorders 0.37 (0.30–0.43), cardiovascular diseases 0.48 (0.39–0.57), mental disorders 0.42 (0.35–0.49) and all other reasons 0.24 (0.17–0.31). The effect of genetic factors decreased with increasing age of retirement. For DP due to depressive disorders, 28% of the variance was explained by environmental factors shared by family members (95% CI 21–36) and 58% of the variance by the age interval specific environmental factors (95% CI 44–71). Conclusions A moderate genetic contribution to the variation of disability retirement due to any medical cause was found. The genetic effects appeared to be stronger at younger ages of disability retirement suggesting the increasing influence of environmental factors not shared with family members with increasing age. Familial aggregation in DPs due to depressive disorders was best explained by the common environmental factors and genetic factors were not needed to account for the pattern of familial aggregation.

Heritability of BMD of femoral neck and lumbar spine: a multivariate twin study of Finnish men.

Of the 80% variation in BMD among male twins that is caused by genetics, part was explained by genetic influences on lifting strength and lean body mass/height. Lifting strength was significant in both the femoral and spine BMD and body weight only for lumbar BMD.

Evidence that BMI and type 2 diabetes share only a minor fraction of genetic variance: a follow-up study of 23,585 monozygotic and dizygotic twins from the Finnish Twin Cohort Study

Aims/hypothesisWe investigated whether BMI predicts type 2 diabetes in twins and to what extent that is explained by common genetic factors.MethodsThis was a population-based twin cohort study. Monozygotic (n = 4,076) and dizygotic (n = 9,109) non-diabetic twin pairs born before 1958 answered a questionnaire in 1975, from which BMI was obtained. Information on incident cases of diabetes was obtained by linkage to nationwide registers until 2005.ResultsAltogether, 1,332 twins (6.3% of men, 5.1% of women) developed type 2 diabetes. The HR for type 2 diabetes increased monotonically with a mean of 1.22 (95% CI 1.20–1.24) per BMI unit and of 1.97 (95% CI 1.87–2.08) per SD of BMI. The HRs for lean, overweight, obese and morbidly obese participants were 0.59, 2.96, 6.80 and 13.64 as compared with normal weight participants. Model heritability estimates for bivariate variance due to an additive genetic component and non-shared environmental component were 75% (men) and 71% (women) for BMI, and 73% and 64%, respectively for type 2 diabetes. The correlations between genetic variance components (rg) indicated that one fifth of the covariance of BMI and type 2 diabetes was due to shared genetic influences. Although the mean monozygotic concordance for type 2 diabetes was approximately twice the dizygotic one, age of onset of diabetes within twin pair members varied greatly, irrespective of zygosity.Conclusions/interpretationA 28-year follow-up of adult Finnish twins showed that despite high trait heritability estimates, only a fraction of covariation in BMI and incident type 2 diabetes was of genetic origin.

Heart Diseases and Long-Term Risk of Dementia and Alzheimer's Disease: A Population-Based CAIDE Study

BACKGROUND Many cardiovascular risk factors are shown to increase the risk of dementia and Alzheimers disease (AD), but the impact of heart disease on later development of dementia is still unclear. OBJECTIVE The aim of the study was to investigate the long-term risk of dementia and Alzheimers disease (AD) related to midlife and late-life atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD) in a population-based study with a follow-up of over 25 years. METHODS Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study includes 2000 participants who were randomly selected from four separate, population-based samples originally studied in midlife (1972, 1977, 1982, or 1987). Re-examinations were carried out in 1998 and 2005-2008. Altogether 1,510 (75.5%) persons participated in at least one re-examination, and 127 (8.4%) persons were diagnosed with dementia (of which 102 had AD). RESULTS AF in late-life was an independent risk factor for dementia (HR 2.61, 95% CI 1.05-6.47; p = 0.039) and AD (HR 2.54, 95% CI 1.04-6.16; p = 0.040) in the fully adjusted analyses. The association was even stronger among the apolipoprotein E (APOE) ε4 non-carriers. Late-life HF, but not CAD, tended to increase the risks as well. Heart diseases diagnosed at midlife did not increase the risk of later dementia and AD. CONCLUSION Late-life heart diseases increase the subsequent risk of dementia and AD. Prevention and effective treatment of heart diseases may be important also from the perspective of brain health and cognitive functioning.

Characteristics and health consequences of intermittent smoking: Long-term follow-up among Finnish adult twins

INTRODUCTION The definition of a smoker as someone who smokes daily has been challenged. No consensus exists regarding whether intermittent smoking represents transition toward daily smoking or cessation or whether intermittent smokers consistently maintain their low tobacco use frequency. Although abundant evidence supports the adverse health consequences of daily smoking, less evidence is available on intermittent smoking. METHODS We examined characteristics and health consequences of intermittent cigarette smoking among Finnish adult twins. We used longitudinal data of 21,340 persons with smoking status from questionnaires in 1975 and 1981 and data on lung cancer incidence from 1982 to 2004 from the Finnish Cancer Registry. RESULTS We identified 641 consistent intermittent smokers comprising 3% of the study population. Consistent intermittent smokers had higher education, less use of other tobacco products, healthier lifestyles, and partly more favorable mental health profiles compared with lifetime regular smokers. However, in terms of other lifestyle factors, intermittent smokers compared mostly unfavorably with never-smokers, despite being better educated. Intermittent smoking showed substantial heritability. There were 213 incident lung cancer cases among all study subjects; only one case was found among the intermittent smokers. The sex- and age-adjusted hazard ratios of lung cancer were not significantly elevated for the intermittent smokers, but they were increased more than 10-fold for all other smokers. DISCUSSION Although the present study did not find evidence of elevated lung cancer risk among intermittent smokers, compared with never-smokers, further studies should investigate other health consequences of intermittent smoking, such as cardiovascular and nonmalignant pulmonary outcomes.