Hilkka Soininen

Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease

BACKGROUND Physical activity may help maintain cognitive function and decrease dementia risk, but epidemiological findings remain controversial. The aim of our study was to investigate the association between leisure-time physical activity at midlife and the subsequent development of dementia and Alzheimers disease (AD). METHODS Participants were randomly selected from the survivors of a population-based cohort previously surveyed in 1972, 1977, 1982, or 1987. 1449 persons (72.5%) age 65-79 years participated in the re-examination in 1998 (mean follow-up, 21 years). 117 persons had dementia and 76 had AD. Multiple logistic regression methods were used to analyse the association between leisure-time physical activity and dementia or AD. FINDINGS Leisure-time physical activity at midlife at least twice a week was associated with a reduced risk of dementia and AD (odds ratio [OR] 0.48 [95% CI 0.25-0.91] and 0.38 [0.17-0.85], respectively), even after adjustments for age, sex, education, follow-up time, locomotor disorders, APOE genotype, vascular disorders, smoking, and alcohol drinking. The associations were more pronounced among the APOE epsilon4 carriers. INTERPRETATION Leisure-time physical activity at midlife is associated with a decreased risk of dementia and AD later in life. Regular physical activity may reduce the risk or delay the onset of dementia and AD, especially among genetically susceptible individuals.

A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD

Objective: To evaluate the long-term clinical efficacy and safety of donepezil versus placebo over 1 year in patients with mild to moderate AD. Methods: Patients (n = 286; mean age, 72.5 years) with possible or probable AD from five Northern European countries were randomized to receive either donepezil (n = 142; 5 mg/day for 28 days, followed by 10 mg/day) or placebo (n = 144) for 1 year. Results: The study was completed by 66.9% of the donepezil- and 67.4% of the placebo-treated patients. The benefit of donepezil over placebo was demonstrated by the Gottfries-Bråne-Steen (a global assessment for rating dementia symptoms) total score at weeks 24, 36, and 52 (p < 0.05) and at the study end point (week 52, last observation carried forward; p = 0.054). Advantages of donepezil over placebo were also observed in cognition and activities of daily living (ADL) assessed by the Mini-Mental State Examination at weeks 24, 36, and 52, and the end point (p < 0.02) and by the Progressive Deterioration Scale at week 52 and the end point (p < 0.05). Adverse events (AE) were recorded for 81.7% of donepezil- and 75.7% of placebo-treated patients, with 7% of donepezil- and 6.3% of placebo-treated patients discontinuing because of AE. Treatment response to donepezil was not predicted by APOE genotype or sex in this population. Conclusion: As the first 1-year, multinational, double-blinded, placebo-controlled study of a cholinesterase inhibitor in AD, these data support donepezil as a well tolerated and effective long-term treatment for patients with AD, with benefits over placebo on global assessment, cognition, and ADL.

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.

Cerebrospinal fluid β-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain

BACKGROUND There is a clear need to develop an objective diagnostic test for Alzheimer disease (AD). Changes in the levels of cerebrospinal fluid (CSF) tau protein and beta-amyloid 42 (Abeta42) peptide in patients with AD have been well documented, but the relationship between these biomarkers and neuropathologic changes in the brain is not established. OBJECTIVE To study the relationship between antemortem CSF biomarker levels and Alzheimer-type neuropathologic changes in the brain. DESIGN Cross-sectional study to correlate levels of CSF Abeta42, total tau, and phosphorylated tau protein with neuropathologic changes in the brain. SETTING Academic research. Patients The study included 123 patients (79 with clinically diagnosed AD, 29 with other dementia, and 15 with other neurologic disease). All underwent clinical evaluation and provided antemortem lumbar CSF samples, and neuropathologic data were collected from September 11, 1990, to March 13, 2003, in the Department of Neuroscience and Neurology, University of Kuopio, Kuopio, Finland. MAIN OUTCOME MEASURES Levels of CSF Abeta42, total tau, and phosphorylated tau protein were measured using standard commercial immunoassays. Neuropathologic evaluations included the classic silver impregnation method and immunohistochemistry for Abeta, hyperphosphorylated tau, and alpha-synuclein. RESULTS Cerebrospinal fluid Abeta42 and tau protein levels were related to amyloid load and the presence of neurofibrillary pathologic abnormalities in the brain. Cerebrospinal fluid Abeta42 level correlated inversely with total Abeta load in the brain, and CSF tau level correlated with results of immunohistochemistry for hyperphosphorylated tau and with the presence of neocortical neurofibrillary tangles. In multivariate logistic regression analysis, the number of neuritic plaques in the brain remained a significant predictor of decreased CSF Abeta42 level and of increased CSF tau level. Based on the ratio of phosphorylated tau level to Abeta42 level, sensitivity was 91.6%, and specificity was 85.7%, with an overall accuracy of 90.2% for the presence of pathologic neuritic plaque in the brain. CONCLUSIONS Cerebrospinal fluid Abeta42 and tau proteins are biomarkers of AD-associated pathologic changes in the brain. The combination of abnormally low CSF Abeta42 level and abnormally high CSF tau level predicted the presence of AD pathologic features with high accuracy. This combination assay may be helpful in diagnosing the presence of AD pathologic changes in the brain.

Consensus Report of the Working Group on : Molecular and Biochemical Markers of Alzheimer's Disease

The ideal biomarker for Alzheimers disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases; it should have a sensitivity >80% for detecting AD and a specificity of >80% for distinguishing other dementias; it should be reliable, reproducible, non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Our review of current candidate markers indicates that for suspected early-onset familial AD, it is appropriate to search for mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes. Individuals with these mutations typically have increased levels of the amyloid Abeta42 peptide in plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and sporadic AD, these measures are not useful, but detecting an apolipoprotein E e4 allele can add confidence to the clinical diagnosis. Among the other proposed molecular and biochemical markers for sporadic AD, cerebrospinal fluid assays showing low levels of Abeta42 and high levels of tau come closest to fulfilling criteria for a useful biomarker.The ideal biomarker for Alzheimers disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases: it should have a sensitivity >80% for detecting AD and a specificity of >80% for distinguishing other dementias: it should be reliable, reproducible non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Our review of current candidate markers indicates that for suspected early-onset familial AD. it is appropriate to search for mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes. Individuals with these mutations typically have increased levels of the amyloid Aβ 42 peptide in plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and sporadic AD. these measures are not useful. but detecting an apolipoprotein E e4 allele can add confidence to the clinical diagnosis. Among the other proposed molecular and biochemical markers for sporadic AD. cerebrospinal fluid assays showing low levels of Aβ 42 and high levels of tau come closest to fulfilling criteria for a useful biomarker.

Apolipoprotein E 4 Allele, Elevated Midlife Total Cholesterol Level, and High Midlife Systolic Blood Pressure Are Independent Risk Factors for Late-Life Alzheimer Disease

Context Apolipoprotein E (apoE) 4 allele, elevated total cholesterol level, and hypertension are risk factors for late-life Alzheimer disease. Are these risk factors independent, or do the effects of apoE polymorphism on cholesterol metabolism mediate the association between apoE and Alzheimer disease? Contribution In this long-term, prospective population-based study, apoE, elevated total cholesterol level, and elevated systolic hypertension increased the risk for Alzheimer disease in an independent and additive manner. Implications The mechanism by which apoE polymorphism contributes to the development of Alzheimer disease appears different than the mechanism that mediates its effect on cholesterol level. Some risk factors for Alzheimer disease (dyslipidemia and systolic hypertension) are potentially treatable, while others (apoE) are not. The Editors Alzheimer disease is a disease of complex origin, and the exact pathogenic mechanisms remain unknown. Several environmental and genetic factors have been implicated in the development of Alzheimer disease. Two lines of research have recently shown an association between serum total cholesterol level and development of the disease. First, two independent, prospective population-based studies have reported an association between elevated midlife total cholesterol levels and late-life Alzheimer disease (1, 2). Second, two recent studies have shown a reduced rate of the disease in persons who used statins to reduce their blood total cholesterol level (3, 4). To date, only the apolipoprotein E (apoE) 4 allele, which is involved in cholesterol metabolism, has been established as a significant genetic risk factor for Alzheimer disease in the general population (5). Whether the associations of elevated level of serum total cholesterol and apoE polymorphism with Alzheimer disease are independent or interrelated is unknown. Earlier cross-sectional and short follow-up studies yielded conflicting results on the putative relationship among apoE, total cholesterol level, and Alzheimer disease (6-8). Although long-term prospective studies may be better suited for resolving this issue, only two such studies have been reported to date. The first study found that elevated serum total cholesterol level was a risk factor for Alzheimer disease, independent of the apoE 4 allele; however, the association between the apoE 4 allele and Alzheimer disease became weaker after adjustment for serum total cholesterol level (1). Thus, the authors of that study concluded that some of the effect of the apoE 4 allele on the risk for Alzheimer disease might be mediated through elevated levels of serum total cholesterol. In contrast, another prospective study suggested that the presence of the apoE 4 allele may increase the risk for Alzheimer disease, independent of its effect on dyslipidemia and atherogenesis (9). Few prospective studies have suggested that elevated blood pressure earlier in life could increase the risk for Alzheimer disease (2, 10, 11). Although the association between apoE and blood pressure appears to be vague, some studies have reported excess cognitive decline in persons with hypertension who have the apoE 4 allele (12, 13). Moreover, atherosclerosis, which can result from an elevated total cholesterol level or blood pressure, has been studied in relation to Alzheimer disease and apoE polymorphism, also with conflicting results (14, 15). Alzheimer disease is becoming an increasingly serious public health problem. Interventions that could delay disease onset could therefore have a major public health impact. The number of patients with Alzheimer disease is projected to quadruple over the next 50 years, and interventions that would postpone the onset of clinical Alzheimer disease by 5 years would decrease the prevalence of the disease by 50% (16). Alzheimer disease might be prevented by use of interventions for modifiable vascular risk factors. However, the relative importance and putative interactions between vascular risk factors and the apoE polymorphism in the development of Alzheimer disease in the general population remain to be established. We have previously reported that elevated total cholesterol level and systolic blood pressure during midlife increased the risk for Alzheimer disease (2). We recently determined the apoE genotypes in this sample and have therefore been able to study the putative relationship among the apoE 4 allele, midlife total cholesterol level, and midlife blood pressure in the development of Alzheimer disease in a prospective, population-based study setting. Methods Participants The participants in this study were derived from four separate, independent population-based samples studied within the framework of the North Karelia Project and the Finnish part of the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (FINMONICA) studies in 1972, 1977, 1982, and 1987 (17, 18). (The survey methods were carefully standardized and followed the World Health Organization protocol for the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease [MONICA] study [17].) The participation rates in these surveys were high, ranging from 82% to 92%. For the current study, we targeted past participants who were still alive at the end of 1997; 65 to 79 years of age; and who lived in or near Kuopio or Joensuu, Finland (n = 2293). We invited a random sample of 2000 persons within this group to a reexamination in 1998. Altogether, 1449 persons (72.5% of the invited sample) participated. The mean follow-up (SD) was 21.0 4.9 years (range, 11 to 26 years). (The duration of follow-up was 26 years for 34.9% of the current study sample, 21 years for 38.1%, 16 years for 15.6%, and 11 years for 11.4%.) The ethics committees of the University of Kuopio and the Kuopio University Hospital, Kuopio, Finland, approved the study protocol. All participants provided written informed consent. Midlife Visit The study protocol is described in detail elsewhere (19). In brief, the survey included a self-administered questionnaire on sociodemographic characteristics; health-related behaviors, including smoking habits and alcohol consumption; and medical history, including cerebrovascular and cardiovascular events and conditions diagnosed by a physician. Height and weight were measured. Blood pressure was measured from the right arm after the participants had been seated for 5 minutes. For most of the current study sample, only a single blood pressure measurement had been recorded in the initial survey. (In the 1972 survey, blood pressure was recorded once; for 186 of 531 participants in the 1977 survey and for all participants in the subsequent surveys, blood pressure was recorded twice.) Venous blood specimens were taken to determine serum total cholesterol levels. Serum total cholesterol level was determined in 1972 and 1977 from frozen serum samples by using the Liebermann-Burchard method; in 1982 and 1987, total cholesterol level in fresh serum samples was measured by using an enzymatic method (CHOD-PAP Monotest, Boehringer, Mannheim, Germany). The enzymatic assay yielded values that were 2.4% lower than those measured by the Liebermann-Burchard method; thus, we corrected the values for total cholesterol level from the 1972 and 1977 surveys accordingly. All cholesterol levels were determined at the same central laboratory, and the laboratory data were standardized against those of national and international reference laboratories. Reexamination in 1998 During the reexamination, the survey methods followed the standards of the previous surveys in all aspects. Cognitive impairment and dementia were diagnosed in three phases: a screening phase, a clinical phase, and a differential diagnostic phase. Cases of dementia were diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (20); Alzheimer disease was diagnosed according to the criteria of the U.S. National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association (21). In addition, mild cognitive impairments were diagnosed by using the criteria proposed by the Mayo Clinic Alzheimers Disease Research Center (22). Blood leukocyte samples were analyzed to determine apoE genotype. To extract DNA, we used a standard phenol-chloroform technique; apoE genotypes were analyzed by polymerase chain reaction and HhaI digestion, as described previously (23). Statistical Analyses We analyzed the data using SPSS software for Windows, version 9.0 (SPSS Inc., Chicago, Illinois). We performed a chi-square test to compare the frequency of the apoE allele between controls and participants with Alzheimer disease. We studied the association between the apoE 4 allele and Alzheimer disease by using logistic regression analyses. We present these results as odds ratios with 95% CIs. From model 1, we determined univariate odds ratios. To study whether the apoE 4 allele was associated with Alzheimer disease, independent of midlife hypercholesterolemia and elevated systolic blood pressure, we included the variables of apoE genotype (4 carriers or noncarriers), total cholesterol level, and systolic blood pressure (according to categories) in the second model (model 2). In model 2, we also adjusted for the additional variables of age, history of myocardial infarction (yes or no), history of cerebrovascular symptoms (yes or no), education (years of formal education), sex, smoking status (current smoker, former smoker, or nonsmoker), and alcohol consumption (none, <10 g/d, 10 to 30 g/d, or >30 g/d). Midlife values for serum total cholesterol were classified as high ( 6.5 mmol/L [ 251 mg/dL]) or normal (<6.5 mmol/L [<251 mg/dL]). Midlife blood pressure was classified according to the following groups: normal (<140 mm Hg), borderline (140 to 159 mm Hg), or high ( 160 mm Hg) for systolic blood pressur

Hippocampus and entorhinal cortex in mild cognitive impairment and early AD

Magnetic resonance imaging (MRI) has been suggested as a useful tool in early diagnosis of Alzheimers disease (AD). Based on MRI-derived volumes, we studied the hippocampus and entorhinal cortex (ERC) in 59 controls, 65 individuals with mild cognitive impairment (MCI) and 48 patients with AD. The controls and individuals with MCI were derived from population-based cohorts. Volumes of the hippocampus and ERC were significantly reduced in the following order: control > MCI > AD. Stepwise discriminant function analysis showed that the most efficient overall classification between controls and individuals with MCI subjects was achieved with ERC measurements (65.9%). However, the best overall classification between controls and AD patients (90.7%), and between individuals with MCI and AD patients (82.3%) was achieved with hippocampal volumes. Our results suggest that the ERC atrophy precedes hippocampal atrophy in AD. The ERC volume loss is dominant over the hippocampal volume loss in MCI, whereas more pronounced hippocampal volume loss appears in mild AD.

Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study.

BACKGROUND Several vascular risk factors are associated with dementia. We sought to develop a simple method for the prediction of the risk of late-life dementia in people of middle age on the basis of their risk profiles. METHODS Data were used from the population-based CAIDE study, which included 1409 individuals who were studied in midlife and re-examined 20 years later for signs of dementia. Several midlife vascular risk factors were studied to create the scoring tool. The score values were estimated on the basis of beta coefficients and the dementia risk score was the sum of these individual scores (range 0-15). FINDINGS Occurrence of dementia during the 20 years of follow-up was 4%. Future dementia was significantly predicted by high age (> or = 47 years), low education (< 10 years), hypertension, hypercholesterolaemia, and obesity. The dementia risk score predicted dementia well (area under curve 0.77; 95% CI 0.71-0.83). The risk of dementia according to the categories of the dementia risk score was 1.0% for those with a score of 0-5, 1.9% for a score of 6-7, 4.2% for a score of 8-9, 7.4% for a score of 10-11, and 16.4% for a score of 12-15. When the cut-off of 9 points or more was applied the sensitivity was 0.77, the specificity was 0.63, and the negative predictive value was 0.98. INTERPRETATION The dementia risk score is a novel approach for the prediction of dementia risk, but should be validated and further improved to increase its predictive value. This approach highlights the role of vascular factors in the development of dementia and could help to identify individuals who might benefit from intensive lifestyle consultations and pharmacological interventions.

Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study

BACKGROUND Alzheimers disease (AD) pathology is common in patients with amnestic mild cognitive impairment (aMCI) without dementia, but the prevalence of AD pathology in patients with subjective cognitive impairment (SCI) and non-amnestic mild cognitive impairment (naMCI) is unknown. AD is characterised by decreased CSF concentrations of Abeta(42) and increased concentrations of tau. We investigated the prevalence of a CSF AD profile in patients with SCI, naMCI, or aMCI and the association of this profile with cognitive outcome in each group. METHODS Patients with SCI, naMCI, aMCI, and neurologically healthy controls were recruited from 20 memory clinics across Europe, between January, 2003, and June, 2005, into this prospective cohort study. A CSF AD profile was defined as an abnormal ratio of Abeta(42):tau. Patients were assessed annually up to 3 years. Outcome measures were changes in memory, overall cognition, mini-mental state examination (MMSE) score, daily function, and progression to AD-type dementia. FINDINGS The CSF AD profile was more common in patients with SCI (31 of 60 [52%]), naMCI (25 of 37 [68%]), and aMCI (56 of 71 [79%]) than in healthy controls (28 of 89 [31%]). The profile was associated with cognitive decline in patients with naMCI (memory, MMSE, and daily function) and in patients with aMCI (MMSE and daily function). In patients with aMCI, a CSF AD profile was predictive of AD-type dementia (OR 26.8, 95% CI 1.6-456.4). INTERPRETATION AD is a common cause of SCI, naMCI, and aMCI and is associated with cognitive decline in patients with naMCI or aMCI. Patients with SCI might be in the early stages of AD, and cognitive decline might become apparent only after longer follow-up. FUNDING European Commission; Ana Aslan International Foundation.

Fast and robust multi-atlas segmentation of brain magnetic resonance images.

We introduce an optimised pipeline for multi-atlas brain MRI segmentation. Both accuracy and speed of segmentation are considered. We study different similarity measures used in non-rigid registration. We show that intensity differences for intensity normalised images can be used instead of standard normalised mutual information in registration without compromising the accuracy but leading to threefold decrease in the computation time. We study and validate also different methods for atlas selection. Finally, we propose two new approaches for combining multi-atlas segmentation and intensity modelling based on segmentation using expectation maximisation (EM) and optimisation via graph cuts. The segmentation pipeline is evaluated with two data cohorts: IBSR data (N=18, six subcortial structures: thalamus, caudate, putamen, pallidum, hippocampus, amygdala) and ADNI data (N=60, hippocampus). The average similarity index between automatically and manually generated volumes was 0.849 (IBSR, six subcortical structures) and 0.880 (ADNI, hippocampus). The correlation coefficient for hippocampal volumes was 0.95 with the ADNI data. The computation time using a standard multicore PC computer was about 3-4 min. Our results compare favourably with other recently published results.