Matti Viitanen

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.

Prevalence of Alzheimer's disease and other dementias in an elderly urban population Relationship with age, sex, and education

We studied the prevalence of different types of dementia in an elderly population in Stockholm, Sweden, in relation to age, sex, and education. The study confirmed Alzheimers disease (AD) as the most frequent type of dementia and the positive association of dementias with age, even in the most advanced ages. In contrast to previously reported data, we found the same proportion of AD and vascular dementia in the different age strata, and no sex differences regarding the prevalence of different dementia types. Finally, less educated people had a higher prevalence of all dementias, due essentially to a higher prevalence of alcoholic dementia and unspecified type of dementia. The prevalence of AD was similar across different levels of education.

Very Old Women at Highest Risk of Dementia and Alzheimer's Disease Incidence Data from the Kungsholmen Project, Stockholm

Objective: To determine the incidence of different types of dementia in the very old, and to explore the relation with age and gender. Design: A dementia-free cohort was followed for an average of three years in Stockholm, Sweden. At the end of the follow-up, the subjects were interviewed by nurses, clinically examined by physicians, and cognitively assessed by psychologists. Deceased cohort members were studied using death certificates, hospital clinical records, and discharge diagnoses. Dementia diagnoses were made according to the DSM-III-R criteria independently by two physicians. Participants: The cohort consisted of 1,473 subjects (75+ years old), of which 987 were clinically examined at follow-up, 314 died before the examination, and 172 refused to participate. Results: During the follow-up, 148 subjects developed dementia. In the age-group 75 to 79, the incidence rates for dementia were 19.6 for women and 12.4 for men per 1,000 person-years, whereas for 90+ year-old subjects the corresponding figures were 86.7 and 15.0 per 1,000 person-years. A similar pattern of distribution by age and gender was seen for Alzheimers disease. In each age stratum, the incidence rates of dementia and Alzheimers disease were higher for women than for men. The age-adjusted odds ratio for women was 1.9 for dementia and 3.1 for Alzheimers disease. Conclusions: (1) The incidence of dementia increases with age, even in the oldest age groups; (2) women have a higher risk of developing dementia than men, especially at very old ages; (3) this pattern is mainly due to the age and gender distribution of Alzheimers disease, rather than vascular dementia. NEUROLOGY 1997;48: 132-138

Vascular Factors and Risk of Dementia: Design of the Three-City Study and Baseline Characteristics of the Study Population

Objective: To describe the baseline characteristics of the participants in the Three-City (3C) Study, a study aiming to evaluate the risk of dementia and cognitive impairment attributable to vascular factors. Methods: Between 1999 and 2001, 9,693 persons aged 65 years and over, noninstitutionalized, were recruited from the electoral rolls of three French cities, i.e. Bordeaux, Dijon and Montpellier. Health-related data were collected during face-to-face interviews using standardized questionnaires. The baseline examination included cognitive testing and diagnosis of dementia, and assessment of vascular risk factors, including blood pressure measurements, ultrasound examination of the carotid arteries, and measurement of biological parameters (glycemia, total, high-density lipoprotein and low-density lipoprotein cholesterol, triglycerides, creatinemia); 3,442 magnetic resonance imaging (MRI) examinations were performed in subjects aged 65–79. Measurements of ultrasound, blood, and MRI parameters were centralized. Two follow-up examinations (at 2 and 4 years) were planned. Results: After exclusion of the participants who had subsequently refused the medical interview, the 3C Study sample consisted of 3,649 men (39.3%) and 5,645 women, mean age 74.4 years, with a relatively high level of education and income. Forty-two percent of the participants reported to be followed up for hypertension, about one third for hypercholesterolemia, and 8% for diabetes; 65% had elevated blood pressure measures (systolic blood pressure ≧140 or diastolic blood pressure ≧90). The proportion of Mini-Mental State Examination scores below 24 was 7% and dementia was diagnosed in 2.2% of the participants. Conclusion: Distribution of baseline characteristics of the 3C Study participants suggests that this study will provide a unique opportunity to estimate the risk of dementia attributable to vascular factors.

Intracerebroventricular Infusion of Nerve Growth Factor in Three Patients with Alzheimer’s Disease

Nerve growth factor (NGF) is important for the survival and maintenance of central cholinergic neurons, a signalling system impaired in Alzheimer’s disease. We have treated 3 patients with Alzheimer’s disease with a total of 6.6 mg NGF administered continuously into the lateral cerebral ventricle for 3 months in the first 2 patients and a total of 0.55 mg for 3 shorter periods in the third patient. The patients were extensively evaluated with clinical, neuropsychological, neurophysiological and neuroradiological techniques. Three months after the NGF treatment ended, a significant increase in nicotine binding was found in several brain areas in the first 2 patients and in the hippocampus in the third patient as studied by positron emission tomography. A clear cognitive amelioration could not be demonstrated, although a few neuropsychology tests showed slight improvements. The amount of slow-wave cortical activity as studied by electroencephalography was reduced in the first 2 patients. Two negative side effects occurred with NGF treatment: first, a dull, constant back pain was observed in all 3 patients, which in 1 patient was aggravated by axial loading resulting in sharp, shooting pain of short duration. When stopping the NGF infusion, the pain disappeared within a couple of days. Reducing the dose of NGF lessened the pain. Secondly, a marked weight reduction during the infusion with a clear weight gain after ending the infusion was seen in the first 2 patients. We conclude from this limited trial that, while long-term intracerebroventricular NGF administration may cause certain potentially beneficial effects, the intraventricular route of administration is also associated with negative side effects that appear to outweigh the positive effects of the present protocol. Alternative routes of administration, and/or lower doses of NGF, perhaps combined with low doses of other neurotrophic factors, may shift this balance in favor of positive effects.

Poor Outcome After First-Ever Stroke Predictors for Death, Dependency, and Recurrent Stroke Within the First Year

Background and Purpose— The purpose of this study was to define predictors of poor outcome after a first-ever stroke. We studied risk factors and stroke severity at baseline in relationship to death, dependency, and stroke recurrence within a year after the event. Methods— The study included a community-based cohort of first-ever stroke patients. Subarachnoid hemorrhage was not included. All patients (n=377) were subjected to investigations regarding risk factors. Stroke severity was evaluated with the National Institutes of Health Stroke Scale, and dependency was defined according to the modified Rankin Scale. Multivariate regression models were used to analyze predictors of survival, dependency, and stroke recurrence. The following independent variables were used: age, sex, cohabitation status, cigarette smoking, dementia, hypertension, ischemic heart disease, heart failure, atrial fibrillation, diabetes mellitus, transitory ischemic attack, peripheral atherosclerosis, and stroke severity. Results— The 1-year mortality was 33%. After 1 year, 37% of the survivors were dependent; 9% of survivors had a recurrent stroke within a year. Dementia, age, stroke severity, and atrial fibrillation were associated with death within a year. Dependency was associated with age, stroke severity, and heart failure. Stroke recurrence was predicted by age and dementia. Conclusions— In addition to age and stroke severity, heart diseases and dementia before the stroke seem to have an impact on mortality and recurrence after 1 year. Finding and, when possible, treating these prestroke conditions may affect stroke morbidity and mortality favorably.

Nerve growth factor affects11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient (Case Report)

SummaryBased on animal research suggesting that nerve growth factor (NGF) can stimulate central cholinergic neurons, the known losses of cholinergic innervation of the cortices in Alzheimers disease (AD), and our experience of infusing NGF to support adrenal grafts in parkinsonian patients, we have initiated clinical trials of NGF infusions into the brain of patients with AD. Here we report a follow-up of our first case, a 69-year-old woman, with symptoms of dementia since 8 years. Intraventricular infusion of 6.6 mg NGF during three months resulted in a marked transient increase in uptake and binding of11C-nicotine in frontal and temporal cortex and a persistent increase in cortical blood flow as measured by PET as well as progressive decreases of slow wave EEG activity. After one month of NGF, tests of verbal episodic memory were improved whereas other cognitive tests were not. No adverse effects could be ascribed to the NGF infusion. Taken together, the results of this case study indicate that NGF may counteract cholinergic deficits in AD, and suggest that further clinical trials of NGF infusion in AD are warranted.

PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment

Background: Patients with mild cognitive impairment (MCI) have increased risk to develop Alzheimer disease (AD). In AD increased brain amyloid burden has been demonstrated in vivo with PET using N-methyl-[11C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) as a tracer. Objective: To investigate whether patients with amnestic MCI would show increased [11C]PIB uptake, indicating early AD process. Methods: We studied 13 patients with amnestic MCI and 14 control subjects with PET using [11C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum ratio in each voxel over 60 to 90 minutes. Group differences in [11C]PIB uptake were analyzed with statistical parametric mapping (SPM) and automated region-of-interest (ROI) analysis. Results: The SPM analysis showed that patients with MCI had significantly higher [11C]PIB uptake vs control subjects in the frontal, parietal, and lateral temporal cortices as well as in the posterior cingulate showing the most prominent differences. These results were supported by the automated ROI analysis in which MCI patients showed in comparison with healthy control subjects increased [11C]PIB uptake in the frontal cortex (39% increase from the control mean, p < 0.01), the posterior cingulate (39%, p < 0.01), the parietal (31%, p < 0.01) and lateral temporal (28%, p < 0.001) cortices, putamen (17%, p < 0.05), and caudate (25%, p < 0.05). Individually, in the frontal cortex and posterior cingulate, 8 of 13 patients with MCI had [11C]PIB uptake values above 2 SD from the control mean. MCI subjects having at least one APOE ε4 allele tended to have higher [11C]PIB uptake than MCI subjects without APOE ε4. Conclusions: At group level the elevated N-methyl-[11C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB) uptake in patients with mild cognitive impairment (MCI) resembled that seen in Alzheimer disease (AD). At the individual level, about half of the MCI patients had [11C]PIB uptake in the AD range, suggestive of early AD process.

Dementia is the major cause of functional dependence in the elderly: 3-year follow-up data from a population-based study.

OBJECTIVES The purpose of this investigation was to study the role of dementia and other common age-related diseases as determinants of dependence in activities of daily living (ADL) in the elderly. METHODS The study population consisted of 1745 persons, aged 75 years and older, living in a district of Stockholm. They were examined at baseline and after a 3-year follow-up interval. Katzs index was used to measure functional status. Functional dependence at baseline, functional decline, and development of functional dependence at follow-up were examined in relation to sociodemographic characteristics and chronic conditions. RESULTS At baseline, factors associated with functional dependence were age, dementia, cerebrovascular disease, heart disease, and hip fracture. However, only age and dementia were associated with the development of functional dependence and decline after 3 years. In a similar analysis, including only nondemented subjects. Mini-Mental State Examination scores emerged as one of the strongest determinants. The population attributable risk percentage of dementia in the development of functional dependence was 49%. CONCLUSIONS In a very old population, dementia and cognitive impairment make the strongest contribution to both the development of long-term functional dependence and decline in function.

Low blood pressure and dementia in elderly people: the Kungsholmen project

Abstract Objective: To examine the relation between blood pressure and dementia in elderly people. Design: Cross sectional, population based study. Setting: Kungsholmen district of Stockholm, Sweden. Subjects: 1642 subjects aged 75-101 years. Main outcome measures: Prevalence and adjusted odds ratio of dementia by blood pressure. Results: People with systolic pressure </=140 mm Hg were more often diagnosed as demented than those with systolic pressure >140 mm Hg: odds ratios (95% confidence interval) adjusted for age, sex, and education were 2.98 (2.17 to 4.08) for all dementias, 2.91 (1.93 to 4.38) for Alzheimers disease, 2.00 (1.09 to 3.65) for vascular dementia, and 5.07 (2.65 to 9.70) for other dementias. Similar results were seen in subjects with diastolic pressure </=75 mm Hg compared with those with higher diastolic pressure. When severity and duration of dementia were taken into account, only moderate and severe dementia were found to be significantly related to relatively low blood pressure, and the association was stronger in subjects with longer disease duration. Use of hypotensive drugs and comorbidity with cardiovascular disease did not modify the results for all dementias, Alzheimers disease, and other dementias but slightly reduced the association between vascular dementia and diastolic blood pressure. Conclusions: Both systolic and diastolic blood pressure were inversely related to prevalence of dementia in elderly people. We think that relatively low blood pressure is probably a complication of the dementia process, particularly Alzheimers disease, although it is possible that low blood pressure may predispose a subpopulation to developing dementia. Key messages Key messages We studied prevalence of dementia in 1642 subjects aged 75-101 and found that those with relatively low blood pressure (</=140 mm Hg systolic, </=75 mm Hg diastolic) were significantly more likely to have dementia When severity and duration of dementia were taken into account, only moderate and severe dementia were found to be significantly related to low blood pressure, and the association was stronger in subjects with longer duration of disease Use of hypotensive drugs and comorbidity with cardiovascular disease could not account for the association We think that relatively low blood pressure is probably a complication of the dementia process, particularly Alzheimers disease, but it is possible that low pressure may predispose some people to developing dementia