Ingmar Skoog

A Population-Based Study of Dementia in 85-Year-Olds

BACKGROUND The aim of this study was to investigate the causes, severity, and prevalence of dementia in a representative sample of 494 85-year-olds living in Gothenburg, Sweden. METHODS The study included a psychiatric interview, neuropsychological and physical examinations, comprehensive laboratory tests, electrocardiography, chest radiography, computed tomography (CT) of the head, and analysis of cerebrospinal fluid. A person close to each subject was also interviewed. Dementia was defined according to the criteria proposed in the Diagnostic and Statistical Manual of Mental Disorders (third edition, revised), Alzheimers disease according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association, and vascular dementia according to recently proposed criteria that incorporate information from CT scanning and the patients neurologic history. RESULTS The prevalence of dementia was 29.8 percent (147 subjects). The condition was mild in 8.3 percent, moderate in 10.3 percent, and severe in 11.1 percent. There were no significant sex-related differences in prevalence or severity. Of the subjects with dementia, 43.5 percent had Alzheimers disease, 46.9 percent had vascular dementia (multi-infarct dementia in 34.6 percent, dementia related to cerebral hypoperfusion in 4.1 percent, and mixed dementia in 8.2 percent), and 9.5 percent had dementia due to other causes. The three-year mortality rate was 23.1 percent in the subjects without dementia, 42.2 percent in the patients with Alzheimers disease, and 66.7 percent in the patients with vascular dementia. Infarcts detected by CT scanning were significantly more common in the subjects with dementia than in those without it (27.9 percent vs. 12.6 percent). CONCLUSIONS Dementia was present in nearly a third of unselected 85-year-olds in Sweden. Almost half these subjects appeared to have vascular dementia, which may currently be more amenable to prevention or treatment than Alzheimers disease.

High total cholesterol levels in late life associated with a reduced risk of dementia

Objective: To examine the longitudinal association between plasma total cholesterol and triglyceride levels and incident dementia. Methods: Neuropsychiatric, anthropometric, laboratory, and other assessments were conducted for 392 participants of a 1901 to 1902 birth cohort first examined at age 70. Follow-up examinations were at ages 75, 79, 81, 83, 85, and 88. Information on those lost to follow-up was collected from case records, hospital linkage system, and death certificates. Cox proportional hazards regression examined lipid levels at ages 70, 75, and 79 and incident dementia between ages 70 and 88. Results: Increasing cholesterol levels (per mmol/L) at ages 70 (hazard ratio [HR] 0.77, 95% CI: 0.61 to 0.96, p = 0.02), 75 (HR 0.70, CI: 0.52 to 0.93, p = 0.01), and 79 (HR 0.73, CI: 0.55 to 0.98, p = 0.04) were associated with a reduced risk of dementia between ages 79 and 88. Examination of cholesterol levels in quartiles showed that the risk reduction was apparent only among the highest quartile at ages 70 (8.03 to 11.44 mmol/L [311 to 442 mg/dL]; HR 0.31, CI: 0.11 to 0.85, p = 0.03), 75 (7.03 to 9.29 mmol/L [272 to 359 mg/dL]; HR 0.20, CI: 0.05 to 0.75, p = 0.02), and 79 (6.82 to 9.10 mmol/L [264 to 352 mg/dL]; HR 0.45, CI: 0.17 to 1.23, p = 0.12). Triglyceride levels were not associated with dementia. Conclusions: High cholesterol in late life was associated with decreased dementia risk, which is in contrast to previous studies suggesting high cholesterol in mid-life is a risk factor for later dementia. The conflicting results may be explained by the timing of the cholesterol measurements in relationship to age and the clinical onset of dementia.

Burden of illness and suicide in elderly people: case-control study

Abstract Objectives: To study the association between physical illness and suicide in elderly people. Design: Case-control with illness determined from interviews with relatives of people who committed suicide and with control participants and from medical records. Setting: Gothenburg and two surrounding counties (210 703 people aged 65 years and over). Participants: Consecutive records of people who had committed suicide and had undergone forensic examination (46 men, 39 women) and living control participants from the tax register (84 men, 69 women). Main outcome measures: Physical illness rated in 13 organ systems according to the cumulative illness rating scale-geriatrics; serious physical illness (organ category score 3 or 4); overall score for burden of physical illness. Results: Visual impairment (odds ratio 7.0, 95% confidence interval 2.3 to 21.4), neurological disorders (3.8, 1.5 to 9.4), and malignant disease (3.4, 1.2 to 9.8) were associated with increased risk for suicide. Serious physical illness in any organ category was an independent risk factor for suicide in the multivariate regression model (6.4, 2.0 to 20.0). When the sexes were analysed separately, serious physical illness was associated with suicide in men (4.2, 1.8 to 9.5) as was high burden of physical illness (2.8, 1.2 to 6.5). Such associations were not seen in women, possibly because of the small sample size. Conclusions: Visual impairment, neurological disorders, and malignant disease were independently associated with increased risk of suicide in elderly people. Serious physical illness may be a stronger risk factor for suicide in men than in women.

A 24-year follow-up of body mass index and cerebral atrophy

Objective: To investigate the longitudinal relationship between body mass index (BMI), a major vascular risk factor, and cerebral atrophy, a marker of neurodegeneration, in a population-based sample of middle-aged women. Methods: A representative sample of 290 women born in 1908, 1914, 1918, and 1922 was examined in 1968 to 1969, 1974 to 1975, 1980 to 1981, and 1992 to 1993 as part of the Population Study of Women in Göteborg, Sweden. At each examination, women completed a survey on a variety of health and lifestyle factors and underwent anthropometric, clinical, and neuropsychiatric assessments and blood collection. Atrophy of the temporal, frontal, occipital, and parietal lobes was measured on CT in 1992 when participants were age 70 to 84. Univariate and multivariate regression analyses were used to assess the relationship between BMI and brain measures. Results: Women with atrophy of the temporal lobe were, on average, 1.1 to 1.5 kg/m2 higher in BMI at all examinations than women without temporal atrophy (p < 0.05). Multivariate analyses showed that age and BMI were the only significant predictors of temporal atrophy. Risk of temporal atrophy increased 13 to 16% per 1.0-kg/m2 increase in BMI (p < 0.05). There were no associations between BMI and atrophy measured at three other brain locations. Conclusion: Overweight and obesity throughout adult life may contribute to the development of temporal atrophy in women.

Update on hypertension and Alzheimer's disease

Abstract Several studies report that blood pressure is increased in victims of Alzheimers disease (AD) decades before the onset of the disease. Years before onset of Alzheimers disease, blood pressure start to decrease and continues to decrease during the disease process. High blood pressure has also been related to pathological manifestations of Alzheimers disease (senile plaques, neurofibrillary tangles, hippocampal atrophy). The exact mechanism behind these associations is not clear. Hypertension is also a risk factor for stroke, ischemic white matter lesions, silent infarcts, general atherosclerosis, myocardial infarction and cardiovascular diseases, and often clusters with other vascular risk factors, including diabetes mellitus, obesity and hypercholesterolemia. Also these risk factors have been related to Alzheimers disease. Hypertension may thus cause cerebrovascular disease that may increase the possibility for individuals with AD encephalopathy to express a dementia syndrome. Hypertension may also lead to vessel wall changes in the brain, leading to hypoperfusion, ischemia and hypoxia which may initiate the pathological process of AD. Finally, subclinical AD may lead to increased blood pressure, and similar biological mechanisms may be involved in the pathogenesis of both disorders. Hypertension is a common disorder and often untreated. Several observational studies have reported that use of antihypertensives decreases risk of AD. Even though hypertension only results in a moderately increased risk of AD, or overall dementia, better treatment of hypertension may have an immense effect on the total number of demented individuals.

Blood Pressure and Risk of Dementia: Results from the Rotterdam Study and the Gothenburg H-70 Study

The association between blood pressure and dementia is debated. Results from population-based studies on blood pressure and dementia are inconclusive, and most are performed in subjects younger than 80 years of age. We examined the relation between blood pressure and dementia and the possible effect modification of this relation by age in a pooled dataset based on two prospective population-based studies. Subjects came from the Rotterdam study (n = 6,668), a longitudinal population-based study among subjects aged 55 years and over, and from the Gothenburg H-70 Study (n = 317), a study on subjects aged 85 years at baseline. Screening and diagnostic procedures for assessment of dementia were similar at baseline and follow-up and comparable between studies. We estimated relative risks of dementia using Cox proportional hazards regression analysis, adjusted for age, gender and study location. The average follow-up was 2.1 years. During this period, 196 subjects developed dementia. The risk of dementia decreased with increasing blood pressure level (per 10 mm Hg systolic blood pressure: RR = 0.93, 95% CI = 0.88–0.99; per 10 mm Hg diastolic blood pressure: RR = 0.89, 95% CI = 0.79–1.00). This association was confined to subjects who used anthypertensive medication. Persons who were demented at baseline had a stronger blood pressure decline during follow-up than those who were non-demented. This study suggests an inverse association between blood pressure and dementia risk in elderly persons on antihypertensive medication. Possibly, they may need higher blood pressure levels to maintain an adequate cerebral perfusion. Alternatively, lower blood pressure may be secondary to brain lesions in preclinical stages of dementia.

Cerebrospinal fluid β-amyloid 1–42 concentration may predict cognitive decline in older women

Background: Low levels of cerebrospinal fluid (CSF) β-amyloid 1–42 (Aβ42) and high total tau (T-tau) are diagnostic for manifest Alzheimer’s disease. It is not known, however, whether these biomarkers may be risk indicators for cognitive decline in otherwise healthy older people. Methods: The longitudinal relationship between CSF markers, Aβ42 and T-tau, measured in 1992, and change in Mini-Mental State Examination (ΔMMSE) score between 1992 and 2002 were investigated in 55 women (aged 70–84 years, mean (SD) MMSE score = 28.3 (1.5)), who were participants in the Prospective Population Study of Women in Gothenburg, Sweden. These women did not have dementia when they experienced lumbar puncture in 1992–3. Results: Over the 8-year follow-up period, ΔMMSE (range =  +3 to −21 points) was correlated with Aβ42 (Spearman’s r = 0.40, p = 0.002), such that lower levels of Aβ42 were related to greater decline. This was also observed after excluding 4 women who developed dementia between 1992 and 2002 (Spearman’s r = 0.34, p = 0.019). A multivariate logistic regression model predicting a decline of ⩾5 points on the MMSE (observed in six women), or a risk of developing dementia over the 8-year follow-up period (observed in four women), including age, education, Aβ42 and T-tau as covariates, showed that Aβ42 was the sole predictor of significant cognitive decline or dementia (OR per 100 pg/ml Aβ42 = 2.24, 95% CI 1.19 to 4.22, p = 0.013). Conclusions: Low levels of CSF Aβ42 may predict cognitive decline among older women without dementia.

Cerebrospinal Fluid Beta-Amyloid 42 Is Reduced before the Onset of Sporadic Dementia: A Population-Based Study in 85-Year-Olds

Deposition of β-amyloid (Aβ) is an early pathogenic event in Alzheimer’s disease (AD). We measured Aβ42 and Aβ40 in cerebrospinal fluid (CSF) in a population-based sample of 85-year-olds, 27 demented and 35 non-demented. During the following 3 years, 7 of the 35 non-demented individuals had developed dementia, while 28 remained non-demented. Reduced CSF levels of both Aβ42 (p = 0.001) and Aβ40 (p = 0.0001) were found in patients with manifest AD and vascular dementia at the age of 85. Non-demented individuals who developed dementia during follow-up had lower levels of CSF- Aβ42 (p = 0.003), but not CSF-Aβ40 (p = 0.96), than those who remained non-demented. The odds ratio for development of dementia was 8.2 (p = 0.027) for individuals in the lower 50th percentile of CSF-Aβ42, while none of those in the highest 33rd percentile of CSF-Aβ42 developed dementia during follow-up. There were no significant differences between carriers and non-carriers of the apolipoprotein E Ε4 allele regarding CSF-Aβ42or CSF-Aβ40.Our study suggests that low CSF-Aβ42 is found also in an unselected population-based sample of old demented patients and provides the first evidence of a disturbance in the metabolism of Aβ, specifically involving Aβ42, before the onset of clinical symptoms in AD.

Status of Risk Factors for Vascular Dementia

The two most common causes of vascular dementia (VAD) are dementia evolving in connection with multiple small or large strokes and dementia related to ischemic white-matter lesions (WMLs) of the brain. The knowledge about risk factors for these disorders is still scarce. Besides sharing risk factors with stroke, dementia with multiple small or large brain infarcts is also associated with non-vascular risk factors such as high alcohol consumption, psychological stress in early life, lower formal education, blue collar occupation, and occupational exposures. Risk factors for dementia in stroke victims include stroke-related and non-stroke related risk factors. Non-stroke-related factors are similar to those found in Alzheimer’s disease. The main risk factors for ischemic WMLs are hypertension or increased blood pressure, but WMLs have also been associated with a number of other vascular risk factors. In recent years, Alzheimer’s disease (AD) has also been reported to be associated with vascular risk factors, including hypertension, coronary heart disease, atrial fibrillation, diabetes mellitus, and WMLs. Although these associations may reflect an overdiagnosis of AD in cases with silent cerebrovascular disease, or that cerebrovascular disease increases the possibility that individuals with Alzheimer lesions will express a dementia syndrome, there are also alternative explanations. AD and cerebrovascular disease may for instance share similar risk factors or etiologic pathways. The pathogenetic implications for the association between AD and vascular factors need to be further explored. There is also a need for more studies on risk factors for VAD and risk factors for dementia in stroke samples, as well as studies on non-vascular risk factors for ischemic WMLs.

Study on COgnition and Prognosis in the Elderly (SCOPE)

The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre, prospective, randomized, double-blind, parallel-group study designed to compare the effects of candesartan cilexetil and placebo in elderly patients with mild hypertension. The primary objective of the study is to assess the effect of candesartan cilexetil on major cardiovascular events. The secondary objectives of the study are to assess the effect of candesartan cilexetil on cognitive function and on total mortality, cardiovascular mortality, myocardial infarction, stroke, renal function, hospitalization, quality of life and health economics. Male and female patients aged between 70 and 89 years, with a sitting systolic blood pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99 mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are eligible for the study. The overall target study population is 4000 patients, at least 1000 of whom are also to be assessed for quality of life and health economics data. After an open run-in period lasting 1-3 months, during which patients are assessed for eligibility and those who are already on antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg o.d., patients are randomized to receive either candesartan cilexetil 8 mg once daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains >160 mmHg, or has decreased by <10 mmHg since the randomization visit, or DBP is >85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964 patients had been randomized. All randomized patients will be followed for an additional 2 years. If the event rate is lower than anticipated, the follow-up will be prolonged.