Merja Hallikainen

Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study

Objective: To evaluate the impact of midlife elevated serum cholesterol levels and blood pressure on the subsequent development of mild cognitive impairment (MCI) and to investigate the prevalence of MCI in elderly Finnish population, applying the MCI criteria devised by the Mayo Clinic Alzheimer’s Disease Research Center. Background: MCI has been considered as a predictor of AD. Vascular risk factors may be important in the development of cognitive impairment and AD. However, the role of vascular risk factors in MCI and the prevalence of MCI still remain virtually unknown. Methods: Subjects were derived from random, population-based samples previously studied in surveys carried out in 1972, 1977, 1982, and 1987. After an average follow-up of 21 years, 1,449 subjects aged 65 to 79 years were reexamined in 1998. Results: Eighty-two subjects, 6.1% of the population (average age, 72 years) met the criteria for MCI. Midlife elevated serum cholesterol level (≥6.5 mmol/L) was a significant risk factor for MCI (OR, 1.9; 95% CI, 1.2 to 3.0, adjusted for age and body mass index); the effect of systolic blood pressure approached significance. Conclusion: Data point to a role for midlife vascular risk factors in the development of MCI in late life.

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.

Hippocampal volumes in Alzheimer's disease, Parkinson's disease with and without dementia, and in vascular dementia An MRI study

Hippocampal atrophy detected by volumetric MRI is a sensitive feature of early Alzheimers disease (AD), but there are no studies evaluating hippocampal atrophy by MR volumetry in other dementing diseases. We therefore compared hippocampal volumes in a total of 113 subjects: 50 patients with mild to moderate AD, 9 patients with vascular dementia (VaD), 12 patients with idiopathic Parkinsons disease (PD) without dementia, 8 patients with PD and dementia (PDD), and 34 elderly control subjects. Thin, coronal, contiguous images were obtained by a 1.5-T MR imager. All patient groups had significantly smaller volumes of the hippocampus compared with the control group. In the PDD group, the absolute volumes were even smaller than in the AD group. In the PD group, the volumes were diminished to a lesser but significant extent. The volumes in the VaD group varied: of nine patients, two had no atrophy, three had unilateral, and four had bilateral atrophy. We postulate that hippocampal atrophy does not seem to be a specific phenomenon of dementia in AD but also occurs in VaD and PDD, and even in PD when no dementia is present. However, coexistence of AD pathology in our PD and VaD patients cannot be ruled out. Further studies with access to neuropathologic data are needed.

MRI of the Hippocampus in Alzheimer’s Disease: Sensitivity, Specificity, and Analysis of the Incorrectly Classified Subjects

In this study, magnetic resonance imaging (MRI) of the hippocampus for the diagnosis of early Alzheimers disease (AD) is evaluated. We measured hippocampal volumes and the area of the medial hippocampus with a 1.5 T MR imager in 160 subjects: 55 patients with probable AD according to the NINCDS-ADRDA criteria, 43 subjects fulfilling the NIMH criteria of age-associated memory impairment (AAMI), 42 cognitively normal elderly controls, and 20 controls younger than 50 years. Three methods for normalization were compared. The hippocampi were atrophied in the AD patients, but not in the AAMI subjects or the elderly controls. There was no significant correlation between hippocampal volumes and age in the nondemented subjects. The discrimination based on volumetry resulted in an overall correct classification of 92% of AD patients vs. nondemented elderly subjects, whereas discrimination based on hippocampal area was less accurate, producing a correct classification in 80% of the subjects. We conclude that the hippocampus as assessed by MRI volumetry is atrophied early in AD, and spared by aging or AAMI. A brief critical review of previous studies is in concordance with the presented data: all the previous studies that have used volumetry, have similarly ended up with a good classification, whereas simpler or subjective measurements, subject to various sources of bias, have produced most variable results.

Volumes of hippocampus, amygdala and frontal lobes in the MRI-based diagnosis of early Alzheimer's disease: Correlation with memory functions

SummaryWe studied the usefulness of measuring volumes of the hippocampus, amygdala and frontal lobes with coronal magnetic resonance imaging (MRI) scans in the diagnosis of early Alzheimers disease (AD). We examined 32 patients diagnosed according to the NINCDS-ADRDA criteria of probable AD and 16 age-matched healthy cognitively normal controls. The AD patients had mild dementia with a mean score of 22.8 in the Mini-Mental Status Examination (MMSE). We used a 1.5T magnetic resonance imager and normalized the volumes for brain area. The AD patients had significantly smaller volumes of the right and the left hippocampus (−38%) (ANOVA, p<0.001) and the left frontal lobe (−16%, p<0.05) compared to controls. The reductions in volumes of the right frontal lobe (−13%), the right amygdala (−14%) or the left amygdala (−18%) were not statistically significant. In the discriminant function analysis which included the volumes of the hippocampus, amygdala, and the frontal lobes and age, the volumes of the left and right hippocampus, the left and right frontal lobe, and the right amygdala entered the model and we could correctly classify 92% of the subjects into AD and control groups (Chi-square 42.6, df 5, p<0.0001). By using the volumes of the hippocampus, the frontal lobes or the amygdala on their alone, the correct classification was achieved in 88%, 65% and 58% of the subjects, respectively. In addition, in AD patients the volumes of the left hippocampus correlated significantly with the MMSE score and with immediate and delayed verbal memory; the smaller the volume the more impaired was their performance. Our data indicate that measurements of volumes of the hippocampus might be useful in diagnosis of early AD.

Prevalence of mild cognitive impairment: a population-based study in elderly subjects

Objectives– Mild cognitive impairment (MCI) has been suggested as a term for a boundary area between normal aging and dementia, especially Alzheimers disease (AD). In follow‐up studies, more than 50% of MCI subjects have been converted to dementia in 3–4 years. However, the epidemiology of MCI is not well known. This study was designed to determine the prevalence of MCI in an elderly population. Methods– A total of 806 subjects (60–76 years of age) from a population‐based random sample of 1150 subjects living in the city of Kuopio in eastern Finland were evaluated. Neuropsychological tests and a structured interview including the modified Clinical Dementia Rating (CDR) were used to apply the diagnostic criteria of MCI as proposed by Mayo Clinic Alzheimers Disease Research Centre. Thus, subjects having a test score more than 1.5 SDs below the age appropriate mean in memory tests and a CDR score of 0.5 but no dementia, were diagnosed as having MCI. Results– A total of 43 subjects, 5.3%, met the MCI criteria. MCI was more prevalent in older and less‐educated subjects, but no difference was found between men and women. The CDR appeared to be the most important part of the criteria. The memory tests had less impact on prevalence variables. Conclusions– The low prevalence of MCI indicate that in a population‐based study design its criteria may identify a more homogeneous group of subjects at the lower end of the cognitive continuum as contrasted with various other criteria of cognitive impairment in the elderly population. This is compatible with follow‐up studies showing a high probability of dementia in the MCI group. Thus, probable candidates for trials of preventive intervention for dementia can be screened from the elderly population using these diagnostic criteria.

Incidence and Risk Factors for Mild Cognitive Impairment: A Population-Based Three-Year Follow-Up Study of Cognitively Healthy Elderly Subjects

Background: Mild cognitive impairment (MCI) has attracted considerable interest as a potential predictor of Alzheimer’s disease (AD). Both the apolipoprotein E (ApoE) Ε4 allele and vascular factors have been associated with a higher risk for AD, recently they have also been linked to the risk of MCI. Objectives: To estimate the incidence of MCI among cognitively healthy elderly subjects during a 3-year follow-up, and to evaluate the impact of demographic and vascular factors as well as the ApoE Ε4 allele on the conversion to MCI. Methods: At baseline, the cognitive abilities of 806 out of 1,150 eligible subjects (aged 60–76 years) from a population-based sample were examined. Cognitively intact subjects (n = 747) were followed for an average of 3 years. Results: 66 subjects (8.8%) had converted to MCI. The global incidence rate of MCI was 25.94/1,000 person-years. Persons with higher age (OR 1.08, 95% CI 1.01–1.16), ApoE Ε4 allele carriers (OR 2.04, 95% CI 1.15–3.64) and persons with medicated hypertension (OR 1.86, 95% CI 1.05–3.29) were more likely to convert to MCI than those individuals of lower age and without an ApoE Ε4 allele or medicated hypertension. Persons with high education (OR 0.79, 95% CI 0.70–0.89) were less likely to convert to MCI than persons with low or no education. In subjects with both the ApoE Ε4 allele and medicated hypertension, the crude OR for conversion was 3.92 (95% CI 1.81–8.49). In subjects with cardiovascular disease, the crude OR for conversion was 2.13 (95% CI 1.26–3.60). Gender, elevated blood pressure, diabetes or cerebrovascular disease had no significant effect on the conversion to MCI. Conclusion: Higher age, the presence of at least one ApoE Ε4 allele and medicated hypertension are independent risk factors, but high education is a protective factor for MCI. The results suggest that vascular factors may have an important role in the pathogenesis of MCI.

A voxel based morphometry study on mild cognitive impairment

Background: Mild cognitive impairment (MCI) is the most widely used concept in classifying cognitive impairment in the elderly who do not fulfil the criteria for dementia. MCI is considered to confer an increased risk of progressing to dementia and most often Alzheimer’s disease (AD). Various approaches such as imaging of the brain have been applied to predict the conversion of MCI to dementia. A number of volumetric magnetic resonance imaging (MRI) studies have detected atrophy of the medial temporal lobe in subjects with MCI, but for the other cerebral regions the results have been inconsistent. Objective: To study the pattern of brain atrophy in MCI. Methods: Thirty two controls and 51 individuals with MCI deriving from population based cohorts were studied by MRI using voxel based morphometry. The threshold of t maps was set at p<0.001. Results: Individuals with MCI had significant unilateral atrophy in the medial temporal lobe on the right side. Less extensive atrophy was found elsewhere—for example, in the temporal lobe, left superior parietal lobule, left anterior cingulate gyrus, and bilaterally in the thalami. Conclusions: The MRI findings in MCI resemble those seen in early AD.

CSF Aβ42 and tau or phosphorylated tau and prediction of progressive mild cognitive impairment

Baseline CSF amyloid β-peptide-42 (Aβ42), tau, and phosphorylated tau (P-tau) levels from 46 control subjects and 78 patients with mild cognitive impairment (MCI) were measured. Twenty-three patients with MCI developed dementia during the study. Abnormal biomarkers were found early in the course of Alzheimer disease (AD). The most predictive assay for AD among the patients with MCI was the combination of Aβ42 and P-tau.