Inhibition of acetylcholinesterase in CSF versus brain assessed by 11C-PMP PET in AD patients treated with galantamine.

The relationship between acetylcholinesterase (AChE) activity in the CSF and brain of patients with Alzheimer's disease (AD) was investigated in 18 mild AD patients following galantamine treatment. The first 3 months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg/day) and six patients placebo. This was followed by 9 months galantamine treatment in all patients. Activities and protein levels of both the "read-through" AChE (AChE-R) and the synaptic (AChE-S) variants in CSF were assessed in parallel together with the regional brain AChE activity by (11)C-PMP and PET. The AChE-S inhibition was 30-36% in CSF, which correlated well with the in vivo AChE inhibition in the brain. No significant AChE inhibition was observed in the placebo group. The increased level of the AChE-R protein was 16% higher than that of AChE-S. Both the AChE inhibition and the increased level of AChE-R protein positively correlated with the patient's performance in cognitive tests associated with visuospatial ability and attention. In conclusion, AChE levels in CSF closely mirror in vivo brain AChE levels prior to and after treatment with the cholinesterase inhibitors. A positive cognitive response seems to dependent on the AChE inhibition level, which is balanced by an increased protein level of the AChE-R variant in the patients.

PET imaging of the in vivo brain acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD.

The effect of galantamine treatment on cortical acetylcholinesterase (AChE) activity and nicotinic receptor binding was investigated by positron emission tomography (PET) in 18 patients with mild Alzheimer's disease (AD) in relation to galantamine concentration and the patients' cognitive performances. The first 3 months of the study was of a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24mg/day) and 6 patients the placebo, and this was followed by 9 months' galantamine treatment in all patients. The patients underwent PET examinations to measure cortical AChE activity ((11)C-PMP) and (11)C-nicotine binding. Neuropsychological tests were performed throughout the study. Inhibition (30-40%) of cortical AChE activity was observed after 3 weeks to 12 months of galantamine treatment. No significant change in mean cortical (11)C-nicotine binding was observed during the study. (11)C-Nicotine binding, however, positively correlated with plasma galantamine concentration. Both the changes of AChE activity and (11)C-nicotine binding correlated positively with the results of a cognitive test of attention. In conclusion, galantamine caused sustained AChE inhibition for up to 12 months. At the individual level, the in vivo cortical AChE inhibition and (11)C-nicotine binding were associated with changes in the attention domain of cognition rather than episodic memory.

The relationship between signs of cardiovascular deficiency and cognitive performance in old age: a population-based study.

The influence of cardiovascular signs (CVS) on cognitive performance was examined in 227 older adults not suffering from dementia between 75 and 96 years of age who were sampled from the community. Participants received a comprehensive physical examination that included specific evaluation of current CVS, including dyspnea, cardiac murmur, and edema in lower limbs. They were administered tests of digit span, episodic recall and recognition, verbal fluency, and visuospatial skill. CVS were found to predict performance on tests of episodic memory and visuospatial skill, after the effects of age, education, gender, relevant drug use, and mood symptoms were controlled for. Although CVS accounted for relatively little general performance variation, the findings are relevant to the understanding of normal variation in late-life cognitive performance. Finally, CVS increased with age and accounted for a sizable proportion of the age-related cognitive variation.

Longitudinal and psychometric profiles of two cognitive status tests in very old adults.

Forty-four nondemented adults, over the age of 75 years, were tested at six-month intervals spanning two years. Study goals were to examine the validity of the Mini-Mental State Examination (MMSE) and the Wechsler Adult Intelligence Scale-Revised (WAIS-R), to assess the long-term reliability of these instruments, and to examine the longitudinal profile of this sample. Results showed that the MMSE was moderately correlated with the WAIS-R. The MMSE had low internal consistency, although the total score behaved reliably across the five occasions. The WAIS-R scales showed a high degree of internal consistency and test-retest reliability. WAIS-R performance remained stable across occasions; however, decline was evident in the MMSE subtests of Attention and Language.

Apolipoprotein epsilon 4 allele and disease progression in patients with late-onset Alzheimer's disease.

A random sample of 60 late-onset Alzheimer's disease (AD) cases from a population-based study were apolipoprotein E (apoE) genotyped and clinically examined with a 3-year interval. The epsilon 4 allele carriers had a significantly lower age of disease onset compared to non-epsilon 4 carriers. However, no significant differences were observed between epsilon 4 allele carries and non-carriers for Mini-Mental State Examination (MMSE) test scores at the first examination, in spite of a longer disease duration in the epsilon 4 allele carriers. After 3 years, MMSE test scores were still not significantly different between epsilon 4 carries and non-carriers but more than twice as many non-carriers had died. All other clinical features were similar between epsilon 4 allele carriers and non-carriers. This study indicates that the epsilon 4 allele is associated with a better prognosis of the disease in late-onset AD but that there are probably factors other than the epsilon 4 allele that are important for the AD phenotype.

Memory complaints of elderly people in a population survey: variation according to dementia stage and depression.

OBJECTIVE: To study the relationship between subjective memory complaints, cognitive functioning, and clinical diagnosis of dementia. DESIGN: Cross-sectional, total-population survey. MEASUREMENTS: A two-phase study was done. All 2368 were screened by Mini-Mental State Examination (MMSE). Then the 314 who screened positive and a sample of 354 who screened negative were examined clinically (by examining the subject and interviewing an informant) for DMS-III-R criteria for dementia, Clinical Dementia Rating (CDR) scale for severity of dementia and the presence of memory complaints or depressed mood. SETTING: An area in Stockholm, Sweden. PARTICIPANTS: All inhabitants of the area (2368) born in 1912 or before, living at home or in institutions. RESULTS: A greater percentage of informants reported marked memory impairment than did the subjects themselves. Neither the informants' nor the subject' reports differed according to the type of dementia, but they differed clearly according to the stage of dementia. Informants reported memory impairment more frequently as dementia severity increased, while the subjects' complaints of marked memory impairment were most common in mild-moderate dementia. Furthermore, non-demented subjects with marked complaints performed more poorly on the MMSE. Subjects with depressed mood were also more likely to complain about their memory, both in the demented and non-demented groups. CONCLUSION: Our data show the validity of the informants' reports about the subjects' memory deficits. Moreover, the study confirmed the clinical impression that the patient's own complaints should not be ignored, as subjects in the mild stage of dementia often have some insight into their own memory deficit. However, depressed individuals may underestimate their own memory, and individuals with moderate-severe dementia may overestimate theirs.

Application of DSM-III-R criteria for major depressive episode to elderly subjects with and without dementia.

OBJECTIVE: The aim of the present study was to see how DSM-III-R criteria for a major depressive episode functioned in a representative sample of elderly subjects with and without dementia. METHOD: Data were used from a population-based study of individuals 75 years old or older living in Stockholm. Subjects were screened for dementia by using the Mini-Mental State. Subjects with scores of 23 or lower as well as age- and sex-matched subjects with scores of 24 or higher were given a medical examination. Dementia was diagnosed according to DSM-III-R and staged for severity by using the Washington University Clinical Dementia Rating Scale. The Comprehensive Psychopathological Rating Scale was used to record symptoms of depression, which were then classified according to DSM-III-R criteria for a major depressive episode. Data on depressive symptoms were available for 643 individuals: 213 with and 430 without dementia. A principal component analysis was carried out on the nine symptoms from criterion. A for a major depressive episode. RESULTS: The depressive symptoms clustered into two groups: mood disturbance and motivation disturbance. The mood disturbance symptoms were most frequent in subjects with mild dementia and less frequent in those with more severe dementia; the subjects with the most severe dementia had the highest rates of motivation disturbance symptoms. CONCLUSIONS: The different manifestations of depression in elderly patients with and without dementia should be taken into account when making the diagnosis of major depression. Further research is needed on the manifestations of depressive symptoms in the elderly in order to validate the diagnostic criteria.

Accuracy of the Mini-Mental Status Examination as a screening test for dementia in a Swedish elderly population.

The aim of this study was to determine the accuracy of the Mini-Mental Status Examination (MMSE) as a screening test for dementia in an elderly Swedish population. All the inhabitants over 74 years of age in one area of Stockholm took the MMSE. The test was then compared to the clinical diagnosis of dementia. With a cut-off point of 23/24, the MMSE had a sensitivity of 87%, specificity of 92%, and positive predictive value (PPV) of 69%. Age, sex, and education did not substantially affect the specificity and the PPV, but had a slight effect on the sensitivity. The main causes of the false positives were somatic and psychiatric disorders. These results are in agreement with studies performed with similar methods and comparable populations.

Predicting dementia from the Mini-Mental State Examination in an elderly population: the role of education.

Our study aimed to assess whether education affects the positive predictive value of the MMSE when it is used as a screening test for dementia. The MMSE has been consistently found to correlate with education and, at the same time, education is regarded by some researchers as being of potential etiological significance for dementia. In the present study, results on the MMSE from a community-based study in Sweden were compared with two standards: the clinical diagnosis of dementia and the Katz index of daily living activities. For both these comparisons, education did not substantially change the predictive ability of the MMSE. Our data, when compared with previous studies, show that the influence of education on the predictive ability of the MMSE varies in different populations. We conclude that differential MMSE cut-off points for different educational levels or adjustment techniques for education are not universally applicable.

Clinical diagnosis of Alzheimer's disease and other dementias in a population survey. Agreement and causes of disagreement in applying Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, Criteria.

In a population survey aimed to detect cases of Alzheimer's disease and other dementias, two preliminary diagnoses were made independently with the purpose of using the concordant diagnoses as final diagnoses. Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, diagnostic criteria were followed. The 668 subjects examined were selected from the population of an area in Stockholm, Sweden, aged 75 years or more, with the Mini-Mental State Examination used as a screening test. The agreement on dementia diagnosis was moderate (kappa = .54) and could be clearly improved (kappa = .70) with modifications to the diagnostic criteria, such as adding a category of questionable dementia and giving more guidelines in the definition of impairment of a function. The agreement on the diagnosis of Alzheimer's disease vs vascular dementia vs secondary dementia was substantial (kappa = .67) when the cases with concordant dementia diagnoses were examined.

Clinical staging of dementia in a population survey: comparison of DSM-III-R and the Washington University Clinical Dementia Rating Scale.

In a population survey in Stockholm, 224 dementia cases were staged using two scales: the Washington University Clinical Dementia Rating Scale and DSM III-R. Both scales had to be modified by adding additional specifications and, in the case of DSM III-R, a new category of questionable dementia. After modification, the comparison of the two scales showed good agreement when all stages were analyzed (kappa = 0.60), but moderate agreement on the questionable and mild stages (kappa = 0.47). These results confirm the staging of mild dementia as the most problematic issue. Finally, the scales both showed moderate agreement with the categorized Mini-Mental State Examination (MMSE) (0-17 for severe and moderate forms; 18-23 for mild cases). Our data suggest new cut-off points for the MMSE when used as a staging scale.

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 Alzheimer's 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.