Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene.

Several families with an early-onset form of familial Alzheimer's disease have been found to harbour mutations at a specific codon (717) of the gene for the beta-amyloid precursor protein (APP) on chromosome 21. We now report, a novel base mutation in the same exon of the APP gene which co-segregates in one family with presenile dementia and cerebral haemorrhage due to cerebral amyloid angiopathy. The mutation results in the substitution of alanine into glycine at codon 692. These results suggest that the clinically distinct entities, presenile dementia and cerebral amyloid angiopathy, can be caused by the same mutation in the APP gene.

Improvement of spontaneous speech in early stage Alzheimer's with rivastigmine.

OBJECTIVES: Placebo-controlled trials have shown that rivastigmine can delay cognitive deterioration in patients with mild to moderate Alzheimer's disease (AD). Benefits on cognitive functioning, as measured with the ADAS-Cog, occur on a daily dose of 6-12 mg when used for at least 6 months. The effect of rivastigmine on the adequacy of spontaneous speech is unknown. This study aimed to (i) compare the spontaneous speech of AD patients with the spontaneous speech of persons with normal cognition, (ii) compare the spontaneous speech of the same group of AD patients before and after treatment with rivastigmine. METHODS: Spontaneous speech of AD patients (n=9) was compared with that of healthy elderly volunteers (n=8). In the patient group, spontaneous speech was analysed before and after treatment with rivastigmine. RESULTS: Before treatment, 100% discrimination was found between the spontaneous speech of AD patients and of healthy volunteers based on two linguistic parameters: empty words and compound sentences. After treatment with rivastigmine the spontaneous speech of the AD patients improved on these two variables, while the ADAS-Cog scores decreased. Mean interval between the two spontaneous speech samples was 8.89 months. CONCLUSION: Assessment of spontaneous speech might be a valid parameter to discriminate between normal cognition and AD, and to evaluate the effects of anti-AD medication.

Regional cerebral blood flow and cerebrovascular risk factors in the elderly population.

Regional cerebral blood flow (rCBF) was studied in 60 elderly persons (aged 65 to 84 years) recruited from a population-based study, with single photon emission computed tomography using technetium 99m-labeled hexamethylpropylene amine oxime. We investigated whether it is only age that affects rCBF or whether other factors can be indentified that explain this relationship. Using multiple linear regression analysis, increasing age was significantly associated with rCBF decrease in parietal, temporo-parietal, and temporal cortex, but not in frontal cortex. Adjustment with several risk factors for cerebrovascular disease, including hypertension, history of myocardial infarction, factor VIIc, factor VIIIc, cholesterol and HDL cholesterol, smoking, and diabetes mellitus had no influence on these relations. Conversely, the association between age and rCBF was no longer statistically significant after adjustment with fibrinogen and indicators of carotid atherosclerosis, including intima-media wall thickness of the carotid artery and plaques in the carotid artery. Correction with local ratings of cortical atrophy did not affect the relations between age and rCBF. The results suggest that in the elderly population rCBF declines with age in posterior cortical areas and that these changes may well be explained by the presence of atherosclerosis. Reduced contractility of the vascular muscle wall with increasing age resulting from atherosclerosis may be the underlying mechanism.

Diabetes mellitus and the risk of dementia: The Rotterdam Study.

OBJECTIVE: To determine the influence of type 2 diabetes mellitus on the risk of dementia and AD. BACKGROUND: Both dementia and diabetes are frequent disorders in elderly people. METHODS: Prospective population-based cohort study among 6,370 elderly subjects. At baseline study participants were examined for presence of diabetes mellitus. Nondemented participants were followed up, on average, for 2.1 years. Incident dementia was diagnosed using a three-step screening and comprehensive diagnostic workup. To complete the follow-up, medical files were studied of persons who could not be reexamined. We estimated relative risks with proportional hazard regression, adjusting for age, sex, and possible confounders. RESULTS: During the follow-up, 126 patients became demented, of whom 89 had AD. Diabetes mellitus almost doubled the risk of dementia (relative risk [RR] 1.9 [1.3 to 2.8]) and AD (RR 1.9 [1.2 to 3.1]). Patients treated with insulin were at highest risk of dementia (RR 4.3 [1.7 to 10.5]). CONCLUSION: The diabetes attributable risk for dementia of 8.8% suggests that diabetes may have contributed to the clinical syndrome in a substantial proportion of all dementia patients.

Education and the incidence of dementia in a large population-based study: the Rotterdam Study.

We assessed the risk of dementia by educational level in a prospective population-based study. In the Rotterdam Study, 6,827 nondemented participants with known education level were followed for an average of 2.1 years. During this period, 137 new cases of dementia occurred. Low education was associated with higher dementia risk in women but not in men, suggesting that the association is modified by sex. Our data indicate that cross-sectional studies may overrate the association between education and risk of dementia.

The diagnostic value of SPECT with Tc 99m HMPAO in Alzheimer's disease: a population-based study.

We studied the diagnostic accuracy of single-photon emission computed tomography (SPECT) with technetium 99m-labeled hexamethylpropylene amine oxime (Tc 99m HMPAO) in 48 patients with probable Alzheimer's disease (AD) according to NINCDS-ADRDA criteria and in 60 controls recruited from a population-based study. With logistic regression, we identified decreased temporal regional cerebral blood flow as the best discriminating variable between patients and controls. Receiver-operator characteristic curves showed that the discriminative ability of SPECT improved with increasing dementia severity. With specificity set at 90%, sensitivity figures were 42% in mild, 56% in moderate, and 79% in severe AD. The diagnostic gain as a function of the prior probability of the disease being present was computed for those with mild AD. When the prior probability varied at around 50%, the diagnostic gain for mild AD patients was substantial (a maximum of 34%) for a positive test result but poor for a negative test result. The results suggest that the practical usefulness of SPECT as a diagnostic adjunct in patients suspected of having mild AD is confined to situations in which, on clinical grounds, there is considerable diagnostic doubt.

Cerebral white matter lesions, vascular risk factors, and cognitive function in a population-based study: the Rotterdam Study.

Cerebral white matter lesions are a common finding on MRI in elderly persons. We studied the prevalence of white matter lesions and their relation with classic cardiovascular risk factors, thrombogenic factors, and cognitive function in an age- and gender-stratified random sample from the general population that consisted of 111 subjects 65 to 84 years of age. Overall, 27% of subjects had white matter lesions. The prevalence and severity of lesions increased with age. A history of stroke or myocardial infarction, factor VIIc activity, and fibrinogen level were each significantly and independently associated with the presence of white matter lesions. Significant relations with blood pressure level, hypertension, and plasma cholesterol were present only for subjects aged 65 to 74 years. White matter lesions tended to be associated with lower scores on tests of cognitive function and were significantly associated with subjective mental decline. This study suggests that classic cardiovascular risk factors, as well as thrombogenic factors, are associated with white matter lesions in subjects over 65 years of age in the general population, and that these lesions may be related to cognitive function.

Risk of left ventricular dysfunction in patients with probable Alzheimer's disease with APOE*4 allele.

OBJECTIVE: To examine the association between the APOE genotype and cardiovascular disease in Alzheimer's disease (AD) patients. DESIGN: Case register study of 100 consecutive referrals to a Memory Clinic where type of dementia and cardiovascular comorbidity were diagnosed and APOE genotype was determined. SETTING: The Memory Clinic, University Hospital Rotterdam Dijkzigt. PARTICIPANTS: One hundred Memory Clinic patients, 59 to 91 years of age, who attended the Memory Clinic in the period between January 1994 and March 1996. MEASUREMENTS: Relative risk of cardiovascular morbidity in probable AD, based on clinical and ECG findings. RESULTS: The diagnosis of probable AD was more frequent in APOE*4 allele-carrying AD patients. When comparing homozygotes for APOE*4 with homozygotes for APOE*3, a nine-fold increase in prevalence of cardiac ischemia on ECG was found in the former. When grouping parameters of left ventricular dysfunction, the prevalence was 7.2 (95% confidence interval 1.2-42.6) times greater in probable Alzheimer patients with APOE4/4. CONCLUSIONS: In patients with probable AD, APOE*4 is associated with cardiac disease indicative of left ventricular dysfunction.

Linguistic deficits in the acute phase of stroke.

BACKGROUND AND PURPOSE: For the diagnosis of aphasia early after stroke, several screening tests are available to support clinical judgment. None of these tests enables the clinician to assess the underlying linguistic deficits, i. e. semantic, phonological and syntactic deficits, which provides indispensable information for early therapeutic decisions. The ScreeLing was designed as a screening test to detect semantic, phonological and syntactic deficits. The ScreeLing's sensitivity, specificity and accuracy in detecting aphasia and semantic, phonological and syntactic deficits were determined. METHODS: The ScreeLing was validated in an acute stroke population against a combined reference diagnosis of aphasia (aphasia according to at least two of the following measures:ne urologist's judgment, linguist's judgment, Tokentest-score). The three ScreeLing subtests were validated in the aphasic population against the presence or absence of a semantic, phonological and/or syntactic deficit according to an experienced clinical linguist. RESULTS: From a consecutive series of 215 stroke patients, 63 patients were included. The ScreeLing was an accurate test for the detection of aphasia (0.92),with a sensitivity of 86% and specificity of 96%. Sensitivity of subtests was 62 % for semantics, 54 % for phonology and 42 % for syntax. Specificity was 100 % for semantics and phonology and 80 % for syntax, and accuracy 0.84 for semantics, 0.87 for phonology and 0.64 for syntax. CONCLUSIONS: The ScreeLing is an accurate test that can be easily administered and scored to detect aphasia in the first weeks after stroke. Furthermore, the ScreeLing is suitable for revealing underlying linguistic deficits, especially semantic and phonological deficits.

Apolipoprotein E genotype and progression of Alzheimer's disease: the Rotterdam Study.

The APOE*4 allele of the apolipoprotein E gene increases the risk of Alzheimer's disease (AD), but whether it also affects the course of the disease is controversial. However, all studies on this issue until now have been based on patients at various stages of disease. In the present population-based study, 97 patients were included at a similar stage, i.e., before the onset of symptoms, and followed for up to 5 years. We found that the APOE*4 allele is not a strong determinant of survival in AD. As change in cognitive function and severity of dementia are similar for AD patients with and without APOE*4, our study suggests that progression of AD is not related to the APOE*4 allele.

Lisuride treatment of Alzheimer's disease. A preliminary placebo-controlled clinical trial of safety and therapeutic efficacy.

In this article, the authors examine the effect of lisuride on 22 patients with probable Alzheimer's disease (NINCDS/ADRDA criteria) in a randomized double-blind, placebo-controlled, parallel group design. Ten patients received lisuride and 12 patients received placebo. Lisuride was administered in a dose-finding phase of four weeks and an efficacy phase of eight weeks, with a maximum dose of 0.3 mg daily. Outcome measures included global clinical impression, general cognitive function, mood, verbal and visual memory, attention, and psychomotor function. Average decline in Mini-Mental State Examination score after 12 weeks treatment was less often statistically significant in lisuride treated patients than in patients receiving a placebo (p < 0.05). Patients treated with lisuride improved their average total score and short-delay cued recall score on the California Verbal Learning Test, a test of verbal memory, whereas placebo-treated patients showed worse performance compared with baseline. These differences approached statistical significance, with p = 0.06 and p = 0.05, respectively. No other differences between the treatment groups were evident. The authors failed to find a consistent effect of lisuride on symptoms of Alzheimer's disease. However, this study's sample size was relatively small, and larger studies are needed to ascertain the treatment effects of serotonergic antagonists on Alzheimer's disease.

Prevalence of Alzheimer's disease and vascular dementia: association with education. The Rotterdam study.

OBJECTIVE: To estimate the prevalence of dementia and its subtypes in the general population and examine the relation of the disease to education. DESIGN: Population based cross sectional study. SETTING: Ommoord, a suburb of Rotterdam. SUBJECTS: 7528 participants of the Rotterdam study aged 55-106 years. RESULTS: 474 cases of dementia were detected, giving an overall prevalence of 6.3%. Prevalence ranged from 0.4% (5/1181 subjects) at age 55-59 years to 43.2% (19/44) at 95 years and over. Alzheimer's disease was the main subdiagnosis (339 cases; 72%); it was also the main cause of the pronounced increase in dementia with age. The relative proportion of vascular dementia (76 cases; 16%), Parkinson's disease dementia (30; 6%), and other dementias (24; 5%) decreased with age. A substantially higher prevalence of dementia was found in subjects with a low level of education. The association with education was not due to confounding by cardiovascular disease. CONCLUSIONS: The prevalence of dementia increases exponentially with age. About one third of the population aged 85 and over has dementia. Three quarters of all dementia is due to Alzheimer's disease. In this study an inverse dose-response relation was found between education and dementia--in particular, Alzheimer's disease.

Value of the Mini-Mental State Examination and informants' data for the detection of dementia in geriatric outpatients.

The Dutch version of the Mini-Mental State Examination was administered to 138 elderly patients who were referred to a geriatric outpatient clinic for a variety of reasons. An optimal cut-off point of 24/25 was found for the detection of dementia. At this cut-off point, the Mini-Mental State Examination was 87.6% sensitive and 81.6% specific in detecting dementia. The discriminative validity was influenced by education and by the presence of psychiatric disorders other than dementia. Informants' data showed better sensitivity and specificity than the Mini-Mental State Examination for the detection of dementia. The findings suggest that informants' data are a primary source of information for the detection of dementia in geriatric outpatients.

Trait-anxiety and achievement motivation are positively correlated with memory performance in patients who visit a geriatric outpatient clinic with amnestic symptoms.

Memory performance was studied in relation to anxiety and achievement motivation in a sample of 35 patients who were referred to a geriatric outpatient clinic for their complaints of memory dysfunction. State-anxiety appeared not to be associated with memory performance or the severity of dementia. Trait-anxiety and achievement motivation were associated positively with memory performance and negatively with the severity of dementia. The evaluation of anxiety symptoms in the assessment of dementia is recommended.