P.K. Mölsä

Survival and cause of death in Alzheimer's disease and multi-infarct dementia.

ABSTRACT Survival and causes of death of 218 patients with Alzheimers disease (AD) and of 115 patients with multi‐infarct dementia (MID) were examined. The patients were originally found in a community‐based epidemiological survey of dementia, and all patients with AD or MID alive on the prevalence day were included. The 6‐years survival rate for AD was 21.1% vs. the expected rate 48.5%, that for MID 11.9% vs. 45.2% expected. A comparison of relative survival rates suggested that MID carries a less favorable survival prognosis than AD. The mean durations were: AD 5.7 years and MID 5.2 years; median duration being 5 years in both diseases. The excess mortality in both AD and MID was independent of age. In AD, the survival rate decreased with increasing severity of dementia, while in MID the mortality was the same regardless of the severity of the dementia. The dementia disorder was the underlying cause of death in 68% of AD patients, and in 38% of MID patients, bronchopneumonia being the most frequent immediate cause of death in both groups. As a cause of death, acute cerebrovascular accidents occurred more often in MID patients than in the general population of comparable age. Malignant diseases were less frequent as a cause of death in both dementia groups than in the general population.

Validity of clinical diagnosis in dementia: a prospective clinicopathological study.

With neuropathological diagnosis as the point of reference, the accuracy of clinical diagnosis was studied in a series of 58 demented patients. Alzheimers disease and multi-infarct dementia were recognised with sensitivities and specificities exceeding 70%, whereas combined dementia as a separate group was relatively unreliably diagnosed. The value of Hachinskis Ischaemic Score in differentiating between Alzheimers disease and vascular dementias was demonstrated. Its performance was to some extent improved by assigning new weights to the items. In a logistic regression model, fluctuating course, nocturnal confusion, and focal neurological symptoms emerged as features with the best discriminating value, and helped to diagnose correctly 89% of the Alzheimer and 71% of the vascular dementia patients.

Extrapyramidal signs in Alzheimer's disease

The occurrence and type of extrapyramidal signs were investigated in 143 patients with dementia of the Alzheimer type. Only 8% of the patients were free of extrapyramidal signs. The most common type of extrapyramidal involvement was a rigid, hypokinetic, and hypomimic pattern. Resting tremor was rarely encountered. Dyskinetic signs, mostly orofacial, were seen in 17%. These observations suggest that in most patients with advanced Alzheimers disease, there is a striatal dopaminergic hypofunction, appearing clinically as hypokinesia and rigidity. However, some patients exhibit predominantly dyskinetic signs, implying more complex basal ganglia dysfunction.

Long-term survival and predictors of mortality in Alzheimer's disease and multi-infarct dementia.

Long‐term survival was examined for 218 patients with Alzheimers disease (AD) and 115 patients with multi‐infarct dementia (MID). The 14‐year survival rate for AD was 2.4% versus an expected rate of 16.6%, and for MID 1.7% versus 13.3% expected. MID showed a more malignant natural course than AD. Men carried a less favourable survival prognosis than women, both in AD and MID: the relative risk of dying for women was half that for men in both diseases. In MID, advanced disability indicated a relative risk of dying over twice as high. In both diseases the risk of death was substantially higher in the event of occurrence of primitive reflexes.

Brain muscarinic receptors in senile dementia

Muscarinic receptors were analyzed in various post-mortem brain samples of 39 patients with different types of dementia and of 30 age-matched controls by the specific binding of [3H]QNB. The diagnoses were verified neuropathologically. The binding of [3H]QNB was significantly decreased in the hippocampus, amygdala and nucleus accumbens in patients with Alzheimers disease (AD) and with combined type of dementia (CD), whereas in patients with multi-infarct dementia (MID) the binding was not significantly decreased in the limbic areas but only in the caudate nucleus. Of the clinical variables, orofacial dyskinesias in patients with AD but not with MID correlated with low brain weight and with the decreased [3H]QNB binding in the striatum and frontal cortex. The results reveal some differences between AD and MID. Changes in muscarinic receptor binding show that the cholinergic neurons in the limbic system are especially vulnerable in patients with AD and CD.

Alzheimer's disease: neuropathological correlates of cognitive and motor disorders

Correlations between clinical symptoms and changes in brain neuropathology were investigated in 34 patients with Alzheimers disease, who were compared with 17 non‐demented, age‐matched controls. The patients were originally found in a community survey of dementia and were followed up prospectively until death. A highly significant correlation emerged between the severity of dementia and the numbers of plaques and tangles in the material as a whole, but no essential difference was found between severely and less severely demented patients. Low brain weight correlated highly with many clinical symptoms and signs and the severity of dementia. A multiple regression model consisting of plaques and tangles in amygdala, gyrus frontalis medius, gyrus angularis, and gyrus temporalis medius, plaques of gyrus rectus, tangles of the hippocampus, gyrus precentralis and gyrus cinguli together with brain weight, emerged to link dementia to neuropathological changes at the level of maximum significance. Dyskinetic movements were associated with damage of several brain areas, implying a multiple etiology.

Brain dopamine D-2 receptors in senile dementia

Brain dopamine D-2 receptors were analysed in the caudate nucleus, putamen and nucleus accumbens in 49 patients with different types of neuropathologically verified dementia and in 39 controls by the binding of3H-spiroperidol. The binding was significantly decreased in all brain areas in patients with Alzheimers disease (AD), while the changes in patients with multi-infarct dementia (MID) or combined dementia (CD) were non-significant. According to a Scatchard analysis, this decrease in binding was due to the reduced number of receptors. On the other hand, the binding of3H-spiroperidol was significantly increased in those patients who had received neuroleptic drugs. Significant correlations between3H-spiroperidol binding and neuropathological changes were seen only in AD patients in the nucleus accumbens. The nucleus accumbens was also the only brain area in which there was a significant correlation between dopamine D-2 and the number of muscarinic receptors in AD patients. The findings of this study on dopamine D-2 receptors suggest the involvement of the nigrostriatal dopaminergic system in AD but not in the other two major types of dementia.

Senile dementia of the Alzheimer type treated with aniracetam: a new nootropic agent

Forty-four patients with senile dementia of the Alzheimer type were randomly allocated into double-blind treatment with either aniracetam (RO 13-5057) 1 g or placebo daily for 3 months. Neurological examinations were made before and after treatment and psychometric tests were performed before and after 1 months and after 3 months treatment. Treatment was interrupted due to occurrence of confusion in four cases in the aniracetam group and in one case in the placebo group. During treatment, an improvement was seen in several cognitive tests, especially those associated with memory, but this improvement occurred in the placebo as well as in the aniracetam-treated group. In clinical evaluation no difference was seen in efficacy between the two treatment groups.

Brain methionine- and leucine-enkephalin receptors in patients with dementia

Brain [3H]Met- and [3H]Leu-enkephalin binding was studied in patients with Alzheimers disease (AD) and vascular dementia (VD), and in age-matched controls. Brain areas investigated were the internal and external globus pallidus, amygdala, hippocampus and temporal cortex. In AD, the binding of both enkephalins decreased in all brain areas examined, except in the external globus pallidus for both enkephalins and in the internal globus pallidus for leucine-enkephalin. Scatchard analysis of amygdaloid samples showed a decrease in the number of receptors (Bmax) without any change in their affinity (Kd). In patients with VD, no significant changes in enkephalin binding were seen. Thus, in AD, enkephalin binding (mainly reflecting delta opioid receptor subtype) is decreased, especially in limbic areas.

Brain dopamine D-1 receptors in senile dementia

Brain dopamine D-1 binding sites were studied by using [3H]flupenthixol in 4 brain regions of 44 senile patients with neuropathologically verified organic dementia and 28 age-matched controls. The D-1 binding sites were decreased in the substantia nigra and nucleus accumbens in patients with Alzheimers disease, while no change was found in multi-infarct or combined dementia. The striatal D-1 binding sites were unchanged in all groups of patients. Only a few correlations between various clinical and post-mortem variables and the [3H]flupenthixol binding of the dementia patients were found. The findings of this study indicate that there is reduction of brain D-1 binding sites in patients with Alzheimers disease.