Neurotransmitter deficits in a non-multi-infarct category of vascular dementia

Brain tissue from 9 severely demented patients cared for in psychiatric long-term wards and with records of stroke episodes, macroscopic signs of brain infarcts and with no clinical evidence of senile dementia of the Alzheimer type was investigated and compared with control material. The mean volume of the brain infarcts in this vascular dementia group was only 6.8 ml. Pronounced disturbances of the serotoninergic and cholingergic systems were found in subcortical and cortical grey matter. These widespread neurotransmitter changes can hardly be explained by the localized brain infarcts per se, but suggest the existence of another category of vascular dementia. Since the neurotransmitter disturbances were found to be similar to those of Alzheimer's disease and senile dementia of the Alzheimer type, it seems more likely that they indicate a common pathway for dementia disorders than that they serve as markers of different dementia categories.     

Sulfatide as a biochemical marker in cerebrospinal fluid of patients with vascular dementia

The myelin-associated glycosphingolipid sulfatide in cerebrospinal fluid (CSF) was investigated in 20 patients with vascular dementia (VAD), 43 with Alzheimer's disease (AD) and 20 age-matched controls. The sulfatide concentration in the VAD group (307 +/- 118 nmol/l) was significantly (p less than 0.0001) higher than that in controls (145 +/- 86 nmol/l) and the AD group (178 +/- 79 nmol/l). Among the VAD patients, 8/20 had a significantly increased concentration of sulfatide (greater than mean + 2 S.D.), as compared with controls, while only 2/43 of the AD patients had a sulfatide concentration above this level. It is suggested that the elevated concentration of sulfatide in CSF from VAD patients reflects demyelination. Furthermore, sulfatide determinations, when combined with clinical findings, may be of diagnostic value, for discriminating between VAD and AD.     

5-Hydroxytryptamine-sensitive [H]imipramine binding of protein nature in the human brain.: II. Effect of normal aging and dementia disorders

Recently, a high-affinity [³H]imipramine binding site of protein nature that appeared related to the 5-hydroxytryptamine (5-HT, serotonin) uptake mechanism was demonstrated in the rat brain. In a preceding paper a similar [³H]imipramine binding site of protein nature and displaceable by 5-HT was demonstrated in the human brain. Most previous [³H]imipramine binding studies of the human brain have used desipramine-sensitive binding, which appears to contain a significant amount of additional binding not related to 5-HT neurons. Therefore this study of the human brain in the normal aging, in Alzheimer's disease/senile dementia of Alzheimer type (AD/SDAT) and in multiinfarction dementia (MID) presents data on 5-HT-sensitive [³H]imipramine binding. The influence of normal aging (17–100 years) was studied in the frontal and cingulate cortices, in the putamen, caudate nucleus, amygdala and in the hippocampus. An age-related change in 5-HT-sensitive [^{3H]imipramine binding was only noted in the cingulate cortex with a 50% loss in B_max over the adult age range. In contrast, desipramine-sensitive [3H]imipramine binding studied in the frontal cortex and in the putamen showed marked increases in B_max with age which correlated with increases in K_d}. It is suggested that these increases are related to an increased binding to lipophilic membrane components not related to 5-HT neurons. The 5-HT-sensitive [³H]imipramine binding ( B_max) was reduced to 60% of control in the cingulate cortex and to 50% in the putamen in AD/SDAT. In MID there was a 50% loss of [³H]imipramine binding sites ( B_max) in the putamen, but a 30% loss in the cingulate cortex did not reach statistical significance. It is concluded that the losses of 5-HT-sensitive [³H]imipramine binding sites reflect a corresponding loss of 5-HT neurites.     

Parenteral administration of GM1 ganglioside to presenile Alzheimer patients

The pharmacokinetic parameters of GM1 ganglioside were examined in 16 patients (mean age 64 +/- 5 years) with Alzheimer's disease. The ganglioside was given intramuscularly and subcutaneously. The maximum GM1 blood level was reached after 48-72 h, the subcutaneous route leading to the highest blood levels, but the individual variability was relatively large. When 100 mg GM1 ganglioside was given daily for a week, maximum serum values of 15 to 20 mumol/l were found in 3 patients. The elimination half-life from serum was 60-75 h.     

Distribution of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in human brain in relation to age,drug influence,agonal status and circadian variation

Summary The post-mortem brain concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in 16 parts of the brain from patients with no history of neurologic, psychiatric or metabolic illness. The causes of death were either ischemic heart disease, infections disease, cancer or accidents. Forty-two men with a mean age of 57 years (range 18–95 years) and 19 women with a mean age of 62 years (range 23–79 years) were included. The influence of several factors were studied: brain weight, time between death and autopsy, storage time before chemical analysis, age, sex, agonal status, cerebral arteriosclerosis, cancer, opiate treatment and time of death during the day.Most correlations between the 5-HT concentrations in different brain parts were positive, the strongest correlations in the basal ganglia and the limbic system. No consistent pattern of age-related 5-HT changes were found. The females had significantly higher 5-HIAA concentrations in the cortex of the gyrus hippocampus. Final hypoxia seemed to decrease 5-HT concentrations. Opiate treatment reduced 5-HT and increased 5-HIAA concentrations. A marked circadian variation of 5-HT was found, most pronounced in the hypothalamus, the limbic system and some neocortical areas.     

Early diagnosis of cognitive impairment in the elderly with the focus on Alzheimer's disease

Summary. In dementia disorders, it can be assumed that the pathological process in the brain has been present for a long time. It is therefore of importance to have a preclinical or an early clinical diagnosis. Obviously, vulnerability genes, such as ApoE-4, can be diagnosed preclinically. As we have no treatment to offer patients with genetic risk factors, genotyping for ApoE-4 is at present of no clinical use. Trained neuropsychologists have today access to sensitive tests which reveal cognitive impairment before the disturbances reach the level of dementia. Laboratory investigations of cerebrospinal fluid have so far yielded no great results. Tau protein appears to be the most sensitive marker, but it is unspecific. Chromogranin A separates early onset from late onset Alzheimer's disease and seems to be a marker for synaptic degeneration. Synaptotagmin was also found to be reduced in patients with early onset Alzheimer's disease. Still we do not know, however, whether these proteins are early markers for degenerative processes in the brain. Laboratory investigations of blood have not yielded markers of use in early or differential diagnosis of dementia disorders. In a study at our own institute, however, we found serum-homocysteine (S-HCY) to be an early and sensitive marker for cognitive impairment. In patients with dysmentia (mild cognitive impairment), no less than 39% had pathological S-HCY levels, indicating insufficient 1-carbon metabolism. Received December 12, 1997; accepted May 7, 1998