Future prospects of research on central cholinergic mechanisms.
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Acetylcholine↗
Biomedical subjects
C G Gottfries
Publications and source records attributed to C G Gottfries.
Consensus Conference on the Methodology of Clinical Trials of "Nootropics", Munich, June 1989. Report of the Consensus Committee.
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Animals↗
Biochemical substrates in normal aging and Alzheimer's disease.
In individuals above 60 years of age, an age-related decrease in the concentrations of dopamine, noradrenaline, and 5-hydroxytryptamine has been found. This may indicate a neuron loss. As the metabolites are not simultaneously reduced, a compensatory mechanism would seem to exist. In the hypothalamus there are significant positive correlations between the neuropeptides galanin and corticotropin-releasing factor on the one hand, and age over 60 on the other. In brains from patients with dementia of Alzheimer type there are reduced concentrations of cholineacetyl transferase. However, in some brain areas reduced concentrations of 5-hydroxytryptamine, dopamine, and noradrenaline have also been found. The metabolites homovanillic acid and 5-hydroxyindolacetic acid are also reduced. These findings indicate that there is not only a neuron loss in these brains but also a dysfunction of the remaining neurons, reducing the compensatory capacity of the brain. Postmortem investigations of hypothalamus from Alzheimer brains have shown reduced concentrations of 5-hydroxytryptamine. However, the concentrations of galanin, arginin, vasopressin, and somatostatin were significantly increased. The latter may be the result of a disturbed higher control over the hypothalamus. Hypothalamic dysfunction is of interest with regard to the neuroendocrine disturbances seen in Alzheimer-demented patients. Investigations of patients with vascular dementia have suggested the same type of neurotransmitter disturbances as in Alzheimer's disease.
Aging↗
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.
Aged↗
Intrathecal synthesis of immunoglobulin G in vascular dementia.
Serum and CSF from 53 vascular dementia (VD) patients and 50 controls were analysed to investigate the possibility of an intrathecal synthesis of IgG, defined as an elevated IgG index (greater than or equal to 7) and/or presence of oligoclonal IgG in cerebrospinal fluid (CSF), but not in serum. Five (9%) patients and no controls exhibited an intrathecal synthesis of IgG. The IgG index increased with the degree of dementia (p less than 0.05). It was positively related to presence/absence of hypertension (p less than 0.05) and correlated positively with diastolic blood pressure (p less than 0.05). The findings suggest that immunological factors might be involved in the pathogenesis of VD.
Aged↗
Blood brain barrier function in vascular dementia.
To investigate blood-brain barrier (BBB) function measured as an albumin ratio (cerebrospinal fluid/serum) in vascular dementia (VD) samples from 53 patients and 30 healthy controls were analysed. The VD group showed a higher mean albumin ratio than controls (8.5 +/- 3.8 and 5.7 +/- 2.1, respectively). The albumin ratio did not correlate significantly with age, nor with individual clinical vascular factors. The results of the present study suggest that the altered BBB might be a consequence of small vessel disorder rather than evidence of infarcts.
Aged↗
Blood-brain barrier disturbance in patients with Alzheimer's disease is related to vascular factors.
To investigate the blood-brain barrier (BBB function), serum and cerebrospinal fluid (CSF) from 118 patients with Alzheimer's disease (AD) and 50 healthy controls was analyzed with regard to albumin concentrations. For the AD group, clinical vascular factors were also recorded. The CSF/serum albumin ratio was used as a measure of BBB function. When compared with controls, the AD group showed a higher mean albumin ratio, indicating a decline in BBB function. However, no significant reduction in BBB function was found in AD patients without vascular factors. These findings support the hypothesis that BBB disturbance is related to vascular factors, coexisting with AD. In the control group, no significant correlation between age and albumin ratio was found, which suggests that aging per se is not primarily associated with a decline in BBB function. The present study provides evidence in favour of the conclusion that a reduced BBB function is related neither to AD nor to aging, but to clinical vascular factors.
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Brain monoamines and their metabolites in dementia.
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Aged↗
Loss of dopamine uptake sites labeled with [3H]GBR-12935 in Alzheimer's disease.
The binding of the dopamine uptake inhibitor [3H]GBR-12935 to postmortem putamen from a control group and patients with Alzheimer's disease/senile dementia of Alzheimer type (AD/SDAT) or vascular dementia (VD) was studied. The binding density (Bmax) in AD/SDAT was significantly reduced to 50% of control. A reduction of Bmax in VD was also noted, but it did not reach statistical significance. No differences in apparent binding affinity (Kd) between controls and dementia groups were obtained. The concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid were also determined. The concentrations of DA and DOPAC were reduced by 30-40% in AD/SDAT and VD, but the reductions did not reach statistical significance. The concentration of 3-MT was reduced by 40% in AD/SDAT and by 30% in VD. The [3H]GBR-12935-binding densities correlated significantly with corresponding concentrations of DA in control brains. It is suggested that the loss of [3H]GBR-12935-binding sites in human putamen in AD/SDAT reflects a degeneration of dopamine neurites.
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The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. A Nordic multicentre study.
In this multicenter study, the clinical efficacy of citalopram was investigated in 98 patients with moderate AD/SDAT or VD using a combined double-blind and open technique with placebo and citalopram. Analyses were made for each diagnosis after four weeks of double-blind treatment. Patients with AD/SDAT treated with citalopram showed a significant improvement in emotional bluntness, confusion, irritability, anxiety, fear/panic, depressed mood and restlessness. Those improvements were not found after treatment with placebo. There were no significant improvements in patients with VD. No improvements were recorded in motor or cognitive impairment. Citalopram provoked few and comparatively mild side-effects. None of the changes observed during the double-blind withdrawal period were identified as withdrawal symptoms or rebound phenomena.
Affective Symptoms↗
Confusional symptomatology distinguishes early- and late-onset Alzheimer's disease.
Symptoms of confusion were examined in 75 patients with Alzheimer's disease (AD). Mild confusion was found in 20, and mode-rate/severe confusion in 8 patients. Confusion was more frequent in the late-onset (26/44-59%) than in the early-onset AD group (2/31-6%) (p less than 0.0001), and patients with confusion were older (p less than 0.0001) than those without confusion. The frequency of confusion was higher in patients with ischemic heart disease (13/28-46%) than in patients without this vascular factor (10/47-21%) (p less than 0.05). An inverse relation was found between confusional symptomatology and parietal-lobe symptoms. The findings in this study suggest that a subgroup of AD patients, fulfilling the NINCDS-ADRDA criteria for probable AD, is characterized by a clinical picture of mild confusional symptomatology together with no or mild parietal-lobe symptomatology, higher age and higher frequency of ischemic heart disease. This group contrasts with the other subgroup of pure AD, which is characterized by a clinical picture of marked parietal-lobe symptomatology, almost no confusional symptomatology, lower age and lower frequency of ischemic heart disease.
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Intra-blood-brain-barrier synthesis of immunoglobulins in patients with dementia of the Alzheimer type.
Serum and cerebrospinal fluid (CSF) of 56 patients with dementia of the Alzheimer type (DAT) and 33 healthy controls were examined in order to investigate intra-blood-brain-barrier (intra-BBB) synthesis of immunoglobulins. Intra-BBB immunoglobulin G (IgG) synthesis was defined as an elevated IgG index (greater than 0.7) and/or presence of oligoclonal IgG in CSF but not in serum on isoelectric focusing, and intra-BBB immunoglobulin M (IgM) synthesis as an elevated IgM index (greater than 0.06). In total, 10 (18%) DAT patients displayed an intra-BBB immunoglobulin synthesis--five (9%) an IgG and five (9%) an IgM synthesis--but none among the controls. Also, the DAT patient group showed higher mean IgG and IgM indexes than the control group. These findings support the hypothesis that immunological mechanisms may play a role in the etiology and/or pathogenesis of Alzheimer disease, at least in a subgroup of patients.
Aged↗
Pharmacological treatment strategies in dementia disorders.
Pharmacological treatment strategies in dementia disorders concern the use of vasodilators, nootropics, psychostimulants, acetylcholinergic drugs, monoaminergic drugs, and neuropeptides. The substitution of essential nutrients and the use of gangliosides and phosphatidylserine may also be considered. On the whole, drugs with vasodilator effects were unsuccessful in the past. However, new drugs have been introduced which also enhance the metabolism in the neurons. These drugs, the nootropics, often combine a vasodilator effect with the activation of brain metabolism and the protection of the brain from toxic effects. The effect of nootropics has mainly been demonstrated in animal experiments, whereas the drugs have been less effective in the treatment of demented patients. The use of psychostimulants should be tested carefully before ruling out their potential benefit. Acetylcholinergic drugs have attracted great interest in dementia treatment but, altogether, trails with these drugs have shown disappointing results. This may be due to the drugs not being effective enough, and therefore continued trials with this type of drug are necessary.
Animals↗
Monoamine metabolites in cerebrospinal fluid and behavioral ratings in patients with early and late onset of Alzheimer dementia.
Patients with Alzheimer disease (AD, onset less than 65 years of age, n = 13) and senile dementia of the Alzheimer type (SDAT, onset greater than or equal to 65 years of age, n = 28) were investigated for cerebrospinal fluid (CSF) content of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG) and compared with a group of controls (n = 26). A geriatric rating scale, the Gottfries-Bråne-Steen scale, was used to assess impairment of motor performance, intellectual and emotional functioning, and symptoms common in dementia disorders. The HVA levels in CSF were significantly lower in the AD group than in the SDAT group and controls. MHPG was slightly but significantly increased in the SDAT group when compared with the controls. The HVA and 5-HIAA concentrations were correlated negatively with impairment of motor performance in the SDAT group; 5-HIAA correlated positively with impaired performance in the AD group; and 5-HIAA/HVA ratios were correlated positively with the performance variables. HVA correlated significantly and negatively with "impaired wakefulness" and "inability to increase tempo" in the SDAT group. 5-HIAA and the ratio 5-HIAA/HVA correlated significantly and positively with some items measuring intellectual and emotional impairment. In the AD group, "anxiety" and "fear-panic" correlated positively with 5-HIAA and "restlessness" with MHPG. The data indicate qualitative differences in the CSF monoamine pattern between AD and SDAT.
Aged↗
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.
Aged↗
Decreased myelin lipids in Alzheimer's disease and vascular dementia.
The lipid composition of white matter and myelin from the semioval centre was studied in autopsy material from cases with Alzheimer's disease (AD) (n = 11), vascular dementia (VD) (n = 7), and age-matched controls (n = 11). In AD and VD the white matter content of phospholipids and cholesterol was reduced to 72-76% of the control values (P less than 0.01), the diminution of cerebrosides and sulphatides was more pronounced (55-69%) (P less than 0.001) while the concentration of gangliosides did not change significantly (87-90%). The myelin composition was the same in the 3 groups, suggesting that the white matter involvement is not caused by alteration of the myelin structure. The altered lipid composition in white matter in AD and VD suggests that the myelin sheath is the primary lesion site.
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White matter low attenuation on computed tomography in Alzheimer's disease and vascular dementia--diagnostic and pathogenetic aspects.
Demented patients with early-onset Alzheimer's disease (AD) (n = 17), late-onset Alzheimer's disease (n = 30) and vascular dementia (VD) (n = 20) were studied with computed tomography of the brain. Semiquantitative evaluation of white matter low attenuation (WMLA) and central and cortical atrophy was performed without knowledge of the clinical diagnosis. In early onset AD there was almost complete absence of WMLA and central atrophy compared with the other groups, which showed moderate to severe changes. This suggests that early-onset AD should be separated from the late-onset form. The increased systolic blood pressure found in the WMLA group supports the opinion that WMLA has a vascular origin. The high percentage of WMLA in VD and late-onset AD indicates that subcortical factors have to be considered in the pathogenesis of these disorders.
Aged↗