Low B12 levels related to high activity of platelet MAO in patients with dementia disorders. A retrospective study

In 35 patients with Alzheimer's presenile disease (AD), 56 patients with senile dementia of the Alzheimer type (SDAT), 54 patients with vascular dementia (VD) and 10 patients with confusional states, age, vitamin B12 in serum, P-folate, B-folate and B-Hb were investigated. Platelet monoamine oxidase (MAO) and cerebrospinal fluid (CSF) levels of homovanillic acid (HVA), 5-hydroxyin-doleacetic acid and 3-methoxy-4-hydroxyphenylglycol were measured. Group differences showed that vitamin B12 levels were reduced in the group of patients with confusional states and SDAT. Five out of ten and 13 out of 56 (respectively) had vitamin B12 concentrations below the lower limit of the reference value (130 pmol/l). A negative correlation was found between B12 levels and platelet MAO activity. The findings indicate that there is a subgroup of patients with late-onset dementia that has low vitamin B12 blood concentrations. HVA levels in CSF, usually found to be reduced in AD patients, were normal in this subgroup.     

Platelet MAO-B activity and vitamin B12 in old age dementias

Platelet MAO-B activity, serum vitamin B₁₂ levels, and plasma folate were measured in patients suffering from presenile (AD) and senile (SDAT) dementia of Alzheimer-type, and vascular dementia (VD). MAO-B was higher in the SDAT group than in AD and controls. An inverse relationship between MAO-B activity and vit. B₁₂ levels was documented in the whole group and in each category studied; furthermore, MAO-B was positively related to age. All the patients were then divided into two groups, according to vit. B₁₂ levels (Group I: <200 pg/mL; Group II: ≥200 pg/mL); Group I showed a significantly higher MAO-B activity with respect to Group II. The results indicate the existence of a negative association between platelet MAO-B activity and serum levels of vitamin B₁₂ and confirm the existence of biological differences between presenile and senile dementia of Alzheimer type.     

Influence of vitamin B12 on brain methionine adenosyltransferase activity in senile dementia of the Alzheimer's type

Summary The influence of vitamin B₁₂ on the activity of methionine adenosyltransferase (MAT) in postmortem brains of patients with senile dementia of the Alzheimer's type (SDAT) was investigated. In samples of cortex gyrus frontalis from SDAT patients with normal and low levels of serum B₁₂, MAT V_max was significantly increased by 25% and 19%, respectively. MAT V_max from a SDAT group chronically treated with B₁₂ was similar to controls. In contrast to cortex gyrus frontalis, no significant alterations were seen in MAT activity in nucleus caudatus. This study provides evidence that SDAT is associated with significant alterations in transmethylation mechanisms in specific regions of the brain. The relationship between blood levels of B₁₂ and the actual status of this vitamin in the brain influencing the rates of synthesis of both methionine and SAM may, however, be far more complex and cannot be directly clarified on the basis of the present human brain results.     

Quantitative EEG in patients with presenile and senile dementia of the Alzheimer type

EEG data obtained from 27 patients with presenile Alzheimer's disease (AD) and 28 patients with senile dementia of the Alzheimer type (SDAT) were compared with data from 30 age- and sex-matched controls. Both patient groups exhibited more pronounced delta and theta activity and less prominent alpha and beta activity than the controls. AD, however, was accompanied by more severe slowing than SDAT. The slowing was distributed in the left temporal and frontal regions in AD, and bilaterally in the frontal regions in SDAT. As the severity of the dementia increased, delta activity alone increased in AD, whereas, there were significantly greater increases in both delta and theta activity and decreases in alpha and beta activity in SDAT. These EEG differences appear to be related to the degree of brain damage and the speed of progression of the disease process.     

Vitamin B12 levels in serum and cerebrospinal fluid of people with Alzheimer's disease

Vitamin B12 levels in the serum and the cerebrospinal fluid (CSF) were compared between patients with Alzheimer's disease (AD) and senile dementia of Alzheimer's type (SDAT) (AD group) and patients with multi-infarct dementia (MID group). The B12 levels in the serum and the CSF were 742 +/- 359 pg/ml and 28 +/- 7 pg/ml (mean +/- SD), respectively, in the AD group, and 962 +/- 254 pg/ml and 50 +/- 26 pg/ml, respectively, in the MID group. CSF B12 levels were significantly lower in the AD group than in the MID group, whereas the serum levels were not different. At the same time, the serum levels of almost all patients were within the normal range, whereas the CSF levels were 25 pg/ml or lower in 10 of 12 AD patients. Therefore, this low level in the CSF is considered to be a characteristic finding in the AD group.     

Serum creatine kinase-BB levels and cerebral cortical creatine kinase activity in senile dementia of the Alzheimer type

A rise in serum creatine kinase-BB (CK-BB) levels has been reported previously in cases of dementia. In the present study the levels of serum CK-BB have been measured in patients clinically assessed to have senile dementia of the Alzheimer's type (SDAT) and in cognitively intact individuals, matched for age, by a specific two-site monoclonal immunoradiometric assay. No significant difference was found between the 2 groups. Total creatine kinase activity in temporal cortex (Brodmann area 21 and 22) was also found to be similar in brains from SDAT or control cases, obtained at autopsy. These results suggest no major change in the permeability of the blood-brain barrier to this enzyme in SDAT patients.     

Reversible central nervous system dysfunction in folate deficiency.

An epileptic patient on chronic anticonvulsant drug therapy is described, in whom anaemia and neurological abnormalities including progressive dementia, bilateral pyramidal tract signs, incontinence and ataxia developed. Vitamin B12 serum levels and absorption were normal, but serum folic acid levels were low. Both the neurological disturbances and anaemia resolved following oral folic acid administration. This sequence of events in our patient suggests a cause and effect relationship between the folate deficiency and the coexistent, transient neurological syndrome.     

Platelet and fibroblast monoamine oxidase in alcoholism

Monoamine oxidase (MAO) activity has been reported to be low in platelets (MAO B) and brain (MAO A and B) of some patients with alcoholism compared to control subjects. Whether the decreased platelet MAO activity found in alcoholism is secondary to the effect of alcohol or exists before alcohol abuse is not clear. The hypothesis that altered MAO A activity is determined by an abnormality in the genetic regulation of the enzyme can be tested by measuring MAO A activity in human fibroblasts cultured under controlled conditions. We first studied the kinetic parameters of platelet MAO B activity in patients hospitalized for treatment of alcoholism. Vmax was 38% lower in the patients (n = 14) than in normal controls (n = 22), but the enzyme affinity (Km) for the substrate tyramine was unchanged. Patients with the five lowest levels of platelet MAO activity had MAO activity measured from fibroblasts cultured from skin punch biopsies. Their fibroblast MAO activity was within the normal range, showing a dissociation between platelet MAO B and fibroblast MAO A activities and suggesting that MAO A activity is not low for genetic reasons in alcoholic subjects who do have low platelet MAO B activity.     

Platelet monoamine oxidase and serum dopamine-beta-hydroxylase activity in chronic alcoholics

Previous independent reports suggest that low platelet monoamine oxidase (MAO) activity and high serum dopamine-beta-hydroxylase (DBH) activity may be associated with alcoholism or vulnerability toward alcoholism. However, there are also contradictory reports in the literature with regard to each of these two enzymes. We measured both platelet MAO and serum DBH activity in alcoholics followed up at periodic intervals for 12 months after hospitalization for acute alcoholism. Platelet MAO activity in the alcoholics was significantly lower compared to that of nonpsychiatric controls throughout the 12-month period, whereas serum DBH activity in the alcoholics was essentially the same as control values. Thus, low platelet MAO activity, previously reported in a spectrum of clinical psychiatric disorders, appears to be a relatively stable phenomenon in chronic alcoholics irrespective of acute intoxication or pathophysiological factors associated with acute decompensation in individuals vulnerable to alcoholism.     

Somatostatin-like immunoreactivity and substance-P-like immunoreactivity in the CSF of patients with senile dementia of Alzheimer type,multi-infarct syndrome and communicating hydrocephalus

Summary The concentrations of somatostatin-like immunoreactivity (SLI) and substance-P-like immunoreactivity (SPLI) in lumbar spinal fluid of patients with senile dementia of the Alzheimer type (SDAT), multi-infarct syndrome, communicating hydrocephalus and control patients were determined by specific radio-immunoassay. Mean SLI and SPLI levels were significantly lower in an aged control patient group (mean age 83.5±5.6 years) than in an adult control patient group (mean age 30.8±10 years). In the latter group SPLI levels correlated negatively with age. Mean SLI levels decreased with deterioration in SDAT patients by up to 33% in late dementia. SPLI correlated with SLI in SDAT patients but was decreased significantly only in late dementia patients. Moderate and insignificant decreases of SLI were observed in patients with multi-infarct syndrome or communicating hydrocephalus. Analysis of SLI by gel-permeation chromatography revealed molecular heterogeneity of SLI. At least four peaks of SLI were eluted, two of which had apparent molecular weights of about 10,000 and 15,500, possibly representing somatostatin precursors. The ratio of SRIF to SLI of higher molecular weight was increased in patients with dementia compared to control patients.     

Central catecholamine metabolism in vivo and the cognitive and motor deficits in Parkinson''s disease.

Cerebrospinal fluid levels of homovanillic acid (HVA) in unmedicated patients with Parkinson's disease were 45% of levels in control subjects. Levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) and platelet monoamine oxidase activity (MAO) did not differ. Within the Parkinson's disease group platelet MAO B activity correlated with HVA (an MAO B substrate) but not MHPG (an MAO A substrate). A mild global dementia was found that did not correlate with the more severe motor deficit. There was a negative correlation between the motor deficit and HVA levels but not with MHPG. Cognitive functioning correlated positively with platelet MAO, and the ratio of HVA to MHPG levels and negatively with MHPG alone. It is postulated that dopaminergic and noradrenergic activity or the functional balance between these systems may contribute to the observed cognitive dysfunction.     

Vitamin B12 and folate concentrations in serum and cerebrospinal fluid of neurological patients with special reference to multiple sclerosis and dementia.

Vitamin B12 and folate concentrations were measured in serum and cerebrospinal fluid (CSF) in 293 neurological patients. Serum and CSF vitamin B12 concentrations showed a positive correlation. In individual patients CSF B12 concentrations varied considerably for a given serum concentration. The median serum vitamin B12 concentration of the Alzheimer's type dementia group was significantly lower compared with that of a control group. Lower median CSF vitamin B12 concentrations were found in groups of patients with multiple sclerosis and Alzheimer's type dementia. Five patients with heterogeneous clinical pictures had unexplained low serum and CSF B12 concentrations without macrocytosis. Two patients had very high serum B12 and low-normal CSF concentrations which could be explained by a blood-brain barrier transport defect. Serum and CSF folate concentrations did not show significant differences between the various groups.     

Suicide attempts, platelet monoamine oxidase and the average evoked response.

The relationship between suicides and suicide attempts and two biological measures, platelet monoamine oxidase levels (MAO) and average evoked response (AER) augmenting, was examined in 79 off-medication psychiatric patients and in 68 college student volunteers chosen from the upper and lower deciles of MAO activity levels. In the patient sample, male individuals with low MAO and AER augmenting, a pattern previously associated with bipolar affective disorders, showed a significantly increased incidence of suicide attempts in comparison with either non-augmenting low MAO or high MAO patients. Within the normal volunteer group, all male low MAO probands with a family history of suicide or suicide attempts were AER augmenters themselves. Four completed suicides were found among relatives of low MAO probands where as no high MAO proband had a relative who committed suicide. These findings suggest that the combination of low platelet MAO activity and AER augmenting may be associated with a possible genetic vulnerability to psychiatric disorders.     

Plasma levels of phenylacetic acid, m- and p-hydroxyphenylacetic acid, and platelet monoamine oxidase activity in schizophrenic and other patients

Blood from chronic schizophrenic patients in two hospitals (A and B) and from institutional and noninstitutional controls was analyzed for platelet monoamine oxidase (MAO) activity toward three different substrates (tryptamine, phenylethylamine, and p-tyramine) and for plasma levels of conjugated and unconjugated phenylacetic acid (PAA) and m- and p-hydroxyphenylacetic acids (mHPA and pHPA). Compared to the controls, schizophrenic patients were found to have significantly reduced MAO activity. Although significant differences were found between unconjugated PAA (reduced) in Hospital B, conjugated pHPA (increased) in Hospital A, and conjugated PAA (increased) in Hospitals A and B and noninstitutional controls, the most consistent significant finding was a reduced unconjugated mHPA in both groups of schizophrenic patients compared with both control groups.     

Increased glutathione peroxidase activity in erythrocytes in patients with Alzheimer''s disease/senile dementia of Alzheimer''s type

Glutathione peroxidase (GSH-Px) activity in erythrocytes was studied in 9 patients with Alzheimer's disease/senile dementia of Alzheimer's type (AD/SDAT) of ages 34-64 years and compared with that in 16 healthy controls of ages 21-66 years. The median GSH-Px activity in erythrocytes from AD/SDAT patients was 408, mu kat/1 (range 338-500 mu kat/1) and that from healthy controls 348, mu kat/1 (range 258-439 mu kat). This difference was significant (p less than 0.005) Wilcoxon rank test. Since there are great clinical and pathological similarities between AD/SDAT and the dementia of Down's syndrome (DS) patients and since both these groups of patients have increased activity of the selenium-dependent enzyme GSH-Px, it is suggested that there could be a similar metabolic background of the dementia. Many findings in the oxidative metabolism of DS suggest increased oxidative damage with an elevation of the turnover of superoxides to peroxides within cells and with a secondary biochemical modification such as increase in tissual GSH-Px activity. A similar mechanism with elevated peroxidation within cells might be responsible for the present finding of increased GSH-Px activity in erythrocytes and for the development of dementia in AD/SDAT.     

Acetylcholinesterase activity in CSF in senile dementia of Alzheimer type, vascular dementia, and Parkinson's disease

Acetylcholinesterase (AChE) activity was measured in cerebrospinal fluid (CSF) from 25 patients with senile dementia of Alzheimer type (SDAT), 11 patients with vascular dementia (VD), 26 patients with Parkinson's disease (PD), and 30 normal controls. AChE activity also was measured in 46 normal subjects whose ages ranged from 15 to 85 to evaluate the effect of age on AChE activity. CSF AChE activity for the SDAT, VD and PD groups showed no significant difference compared with the value for the control group. However, there were significant decreases in CSF AChE activity in the VD and PD groups with the development of ventricular enlargement. There was no significant correlation between CSF AChE activity decrease and ventricular enlargement in the SDAT group. AChE activity increased significantly over the age range of 15 to 85. These results suggest that, although CSF AChE activity is not a useful parameter in the diagnosis of dementia, it may be a marker indicating abnormalities of the intracerebral cholinergic system during the process of cerebral atrophy.     

Platelet monoamine oxidase and plasma dopamine-beta-hydroxylase activities in patients with multiple sclerosis

Platelet monoamine oxidase (MAO) and plasma dopamine-beta-hydroxylase (DBH) activities were determined in a large group of multiple sclerose patients in relapse (49 patients) and in remission (28 patients), and compared with an age- and sex-matched control group (52 normal subjects). The activities of both enzymes did not differ from normal in both patient groups. Women had higher MAO activities both in normal and in patient groups. Multiple linear regression analysis revealed an association of low platelet MAO to the score in the mental subscale in the Kurtzke Disability Status Scale. Both male and female patients with mental symptomatology had significantly (p = 0.02) lower platelet MAO activities compared to the patients without. The possibility of a relationship between MAO activity and psychiatric vulnerability in MS is considered.     

Correlations between cognitive, behavioural and psychological findings and levels of vitamin B12 and folate in patients with dementia

BACKGROUND: Associations between low levels of folate and vitamin B12 and cognitive impairment in patients with dementia have been reported. Some studies revealed correlations between low levels of vitamin B12 and behavioural and psychological signs and symptoms of dementia (BPSD) in Alzheimer's disease (AD) patients. Given the lack of studies in frontotemporal dementia (FTD) and on folate and given the methodological shortcomings of former publications, we set up a prospective study. METHODS: At inclusion, AD (n=152) and FTD (n=28) patients underwent a neuropsychological examination. Behaviour was assessed using a battery of behavioural assessment scales. Determination of serum vitamin B12 and red cell folate levels were performed within a time frame of two weeks of inclusion. RESULTS: In both patient groups, significantly negative correlations between levels of serum vitamin B12 and red cell folate and the degree of cognitive deterioration were found. No correlations with BPSD were found in the AD patient group. In FTD patients, levels of vitamin B12 were negatively correlated with both hallucinations (p=0.022) and diurnal rhythm disturbances (p=0.036). CONCLUSIONS: The observed negative correlations between levels of vitamin B12 and folate and cognitive impairment in both AD and FTD patients, raise the possibility of a non-specific etiological role. Although levels of vitamin B12 and folate did not correlate with BPSD in AD patients, negative correlations between serum vitamin B12 levels and BPSD in FTD patients were revealed. Decreased serum vitamin B12 levels may predispose FTD patients to develop hallucinations and diurnal rhythm disturbances.     

Platelet MAO activity in geriatric patients with depression and dementia

The authors studied platelet MAO activity in psychiatrically hospitalized geriatric patients with depression and dementia. Platelet MAO activity was higher in demented patients with and without depression and in depressed patients with reversible dementia than in nondemented depressed patients. The data suggest that abnormally high platelet MAO activity may reflect a predisposition to the development of a dementia syndrome.