CSF monoamine metabolites in old age dementias

Cerebrospinal Fluid (CSF) levels of the main metabolites of monoamines (HMPG, 5-HIAA, and HVA) were measured in patients with early onset (AD) and late-onset (SDAT) Alzheimer’s disease, vascular dementia (VD), and elderly controls. Psychobehavioral assessment was carried out by means of MMSE and GBS. Mean HMPG levels did not differ from controls; 5-HIAA was lower in VD when compared to both controls and SDAT. HVA was decreased in AD, SDAT, and VD with respect to controls. Significant correlations between HVA and psychobehavioral parameters were observed in SDAT and VD groups, whereas no relationship was documented in AD. The SDAT group was divided in SDAT-A (age at onset: >65≤80 yr) and SDAT-B (age at onset: >80 yr). SDAT-A had significantly lower CSF HVA values than SDAT-B (165±64 vs 235.7±85). SDAT-B HVA levels were similar to those observed in controls. Correlation analysis between HVA and neuropsychological variables was significant in SDAT-A, but not in SDAT-B. These results might support the evidence of SDAT heterogeneity.     

Nimodipine in the treatment of old age dementias

1. In a multicenter, placebo-controlled, double-blind clinical study in 178 elderly patients with cognitive decline, nimodipine, a calcium antagonist was found to be a therapeutically effective agent in the treatment of old age dementias. 2. Treatment with 90 mg of nimodipine administered orally in divided doses for 12 weeks was significantly superior to an inactive placebo on all outcome measures including the Wechsler Memory Scale, the Mini Mental State Examination, the Global Deterioration Scale, the Sandoz Clinical Assessment Geriatric Scale, the Plutchik Geriatric Rating Scale, the Severity of Illness and Global Improvement Scales of Clinical Global Impression, and the Hamilton Psychiatric Rating Scale for Depression. 3. Adverse effects with nimodipine were few and mild. The drug was equally well tolerated and equally effective in the two major dementias of old age, i.e., primary degenerative and multi-infarct. The number of abnormal laboratory test readings remained essentially unchanged from pre-treatment to post-treatment.     

Glycosaminoglycan polysulfate in the treatment of old age dementias

1. In a multicenter, placebo-controlled, double-blind clinical trial in 155 elderly patients with cognitive decline, glycosaminoglycan polysulfate was found to be a therapeutically effective agent in the treatment of old age dementias. 2. Treatment with glycosaminoglycan polysulfate in the daily dosage of 600 LRU, administered on the basis of a divided dosage schedule for 12 weeks, was significantly superior to an inactive placebo on several outcome measures including the Wechsler Memory Scale-Russell Revision (Easy Paired Associates Learning and Immediate Visual Reproduction), Mini Mental State Examination, the Sandoz Clinical Assessment Geriatric (Cognitive Dysfunction and Depression), Hachinski Dementia Scale, Brief Psychiatric Rating Scale (Confusion and Depressive Withdrawal) and Global Improvement Scale of the Clinical Global Impression. 3. Adverse effects with glycosaminoglycan polysulfate were few and mild. The drug was equally well tolerated and equally effective in the two major dementias of old age, i.e., primary degenerative and multi-infarct. The number of abnormal laboratory test readings remained essentially unchanged from pre-treatment to post-treatment.     

Platelet monoamine oxidase B (MAO-B) activity and its relationship to DL-fenfluramine-induced prolactin response in healthy men

Summary. Several techniques are used to assess central serotonergic neurotransmission in man, e.g. challenge tests (hormonal and physiological responses to serotonin active drugs), platelet MAO-B activity as well as brain imaging techniques. Little is known about how these tests relate to each other. The aim of the present study was therefore to investigate if platelet MAO-B activity could be related to hormonal and temperature responses to the serotonin active drug DL-fenfluramine in healthy men. Twelve male subjects without any history of psychiatric disorders or drug abuse/dependencies were recruited. Prior to the challenge with 60 mg DL-fenfluramine, which was given orally, blood for determination of platelet MAO-B activity was drawn. Blood samples for determination of serum prolactin and serum cortisol were drawn at baseline and thereafter every hour for the following six hours. In addition, body temperature was measured at the same time-points. Δ-values were calculated as the difference between the baseline values and the highest (prolactin and cortisol) or lowest value (temperature) thereafter. There was a strong positive correlation (r = 0.75, p < 0.02) between platelet MAO-B activity and Δ-prolactin. No correlations were found to Δ-cortisol, Δ-temperature or any of the baseline values. The results support the notion that the peripheral marker platelet MAO-B activity is related to the function of the central serotonergic neurotransmitter system as assessed by the prolactin response to 60 mg DL-fenfluramin.     

Platelet membrane properties in Alzheimer and multi-infarct dementias

Recent investigations revealed that the physical properties of both central and peripheral cell membranes are changed in dementia of the Alzheimer Type (DAT). We attempted to ascertain whether this effect is specific for DAT by studying the polarization of diphenylhexatriene (DPH) fluorescence (an indicator of membrane "microviscosity") in the membranes of platelets isolated from DAT patients, patients with multi-infarct dementia and healthy controls. The 3 groups were matched as closely as possible for age and sex distributions. Platelet phospholipid composition was also examined in an attempt to identify the chemical basis of the membrane change(s). These studies revealed that DPH fluorescence polarization is significantly reduced in platelets from DAT patients, but not in patients with multi-infarct dementia, compared with controls. Analysis of the phospholipid composition of platelets from the 3 groups of subjects did not find any significant differences which might explain the change in membrane properties.     

Incidence of vitamin B 12 and folic acid deficiencies on old aged psychiatric patients

The authors have studied Vitamin B 12 and Folic-acid serum levels on 27 women admitted in geriatric psychiatry, aged 60 to 93. They have confirmed the high frequency of Vitamin B 12 deficiency and considered the quasi-constant deficiency of folic-acid. Then follow the implications of this study.     

Physical activity and cognition in old age

PURPOSE OF REVIEW: With the rapid ageing of the world's population, investigating protective factors that may prevent or delay age-related disorders has become a new public health priority. Dementia is a common age-related disorder, affecting up to one in every two people reaching 80 years of age or above. Amongst the various potential 'protective factors' currently under investigation, physical activity seems to hold promise for the primary and the secondary prevention of dementia. This paper critically reviews the evidence in support of the association between exercise and cognitive decline/dementia, as reported by cohort studies or clinical trials. RECENT FINDINGS: The results of cohort studies show that physical activity is associated with better cognitive function and less cognitive decline in later life although there is only scant evidence suggesting that physical activity may in fact reduce the risk of dementia and Alzheimer's disease. In addition, data to support the systematic introduction of physical activity programmes to reduce the risk of dementia in later life are not as yet available from randomized clinical trials. SUMMARY: The results of observational studies are largely consistent with the hypothesis that physical activity reduces the risk of cognitive decline and dementia in later life. These findings are, however, not as yet adequately supported by data from randomized clinical trials.     

Platelet MAO-B activity and the psychopathology of Parkinson's disease, senile dementia and multi-infarct dementia

Monoamine oxidase-B (MAO-B) activity of platelets of an age- and sex-matched group of controls was compared with several groups of inpatients having non-familial dementia of Alzheimer type (DAT), Parkinson's disease (PD), multi-infarct dementia (MID), mixed types of these 3 diseases and a group of other central nervous system (CNS) organic disorders. All patients were subjected to several psychometric tests, including the Sandoz Clinical Assessment--Geriatric Scale, Hamilton Rating Scale for Depression, Mini-Mental State Examination and the Organic mental Disorder Scale (OMDS). A statistically significant enhancement of MAO-B activity could be observed in DAT patients and in PD patients, whereas the MID group showed a mean activity similar to that of the control group and the group with other organic CNS disorders. In DAT patients the degree of dementia in the OMDS test and the enhancement of MAO activity were positively correlated, but PD did not show such a correlation. It is concluded that the increase of MAO activity in PD and in DAT might be due to a disease-related enhanced affinity to oxygen and to such oxygen-derived radicals as superoxide or hydroxyl radicals. However, a possible drug-induced enhancement of MAO activity in PD cannot be excluded. Furthermore, the MAO-B activity values in platelets of individual patients or controls are not indicative of diagnosis or prognosis of any of these diseases and are of no disease-related specificity.     

Orthostatic tolerance in older patients with vitamin B12 deficiency before and after vitamin B12 replacement

Abstract. Orthostatic hypotension (OH) and vitamin B12 deficiency are common disorders in older people. Several case series have reported an association between vitamin B12 deficiency and OH. The effect of vitamin B12 replacement on this dysfunction has not been studied. We prospectively studied responses to head up tilt in patients over 70 years with vitamin B12 deficiency (intervention group) and compared their responses after replacement to those of matched patients with idiopathic OH and normal serum vitamin B12 concentrations (control group). Blood pressure (BP), heart rate (HR) and systemic vascular resistance (SVR) changes during orthostatic stress were evaluated using digital artery photoplethysmography. Eight patients and eight controls were studied. Initial head up tilt produced a mean BP decrease of 44/29 mmHg (s. e. m. 4/4 mmHg) in the intervention group and 33/12 mmHg (s. e. m. 3/2 mmHg) in the control group. Repeat head up tilt 6 months after vitamin B12 replacement produced a mean BP decrease of 15/9 mmHg (s. e. m. 5/2 mmHg) in the intervention group. The mean decrease in the control group was 30/12 mmHg (s. e. m. 2/2 mmHg). The difference in BP decreases between groups was statistically significant for both systolic and diastolic BP (p < 0.001 for both systolic BP and diastolic BP). Mean SVR in the intervention group decreased by 658 dynes/cm⁵/ sec (s. e. m. 74 dynes/cm⁵/sec) during initial head up tilt. Mean SVR during repeat head up tilt decreased by 79 dynes/cm⁵/sec (s. e. m. 12 dynes/cm⁵/sec). Mean SVR in the control group decreased by 158 dynes/cm⁵/sec (s. e. m. 10 dynes/cm⁵/sec) during initial head up tilt and by 258 dynes/cm⁵/sec (s. e. m. 31 dynes/cm⁵/sec). The difference in SVR changes between groups was statistically significant (p = 0.02). We conclude that replacing vitamin B12 in older patients with vitamin B12 deficiency is associated with improved orthostatic tolerance to head up tilt.     

HLA phenotype A2;B12 in vitamin B12 neuromyelopathy

Severe neurological complications (either peripheral neuropathy, subacute combined degeneration of the cord or cerebral changes) are a characteristic feature in some patients with marked vitamin B₁₂ deficiency. Although Addisonian pernicious anaemia (PA) is the major cause of this neurological syndrome, the disorder has been described in association with other conditions in which there is a profound depletion of vitamin B₁₂ stores.Sixteen patients with vitamin B₁₂ neuromyelopathy, associated with PA, have been HLA-typed for 27 alleles of the A and B loci and compared with 53 cases of PA without neurological damage and 60 controls of the same ethnic group. There is a significantly increased frequency of the HLA phenotype, A2;B12 (44% instead of 4% in PA patients without neurological damage) in the disease group studied (P < 0.0005).The significance of these findings in relation to the pathogenesis of vitamin B₁₂ neuromyelopathy is discussed.     

Somatosensory conduction in vitamin B12 deficiency

We tested the hypothesis that the somatosensory central conduction time (CCT) can reveal central nervous system involvement in vitamin B12-deficient patients when this cannot be established on clinical grounds alone. Three patients with pernicious anemia and without clinical signs of upper motor neuron lesion had a striking increase of CCT. This increase was shown to be reversible in 1 patient who improved over 3 years of treatment. Detailed analysis of the CCT showed that the decrease of conduction velocity occurred in the posterior columns, whereas the conduction was normal at the thalamo-cortical level. We conclude that CCT is a useful parameter to localize and quantify central nervous system disease in vitamin B12 deficiency.     

Evoked responses in vitamin B12 deficiency

Abnormalities of visual, brainstem auditory, and somatosensory evoked responses were demonstrated in two of seven individuals with vitamin B₁₂ deficiency. The evoked response delays correlated directly with the degree of neurological dysfunction. Abnormalities were present in sensory systems without clinical evidence of involvement and were similar to those found in individuals with multiple sclerosis.     

Multiple sclerosis and vitamin B12 metabolism

Multiple sclerosis (MS) is occasionally associated with vitamin B12 deficiency. Recent studies have shown and increase risk of macrocytosis, low serum and/or CSF vitamin B12 levels, raised plasma homocysteine and raised unsaturated R-binder capacity in MS. The aetiology of the vitamin B12 deficiency in MS is often uncertain and a disorder of vitamin B12 binding or transport is suspected. The nature of the association of vitamin B12 deficiency and MS is unclear but is likely to be more than coincidental. There is a remarkable similarity in the epidemiology of MS and pernicious anaemia. Vitamin B12 deficiency should always be looked for in MS. The deficiency may aggravate MS or impair recovery. There is evidence that vitamin B12 is important for myelin synthesis and integrity but further basic studies are required.     

MRI in vitamin B12 deficiency myelopathy

BACKGROUND: Little is known about vitamin B12 deficiency myelopathy's magnetic resonance imaging (MRI) manifestations and their relationship to the onset, evolution, and resolution of neurologic signs and symptoms. METHODS: We present a case and review eleven additional reported cases of subacute combined degeneration of the spinal cord detected by MRI. RESULTS: Our patient had increased T2-weighted signal and gadolinium contrast enhancement of the posterior columns in the cervical and thoracic regions and enhancement of the lateral columns in the high cervical region. This is a case with imaging evidence for lateral column lesions. Two prior reports have shown posterior column enhancement. T1-weighted images may show decreased signal in the posterior columns and sometimes demonstrate reversible spinal cord swelling. MRI abnormalities typically improve after vitamin replacement therapy. However, clinical signs may persist despite resolution of imaging abnormalities, and these abnormalities do not always resolve completely. In addition, symptoms may precede the imaging abnormality. CONCLUSIONS: Vitamin B12 deficiency may produce an increased T2-weighted signal, decreased T1-weighted signal, and contrast enhancement of the posterior and lateral columns of the spinal cord, mainly of the cervical and upper thoracic segments. Because the symptoms may precede any imaging abnormality, it is clear that spinal cord MRI may not be a highly sensitive, early test for subacute combined degeneration.