Detection of complement factor B in the cerebrospinal fluid of patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy disease using two-dimensional gel electrophoresis and mass spectrometry.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary condition with onset in mid-adulthood and is associated with mutations in the Notch-3 gene. (Joutel, A., Corepechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenda, V., Cecilion, M., Marechal, J., Vayssiere, C., Cruaud, C., Cabanis, E.A., Ruchoux, M.M. , Weissenvach, J., Bach, J.F., Bousser, M.G. and Tournier-Lasserve, E., Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature, 383 (1996) 707-710) Ultrastructural examination of the pathology of the cerebral infarcts reveals deposits in the vascular smooth muscle cells of the small arteries of the brain, but there is no obvious indication how the Notch-3 mutations give rise the observed pathology, nor is there any information on the exact nature of the deposits. We have investigated cerebrospinal fluid (CSF) from three CADASIL cases with known mutations in Notch-3 using two-dimensional gel electrophoresis. CSF from these patients was compared to that of six controls. We detected a single spot in the protein maps of patients which was absent from all the controls. In-gel tryptic digestion of this protein followed by mass spectrometric analysis of the tryptic fragments and a database search identified the spot as human complement factor B. These preliminary findings suggest that the alternative complement pathway may play a role in the pathogenesis of CADASIL.

The effect of dehydroepiandrosterone sulfate administration to patients with multi-infarct dementia.

We measured cerebrospinal fluid (CSF) levels of dehydroepiandrosterone sulfate (DHEAS) by radioimmunoassay in seven patients with multi-infarct dementia (MID), fourteen age- and gender-matched non-demented patients with a history of cerebral infarction and fifteen age- and gender-matched patients without neurological disorders. The levels of DHEAS in CSF of patients with MID were significantly lower than those in non-demented patients with a history of cerebral infarction or those in patients without neurological disorders. Daily intravenous administration of 200 mg DHEAS for 4 weeks markedly increased serum and CSF levels of DHEAS in seven MID patients, improved decrease of daily activities and emotional disturbances in three patients and EEG abnormalities in two patients. The DHEAS therapy may provide a beneficial effect on MID patients.

The cerebrospinal fluid oxidized NO metabolites, nitrite and nitrate, in Alzheimer's disease and vascular dementia of Binswanger type and multiple small infarct type.

The concentration of the nitric oxide (NO) metabolites nitrite (NO2-) and nitrate (NO3-) in the cerebrospinal fluid from patients with Alzheimer's disease (AD), vascular dementia of the Binswanger type (VDBT) or multiple small infarct type (MSID), and controls were determined using high performance liquid chromatography. The nitrite concentration was significantly higher in VDBT/MSID patients than in controls (p < 0.005). The nitrate concentration and the combined nitrite and nitrate concentration was significantly higher in both AD (p < 0.05) and VDBT/MSID (p < 0.001) patients than in controls, with these concentrations being significantly greater in VDBT/MSID than AD patients (p < 0.005). The combined nitrite and nitrate concentration significantly decreased as the severity of dementia progressed in AD (rs=0.70, p < 0.01), but remained elevated in all stages of VDBT/MSID. These results suggest that NO production or oxidation in the brain increases in the early stage of AD and then decreases as neuronal cell loss progresses, but increases throughout the course of disease in VDBT/MSID, which may in part contribute to neuronal degeneration in both conditions.

Amino acid concentration in dementia of the Alzheimer type and multi-infarct dementia.

Amino acids were measured in nine cases of dementia of the Alzheimer type, 10 cases of multi-infarct dementia, and 10 healthy controls. The severity of dementia was examined using mini-mental state test (MMST). Amino acid analysis (41 kinds) in the cerebrospinal fluid (CSF) and serum was performed in the Special Reference Laboratories. In the dementia of the Alzheimer type group, methionine and alanine concentrations in the CSF were significantly increased, and the CSF/serum ratios for both the alanine and glycine concentrations were significantly increased, in comparison with the healthy control group. In the multi-infarct dementia group, glycine, methionine, threonine, phenylalanine, and citrulline concentrations in the CSF were all higher than in the healthy control group. Significant negative correlations were found between the MMST score and the alanine, urea, arginine, and alpha-aminobutyric acid concentrations in the CSF. The number of amino acids which exhibited abnormality in dementia of the Alzheimer type and multi-infarct dementia was greater in the present study than in previous reports.

Cerebrospinal fluid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia.

The acetylcholine (ACh) and choline (Ch) concentrations in the cerebrospinal fluid were investigated in patients with vascular dementia of the Binswanger type (VDBT) or multiple small infarct type (MSID) as compared with patients with Alzheimer-type dementia (ATD). The ACh concentration in patients with ATD was found to be significantly lower than in controls (73%, p < 0.0001), and showed a significant positive correlation with dementia scale scores (rs = 0.63, p < 0.03). The Ch concentration in the CSF of ATD patients was approximately the same as in controls. In VDBT/MSID patients, the ACh concentration was significantly lower than in controls (p < 0.001) also showing a significant positive correlation with dementia scale scores (rs = 0.62, p < 0.02), but was significantly higher than in ATD patients (p < 0.001). Moreover, the Ch concentration in VDBT/MSID patients was significantly higher than in controls (p < 0.001) or ATD patients (p < 0.001). These results suggest that simultaneous determination of ACh and Ch concentrations in CSF may be useful for differentiating VDBT/MSID from ATD and that increasing the ACh level using cholinergic agents may be a beneficial therapeutic strategy for the treatment of ATD as well as VDBT/MSIT, and is worthy of further investigation.

Endothelin-1 in cerebrospinal fluid in elderly patients with hypertension and dementia.

Endothelin-1, a potent endothelium-derived vasoconstrictive peptide, is also known to exist in the central nervous system. We determined endothelin-1-like immunoreactivity in cerebrospinal fluid by a radioimmunoassay in 32 normotensive or hypertensive elderly subjects (79 +/- 8 years old) with or without multi-infarction dementia. The mean value of endothelin-1-like immunoreactivity in cerebrospinal fluid was significantly (P < .05) elevated in subjects with essential hypertension (> or = 160/95 mm Hg, n = 5, 79 +/- 9 years old) compared with those with borderline hypertension (140-159/90-94 mm Hg, n = 4, 78 +/- 5 years old) and normotensive subjects (< 140/90 mm Hg, n = 23, 79 +/- 8 years old). The value of endothelin-1-like immunoreactivity in cerebrospinal fluid was significantly (P < .05) positively correlated with both systolic (r = .38) and diastolic (r = .42) blood pressures in all subjects. On the other hand, mean values of endothelin-1-like immunoreactivity in cerebrospinal fluid were also significantly (P < .05) elevated in the groups of patients with multi-infarction dementia that had profoundly decreased Mini-Mental State scores (< or = 10, n = 6) and moderately decreased Mini-Mental State scores (11 to 20, n = 14) compared with those values in subjects with normal cognitive function (score for Mini-Mental State > or = 21, n = 12).(ABSTRACT TRUNCATED AT 250 WORDS)

A long-term follow-up study of cerebrospinal fluid 5-hydroxyindoleacetic acid in delirium.

Cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) was determined for elderly delirious patients during the acute stage and after a 1-year follow-up period, and the 5-HIAA levels were compared with age-equivalent controls. As compared with the controls, the 5-HIAA levels were significantly higher at the beginning of the index admission in patients with multi-infarct dementia and patients with no apparent CNS disease. The 5-HIAA levels were also higher in the latter subgroup in the 1-year sampling, but no other differences between delirious patients and controls were observed. The one-way procedure showed no differences between the subgroup means of delirious patients when divided according to the severity of cognitive decline or type of delirium in any of the samples. The 5-HIAA levels measured during the index admission correlated with the length of life after delirium suggesting that serotonergic dysfunction may have prognostic significance in delirious patients.

The urate and xanthine concentrations in the cerebrospinal fluid in patients with vascular dementia of the Binswanger type, Alzheimer type dementia, and Parkinson's disease.

We determined the urate and xanthine concentrations in the cerebrospinal fluid (CSF) in patients with vascular dementia of the Binswanger type (VDBT), Alzheimer type dementia (ATD), and Parkinson's disease (PD). We found that the urate concentration was significantly increased in VDBT patients, but significantly decreased in ATD patients compared with controls. The ratio of the concentrations of uric acid (UCSF) to xanthine (XCSF) in the CSF (UCSF/XCSF) had a significant correlation with the ratio of the UCSF to the urate concentration in serum (U(serum)) (UCSF/U(serum)) in ATD and PD, whereas UCSF/U(serum) increased independently of UCSF/XCSF in VDBT. We concluded that the significant increase in the urate concentration in VDBT is mainly due to an impairment of the blood-brain barrier (BBB), and its significant reduction in ATD may reflect impaired brain metabolism.

[A preliminary study of cerebrospinal fluid cytology in aged patients with dementia].

31 cases of dementia of the aged were studied with the method of CSF cytology. Of the 31 cases, 14 were of Alzheimer dementia (AD), 17 multi-infarct dementia (MID), and 25 aged subjects were studied as control. The results showed that the number of lymphocytes in the CSF in AD group was obviously higher than that in MID group. The number of monocyte--macrophages was decreased in both two studied groups in comparing with that of the control group. We didn't find macrophages in AD group. The number of neutrophils in the CSF was high in both observed groups, and more markedly in AD group. The significance and specialty of the results need further study.

Marked increase in cerebrospinal fluid ubiquitin in Creutzfeldt-Jakob disease.

We have established the radioimmunoassay for ubiquitin in the cerebrospinal fluid (CSF) and measured the ubiquitin concentration in CSF from 4 cases of neuropathologically verified Creutzfeldt-Jakob disease (CJD), 10 cases of multi-infarct dementia (MID), 7 cases of senile dementia of Alzheimer type (SDAT), and 18 controls. The normal values were determined to range from 7.3 to 21.0 ng/ml, 14.3 +/- 1.1 ng/ml in the mean +/- S.E.M. The CSF ubiquitin levels in the cases of MID and SDAT were 16.6 +/- 6.4 ng/ml and 21.3 +/- 6.1 ng/ml, respectively. In the cases of CJD, the CSF ubiquitin was markedly increased at the early and middle stages of the disease (230.6 ng/ml in Case 1, 107.6 ng/ml in Case 2, 212.5 ng/ml in Case 3, and 377.0 ng/ml in Case 4) and these gradually decreased as the disease progressed. The measurement of CSF ubiquitin seems useful to make an early diagnosis of CJD.

Cerebrospinal fluid neuropeptides in mood disorder and dementia.

Cerebrospinal fluid (CSF) concentrations of immunoreactive corticotropin-releasing hormone (CRH) and somatostatin (SRIF) were measured in female psychiatric inpatients with DSM-III-R diagnoses of major depression, mania, generalized anxiety and somatization disorder. In addition, elderly patients with dementia disorders, with or without concomitant major depression, were also investigated. CSF SRIF was not significantly different among these groups; on the other hand, mean CSF CRH concentrations were significantly higher in major depression and in dementia with depression as compared with neurological controls with no psychiatric disorders. CSF CRH levels in mania, simple dementia, or anxiety or somatization disorder were not significantly different from the controls. Background physical or clinical variables did not account for the differences in CRH concentrations. It is concluded that CSF CRH elevation may be present in some patients with major depression independent of age and an underlying dementia disorder.

Vitamin B12 in CSF: reduced CSF/serum B12 ratio in demented men.

Vitamin B12 concentrations were determined in serum and cerebrospinal fluid (CSF) of 32 controls and 102 patients with dementia. The dementias were classified as Alzheimer's disease (AD), senile dementia of Alzheimer type (SDAT) and multi-infarct dementia (MID). A substantial number of patients (n = 42) could not be assigned to any of these diagnostic groups, as their dementias were of non-AD/SDAT and non-MID types. They were instead assigned to a group called non ultra descriptum (NUD). CSF B12 correlated significantly with serum B12. There were no statistically significant differences in serum B12 levels between the groups. Although with considerable overlap, CSF B12 concentrations and CSF/serum B12 ratios were significantly lower in the NUD group than in the control group. The NUD group had significantly lower CSF/serum B12 ratios than the group of patients with AD/SDAT. There was significant male predominance in the group of demented patients that had low CSF/serum B12 ratios outside the bivariate reference region. CSF and serum B12 levels appear insufficient as measures of the true brain vitamin B12 status. It may be a more dynamic approach to use the CSF/serum B12 ratio as an indication of transport function across the blood brain barrier, and possibly also across the CSF brain cell barrier.

Cerebrospinal fluid interleukin-1 beta (IL-1 beta) in Alzheimer's disease and neurological disorders.

Recent studies indicate that patients with Alzheimer's disease (AD) exhibit an immune dysfunction at the central and peripheral levels. We have studied the concentration of IL-1 beta in the cerebrospinal fluid (CSF) of patients with AD, multi-infarct dementia (MID), normal pressure hydrocephalus (NPH), and multiple sclerosis (MS). CSF IL-1 beta levels were significantly higher in AD (131 +/- 17.33 pg/ml) than in MID (79.71 +/- 24.37 pg/ml, p less than 0.01), NPH (84.75 +/- 23.17 pg/ml, p less than 0.01), and MS (79.4 +/- 10.23 pg/ml, p less than 0.01). In patients with neurological disorders CSF IL-1 beta levels showed a progressive increase with age (r = +0.49, p less than 0.015). The concentration of IL-1 beta in CSF of demented patients correlated with mental deterioration (r = -0.476). According to these results we postulate that high levels of central IL-1 beta in AD might reflect a reactive neuroimmune response to: (a) abnormal epitopes exposed by lesioned neurons, (b) reactive microglia activated by exogenous and/or endogenous factors and (c) endogenous neurotrophic activation.

Calcium and phosphorus levels in serum and CSF in dementia.

Marked differences in CSF levels of both calcium and phosphorus were observed in patients with dementia and aged controls when compared with adult controls. A significant decrease in both Ca and P in CSF was observed in Alzheimer's type dementia (p less than 0.01) and multi-infarct dementia cases (p less than 0.01). The geriatric controls also showed a significant decrease in both Ca and P. A 60% decrease in diffusible Ca in CSF was noted both in patients and geriatric controls when compared to adult controls (p less than 0.001). Diffusible P was also decreased in all three groups (p less than 0.05). A marginal decrease in serum Ca and slight increase in P was observed in both patients and geriatric controls. The significant decrease in CSF Ca and P in both groups of patients compared with aged controls suggests this lowering of Ca and P is not due to solely to the aging process and indicates a role in the pathology of age-related disorders.

Somatostatin cerebrospinal fluid levels in dementia.

Somatostatin levels were measured in cerebrospinal fluid of patients with Alzheimer's disease, multi-infarct dementia and normal pressure hydrocephalus and compared with levels from a normal control group. All pathological groups showed a statistically significant decrease of somatostatin with respect to the control group, but no significant differences were found amongst them. A negative correlation was found between the Mini Mental State Test and the somatostatin levels in Alzheimer's disease patients but not in the other groups. Our results confirm that the lower levels of somatostatin in cerebrospinal fluid are not specific to Alzheimer's disease and indicate that the decrease found in all the groups is probably the result of neuronal destruction or damage in the diseases examined.

Cerebrospinal fluid and plasma corticotropin-releasing hormone in senile dementia.

Cerebrospinal fluid (CSF) levels of corticotropin-releasing hormone (CRH) and ACTH, and plasma levels of CRH, ACTH and cortisol were determined in samples taken simultaneously from 28 patients with dementia including senile dementia of the Alzheimer type (SDAT), multi-infarct dementia (MID), dementia following a cerebrovascular accident (CVD), and the borderline-to-normal state. CRH levels in CSF were significantly reduced in patients with SDAT and CVD, but not in those with MID, as compared with the borderline cases. ACTH levels in CSF were significantly reduced in the patients with SDAT compared to those with MID. Reduced CRH levels in CSF were found in the patients who showed severe dementia and poor activities of daily living (ADL). Plasma levels of CRH, ACTH and cortisol were normal and were not significantly different among the four groups of patients. CRH levels in CSF were positively correlated with ACTH levels in CSF, but not with the levels of plasma CRH, ACTH or cortisol. Plasma CRH levels were positively correlated with plasma ACTH levels. These results suggest that: 1) abnormalities in the extrahypothalamic CRH system play a role in the pathophysiology of senile dementia, which may not be specific to SDAT; 2) CSF CRH is correlated with the severity of dementia and ADL; 3) the levels of CRH in CSF and plasma are independent, and 4) the plasma CRH reflects, at least in part, the activity of the hypothalamic CRH regulating the secretion of pituitary ACTH.

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.

Is multi-infarct dementia representative of vascular dementias? A retrospective study.

Multi-infarct dementia (MID) indicates a dementia disorder primarily caused by multiple cerebral infarcts. Since other pathogenetic mechanisms cause vascular dementia we evaluated clinical, CT scan and CSF neurochemical parameters of 134 MID and 67 PVD (probable vascular dementia) patients. We found no differences with regard to the presence of major risk factors. Only TIA/stroke episodes and focal neurological signs were significantly more frequent in MID than in PVD cases, an anticipable result on the basis of MID definition. CT scan findings showed a prevalence of subcortical with respect to cortical lesions in both groups, with a higher frequency in MID patients. Subjects with deep infarcts more frequently showed TIA/stroke episodes and diabetes mellitus. No differences were detectable in CSF monoamine metabolite levels. We conclude that in the majority of vascular dementias subcortical damage seems to have a major pathogenetic role.

Amino acid concentrations in cerebrospinal fluid in presenile and senile dementia of Alzheimer type and multi-infarct dementia.

Free amino acid levels were measured in cerebrospinal fluid (CSF) from demented patients (D, n = 30) suffering from presenile and senile dementia of Alzheimer type (PDAT, n = 7; SDAT, n = 9), multi-infarct dementia (MID, n = 14) and a reference sample group consisting of young neurotic patients (R, n = 16). Comparing the amino acid levels in the dementia subgroups, significantly higher alanine, methionine, phenylalanine and tyrosine levels were found both in MID and SDAT vs. PDAT. No difference was seen between SDAT and MID. Compared to the reference sample group, higher glycine levels were found in each dementia subgroup; higher alanine, methionine and ornithine levels in MID, and SDAT; and higher phenylalanine levels in MID. In PDAT the level of tyrosine was lower. Coefficients of correlation were calculated between amino acid levels and age, and the findings in the reference sample groups were divergent from those observed in dementia. The differences observed are discussed in terms of amino acid, carbohydrate and neurotransmitter metabolism.