Homocysteine and methylmalonic acid concentrations in cerebrospinal fluid: relation with age and Alzheimer's disease.

BACKGROUND: Homocysteine may be involved in the pathogenesis of late onset Alzheimer's disease. It is implicated in the metabolism of several important pathways in the brain. Methylmalonic acid (MMA) is related to the metabolism of branched chained amino acids and fatty acids. OBJECTIVES: To compare cerebrospinal fluid (CSF) total homocysteine and MMA in elderly subjects, patients with Alzheimer's disease, and younger healthy controls. SUBJECTS: CSF samples were obtained from 33 patients under 20 years of age; 28 patients aged 21 to 60 years; 22 normal elderly subjects aged over 60; and 38 Alzheimer patients aged over 60. RESULTS: CSF total homocysteine increased with age (mean (SD): 57 (35) nmol/l in the youngest group v 123 (89) nmol/l in the elderly group (p<0.001)). There was no difference between the elderly group and Alzheimer patients (115 (62) nmol/l). CSF MMA did not differ in the elderly group and the Alzheimer group (38 (13) v 35 (14) ng/ml). In the youngest group, it was significantly higher (60 (15) ng/ml). CONCLUSIONS: CSF total homocysteine is not increased in Alzheimer's disease compared with age matched controls. CSF total homocysteine was correlated with age. The decrease in CSF MMA levels with age eliminates a lack of vitamin B-12 at neuronal level.

Choroid plexus and ageing in rats: a morphometric and ultrastructural study.

Choroid plexuses (CP) are intraventricular structures involved in the production of cerebrospinal fluid (CSF) and in the synthesis and transport of numerous CSF components. Age-related modifications of the CP structure are still ill defined. We performed an ultrastructural and morphometric study of ageing CP in nine Sprague-Dawley rats 6, 18 and 30 months of age. Epithelial cells of CP villi were cubic in shape at 6 months, more dome-like at 18 months, and significantly flattened at 30 months of age. Epithelial basement membranes were thin and regular at 6 months, significantly thicker at 18 months and thicker and irregular at 30 months. Intravillous stroma increased nonhomogeneously with age. The ageing of CP in rats is characterized morphologically by epithelial atrophy, irregular fibrosis of the stroma and a thickening of epithelial basement membranes. These modifications suggest an alteration of secretory and filtrating functions in ageing CP.

Increased protein glycation in cerebrospinal fluid of Alzheimer's disease.

Accumulation of advanced glycation end products occurs in the brain with ageing and was proposed to be involved in pathogenesis of Alzheimer's disease. We studied changes in the level of an early glycation product, an Amadori product, in cerebrospinal fluid (CSF) in ageing and in late-onset Alzheimer's disease. The work was carried out on 99 consecutive patients. The concentration of Amadori product in CSF correlated with CSF glucose concentration but was not changed with age (n = 70). In contrast, level of CSF Amadori product was 1.7-fold higher in Alzheimer's disease patients (n = 29) as compared with non-demented age-matched control group (n = 20; P < 0.0005), although CSF glucose concentration was similar in both groups (4.1 +/- 1.3 vs. 3.8 +/- 0.6 mmol/liter, resp.). An increased accumulation of Amadori products was found in all major proteins of CSF of Alzheimer's disease including albumin, apolipoprotein E and transthyretin. We propose that the increased early glycation of CSF proteins in the Alzheimer's patients may stimulate the formation and the consequent deposition of advanced glycation end products as well as oxidative stress in the brain.

CSF-folate levels are decreased in late-onset AD patients.

Folates are involved in the cerebral metabolism of cobalamine, methionine, L-tyrosine and acetylcholine. Remarkably CSF-folate levels are 3 to 4 times higher than blood-folate levels. To reach the brain, folates are actively transported by choroid plexus (CP) as well as vitamins B6, B12, C and E. Epithelial atrophy having been reported in aging and in Alzheimer's disease (AD), we measured the CSF folate-levels of 126 patients, including 30 AD consecutive patients to evaluate whether CP functions of folate-transport were impaired. CSF-folate concentrations did not vary with age (10.47 +/- 1.93ng/ml between 20 and 60 years; 9.96 +/- 2.01 ng/ml in elderly control patients older than 60 years of age, p > 0.05) while late-onset AD patients had significantly lower CSF-folate levels (8.26 +/- 1.82 ng/ml, p < 0.001). These data support a specific alteration of CP transport function in AD patients.

Apolipoprotein E polymorphism and serum concentration in Alzheimer's disease in nine European centres: the ApoEurope study. ApoEurope group.

As part of the ApoEurope Project, apolipoprotein E (apo E) common polymorphism and serum concentration were determined in 489 Alzheimer's disease patients and 429 controls. Patients and controls were recruited through nine centres in eight European countries. Age, sex ratios and education levels of both case and control populations were similar, although discrete differences appeared between centres. The prevalence of the epsilon4 allele was higher in Alzheimer's disease than in controls (increased by 140%), while serum apo E concentration was lower by 11.2% (p<0.001). In addition, serum total cholesterol and triglyceride concentrations were lower in Alzheimer's disease (p<0.001), while that of apo Al was not affected. The decrease in serum apo E concentration was not accounted for by the epsilon4 allele, age or gender, suggesting that apo E concentration might represent an additional risk factor for Alzheimer's disease, complementary and independent of the epsilon4 allele. Further analysis will be aimed at determining whether the quantitative link between apo E concentration and Alzheimer's disease occurs through the effect of apo E genotype on lipid parameters or by other mechanisms.

Decreased high-density lipoprotein cholesterol and serum apolipoprotein AI concentrations are highly correlated with the severity of Alzheimer's disease.

Serum apolipoprotein (apo) AI concentration was studied in 98 Alzheimer's disease (AD) patients (77.56+/-8.83 years) and 59 healthy, elderly controls (75.37+/-5.27 years). ApoAI levels were significantly lower (p<10(-7)) in AD patients. An apoAI cutoff value of 1.50 g/L, could distinguish between the two groups with a sensitivity of 71% and a specificity of 69%. ApoAI levels were highly correlated with mini-mental state (MMSE) scores of patients (p<0.0001). These relationships remained significant after adjustment for multiple testing. Our findings raise the question of the potential implication of apoAI in the etiopathology of AD and bring serum apoAI concentration to the fore as an important biochemical marker.

Monocyte-derived IL-10-secreting dendritic cells in choroid plexus epithelium.

Choroid plexuses form an interface between peripheral blood and cerebrospinal fluid. Dendritic-like cells have been reported in a few studies of choroid plexuses in man. Here we used electron microscopy and immunophenotyping to precise the morphologic features and phenotype of these cells. Examination of 10 human choroid plexuses evidenced intra-epithelial dendritic cells with a clear cytoplasm, reniform nucleus and long expansions. These cells express MHC Class II, CD11b, CD14, CD32, CD68 and IL-10, but not CD40, CD80 or CD86, suggesting an immunosuppressive role for these dendritic cells. Their sentinel position could make them participate to the immunological silence of the brain.

Morphological alterations of the choroid plexus in late-onset Alzheimer's disease.

Anomalies of the cerebrospinal fluid flow rate and composition that have been reported in patients suffering from Alzheimer's disease (AD) could be related to alterations of the choroid plexuses (CD). Here we report a photonic and electron morphometric study in which we compared the height of CP epithelial cells and the thickness of their basement membrane on post-mortem samples from AD patients, age-matched controls and two newborns. Ageing appeared associated with epithelial atrophy and basement membrane thickening, but these features were significantly accentuated in AD. These data suggest that a dramatic alteration of the secretion and filtration could be involved in the multiparametric pathogenesis of late-onset AD.

Apolipoprotein E, transthyretin and actin in the CSF of Alzheimer's patients: relation with the senile plaques and cytoskeleton biochemistry.

We measured the levels of two beta-amyloid (Abeta)-sequestering proteins, apolipoprotein (Apo) E and transthyretin (TTR), in ventricular human cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients and controls in relation to brain histological findings. We also studied actin levels in CSF as a marker of the biochemical role of these two proteins in the cytoskeleton. We show that TTR levels in CSF were significantly decreased in AD patients compared to controls and negatively correlated with the senile plaque (SP) abundance. Moreover, actin levels were positively linked to TTR levels and increased in CSF samples of patients homozygous for the ApoE epsilon4-allele. We propose that TTR and ApoE4 may have competition in the aggregation of Abeta and its deposition in the SP of AD brain. The relationships between ApoE, TTR and actin could suggest a metabolic implication of ApoE genetics and TTR levels in cytoskeletal biochemistry which may be relevant to the pathogenesis of AD.

Cerebrospinal fluid transthyretin: aging and late onset Alzheimer's disease.

The deposition of insoluble beta-amyloid protein fibrils is probably the central event in the pathogenesis of Alzheimer's disease. Cerebrospinal fluid inhibits this fibril formation, likely by the intervention of one or several proteins binding to soluble beta-amyloid protein. In vitro, transthyretin (TTR), a CSF protein, impedes amyloid fibrillogenesis. Lowered concentrations of CSFTTR could therefore be associated with Alzheimer's disease. Concentrations of TTR in CSF samples from 149 consecutive patients were assayed, using a kinetic nephelemetric method. These concentrations were correlated positively with age, but were significantly lower in patients with Alzheimer's disease. These data raise the possibility that amyloid fibril formation could be promoted in patients with late onset Alzheimer's disease by the lack of sufficient concentrations of TTR.

Ultrastructural and immunohistological evidence for dendritic-like cells within human choroid plexus epithelium.

Ultrasonic examination of human choroid plexus (CP) disclosed the presence of a possibly new type of CP cells displaying many of the features of dendritic cells and apparently expressing HLA Class II antigens. These cells bear long processes, devoid of tight junctions, inserted between CP epithelial cells, and have close contacts with CP basement membrane. They could, therefore, play a key role in immunosurveillance in the central nervous system.

Comparative immunohistochemical characteristics of human choroid plexus in vascular and Alzheimer's dementia.

Autoimmune alterations are indirectly supported in Alzheimer's disease by the demonstration of circulating antibodies directed to the epithelial basement membrane (BM) of the choroid plexus. We used immunohistochemical methods to compare the characteristics of choroid plexuses obtained postmortem from 15 patients. Six had a diagnosis of Alzheimer's disease, five had multi-infarct dementia (MID), and one suffered from mixed dementia. Similar tissue from three age-matched, non-demented controls was studied as well. Age-related psammoma bodies, lipofucsin, and flattened epithelial cells were present in all cases. Specific alterations were evident in Alzheimer's disease patients only. These were comprised of pseudolinear deposits of immunoglobulin (Ig)G and coarse deposits of C1q along the thickened and segmented epithelial BM, and were associated with IgM in five cases. Although no lymphoid infiltration was demonstrated, MHC Class II+ macrophages were observed in the plexus stroma, and numerous epithelial cells were class II+. These observations suggest that immune alterations, possibly of autoimmune origin, may be involved in Alzheimer's disease, leading to severe lesions of the choroid plexus. Such anomalies could be responsible for some of the alterations of cerebrospinal fluid (CSF) production or composition noted in this disease.

Antibodies to choroid plexus in senile dementia of Alzheimer's type.

AIMS: To investigate whether autoantibodies to choroid plexus are present in human senile dementia. METHODS: Serum samples from 40 elderly people presenting with characteristic, diagnostic criteria of senile dementia of Alzheimer's type and 20 age matched healthy controls were tested by indirect immunofluorescence for the presence of autoantibodies to choroid plexuses, using frozen sections of rat or human fetal brain tissue. RESULTS: Significant labelling of choroid plexus basement membrane was observed in 17 of the 40 samples from patients with senile dementia; in the control series one sample of rat but not human plexus labelled positively (p < 0.01). CONCLUSIONS: The antibodies identified in this series of patients with Alzheimer's disease suggest that autoimmune mechanisms might be responsible for some of the changes in cerebrospinal fluid production described in this disorder.

Pharmacokinetics of salicylates in elderly.

In order to study changes in the pharmacokinetics of salicylates in old people, we used two groups of inpatients without hepatic or renal impairment: the first comprised 15 patients more than 65 years old, mean age 77 years; the second, 7 patients of mean age 21 years. Each patient was given 1 g of acetylsalicylic acid orally in the morning while fasting. Blood samples were subsequently taken after 30, 60 and 90 min and 2, 3, 4, 6, 8, 10, and 24 h. Fluorimetric assay results were analyzed kinetically with a mathematical model corresponding to a single diffusion compartment model. The results showed only a slight increase in the absorption half-time in old subjects, and a marked increase in elimination half-time (3.71 and 2.38 h in old and young subjects, respectively; t = 2.33: p less than 0.05) and in the volume of distribution (5.51 and 3.83 liters respectively; t = 3.20: p less than 0.1). On the other hand, bioavailability varied little, as did metabolic clearance. This study confirms that intestinal absorption of this drug is not much impaired in old people, while hepatic and/or renal elimination functions are changed. This finding agrees with results found for aminopyrine, antipyrine, and digoxin.

[Kinetics of bone uptake of 99m Tc-labeled diphosphonates. Preliminary results]. / Etude de la cinétique de fixation osseuse des diphosphonates marqués au 99m tc. Résultats préliminaires.

The bone fixation of diphosphonates depends on the degree of osteogenesis, the blood bone flow and the capillary permeability. The precise characteristics of the fixation kinetic are not very well known. The authors propose a new method which makes possible to study them and expose their results. For average persons the fixation curves present an ascending line, an apex, reach within 40 mn and a descending line. Any affection don't seem to have characteristic curves; on the contrary it is possible to have different curves for a same affection which implies doubtless various anatomic and metabolic data.