Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype.

Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF biomarkers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage.

Measurement of total antioxidant capacity of human plasma: setting and validation of the CUPRAC-BCS method on routine apparatus ADVIA 2400.

BACKGROUND: Quantification of Total Antioxidant Capacity (TAC) of human plasma is an important clinical target, since many diseases are suspected to be related with oxidative stress. The CUPRAC-BCS (BCS=Bathocuproinedisulfonic acid) method was chosen since it works using the photometric principle, with stable and inexpensive reagents and at physiological pH. METHODS: The method is based on the complex equilibria between Cu(II)-BCS (reagent) and Cu(I)-BCS. Cu(I)-BCS complex is formed by reducing ability of the plasma redox active substances. The photometric signal is achieved at 478 nm and calibration is performed using urate as a reference substance. RESULTS: Linearity, linear working range, sensitivity, precision, LoD, LoQ, selectivity and robustness have been considered to validate the method. Absorbance at 478 nm was found linear from 0.0025 up to 2.0 mmol L(-1) of urate reference solution. Precision was evaluated as within-day repeatability, Sr=4 µmol L(-1), and intermediate-precision, SI(T)=15 µmol L(-1). LoD and LoQ, resulted equal to 7.0 µmol L(-1) and 21 µmol L(-1) respectively while robustness was tested having care for pH variation during PBS buffer preparation. Tests on plasma (80 samples) and on human cerebrospinal fluid (30 samples) were conducted and discussed. CONCLUSIONS: By the analytical point of view, the photometric method was found to be simple, rapid, widely linear and reliable for the routine analysis of a clinical laboratory. By the clinical point of view, the method response is suitable for the study of chemical plasma quantities related to redox reactivity.

Relationship between cerebrospinal fluid visfatin (PBEF/Nampt) levels and adiposity in humans.

OBJECTIVE: Observations of elevated circulating concentrations of visfatin (PBEF/Nampt) in obesity and diabetes suggest that this recently described adipokine is involved in the regulation of body weight and metabolism. We examined in humans whether visfatin is found in cerebrospinal fluid (CSF) and, if so, how CSF visfatin concentrations relate to adiposity and metabolic parameters. RESEARCH DESIGN AND METHODS: We measured visfatin concentrations in the plasma and CSF of 38 subjects (18 men and 20 women; age 19-80 years) with a wide range of body weight (BMI 16.24-38.10 kg/m2). In addition, anthropometric parameters and endocrine markers were assessed. Bivariate correlation coefficients were determined and stepwise multiple regression analyses were performed to detect associations of CSF and plasma visfatin levels with relevant parameters. RESULTS: Plasma visfatin levels increased with rising BMI (P < 0.0001) and body fat mass (P < 0.0001). In contrast, CSF visfatin levels decreased with increasing plasma visfatin concentrations (P < 0.03), BMI (P < 0.001), body fat mass (P < 0.0001), and insulin resistance (P < 0.05). Body fat was the only factor independently associated with CSF visfatin, explaining 58% of the variation of CSF visfatin levels (P < 0.0001). Neither plasma (P > 0.13) nor CSF (P > 0.61) visfatin concentrations differed between men and women. CONCLUSIONS: Our data indicate that visfatin concentrations in human CSF decrease with rising body fat, supporting the assumption that visfatin transport across the blood-brain barrier is impaired in obesity and that central nervous visfatin insufficiency or resistance are linked to pathogenetic mechanisms of obesity.

Spinal anaesthesia with 0.5% isobaric bupivacaine in patients with diabetes mellitus: the influence of CSF composition on sensory and motor block.

BACKGROUND AND OBJECTIVE: We investigated cerebrospinal fluid characteristics in patients with and without diabetes mellitus and the influences that changes in these characteristics have on sensory and motor block when spinal anaesthesia is performed. METHODS: We included 44 patients in each study group. All received spinal administration of 15 mg of 0.5% isobaric bupivacaine. Blood and cerebrospinal fluid were analysed for glucose, total protein, urea, albumin, immunoglobulin G, sodium, chloride, potassium, calcium, magnesium and osmolarity as well as the performance of the local anaesthetic from establishment until complete regression of sensory and motor block. RESULTS: The cerebrospinal fluid of the two groups differed significantly (P < 0.05) in the levels of total protein, albumin, immunoglobulin G, glucose and osmolarity. Sensory and motor block was established more rapidly in the diabetic group (P < 0.05), and the total duration from maximum block until regression to two dermatomes was greater (P < 0.05), as was the complete regression from sensory and motor block (P < 0.05). CONCLUSION: This study shows that diabetes mellitus has an influence on sensory and motor block after the administration of spinal isobaric bupivacaine.

Elevation of cerebrospinal fluid protein in patients with diabetes mellitus is associated with duration of diabetes.

We investigated the relationships between total cerebrospinal fluid (CSF) protein in diabetic patients and the clinical characteristics of diabetes mellitus. The subjects comprised 16 diabetic patients (median age = 60.5 years, range = 47-71) who were studied retrospectively. Patients with diseases known to be associated with increases in total CSF protein were excluded as far as possible. The median total CSF protein and albumin quotient in the diabetic group were 52.5 mg/dl (range = 41-84) and 6.13 x 10(-3) (range = 4.0 x 10(-3) to 13.1 x 10(-3)), respectively. These results were significantly higher than those in 28 age-matched nondiabetic patients (median = 59.0 years, range = 50-71) (p < 0.01). Duration of diabetes was associated with total CSF protein (r = 0.642, p < 0.01). If the CSF shows increased total protein in a diabetic patient who has not suffered from long-term diabetes (> or =5 years), causes other than diabetes should be considered to explain increases in total CSF protein. We need to confirm the present results by studying a larger population of diabetic patients.

[Correlation between levels of blood glucose and cerebrospinal fluid glucose and proteins in diabetes mellitus]. / Korelacija nivoa glukoze u krvi i glukoze i proteina u likvoru u toku diabetes mellitusa.

Patient with diabetes mellitus is prone to develop the vascular lesion of blood vessels of all kinds. Microangiopathy and atherosclerosis are progressive during the illness. Also with this study blood brain barrier change in the diabetes mellitus patients was observed. In patients with diabetes mellitus the level of glucose and total proteins increased in the cerebrospinal fluid. During diabetes mellitus the change of permeability blood brain barrier is evident. Blood brain barrier permeability changes in the patients with ICV as well as in the patients without ICV correlate with the values of diabetes mellitus in blood.

Testing of potassium, sodium and chlorine in liquor at the patients with diabetes mellitus.

Patient with diabetes is susceptible to development of vascular lesions of the blood vessels of all sizes. During the discase there is a progressive development of microangiopatys and arterioscleroses. Continuing the works of Stanley I., Rapaport and other rescarches about changes of permeability of hcmatoenchepal barrier in experimental conditions, (according1) the changes of the barrier at patients with diabetes mellitus was examined in this work. At the patients with diabetes mellitus level of sodium in liquor increases, and the level of chlorine and potassium in liquor decreases.

Antibodies to sulfatide in cerebrospinal fluid of patients with multiple sclerosis.

The identity of target antigen(s) in multiple sclerosis (MS) remains elusive despite much effort to identify it. We analyzed cerebrospinal fluid (CSF) from patients with MS, other neurological diseases (OND), other diseases (OD) and healthy controls for antibodies against purified sulfatide, a major glycosphingolipid of human myelin, by an enzyme-linked immunosorbent assay (ELISA) and a thin-layer chromatogram (TLC)-immunostaining technique. Elevated anti-sulfatide antibodies were significantly higher in MS patients as compared with the OND group (p<0.05) and all controls combined (P<0.025). Binding of high titer antibodies to sulfatide was confirmed with TLC-immunostaining. Anti-sulfatide antibodies were detected in all subtypes of MS although the frequency was higher in patients with secondary progressive MS (SPMS) than in patients with primary progressive (PPMS) and relapsing-remitting MS (RRMS). The data demonstrate a humoral response to sulfatide in the CSF of patients with MS.

A cerebrospinal fluid glucose biosensor for diabetes mellitus.

A cerebrospinal fluid (CSF) glucose biosensor is introduced. The biosensor is a polarimeter that measures the rotation of plane polarized light proportional to glucose concentration. Preliminary in vitro studies revealed a linear response with good sensitivity over a range of glucose solutions (0-400 mg/dl). Anesthetized, adult dogs underwent intravenous glucose loading, and these preliminary in vivo studies resulted in good correlation (r = 0.98) between CSF polarimeter readings and CSF glucose by laboratory assay. This in vivo correlation suggests that both mutarotation of glucose anomer and changes from other optically active substances present in CSF are either negligible or constant over the range of glucose concentrations studied. The CSF polarimeter showed a significant rise soon after the intravenous loading of glucose (1-30 min) but a longer lag time (45-60 min) between the peak blood glucose and peak CSF polarimeter reading. This preliminary work extends, to the CSF, the concept of measuring optical rotation.

Cerebrospinal fluid lactate in patients with diabetes mellitus and hypoglycaemic coma.

Cerebrospinal fluid (CSF) lactate and pyruvate concentrations were determined in 20 patients with diabetes mellitus but without disturbance of consciousness and five who recovered from hypoglycaemic coma. CSF lactate was slightly but significantly higher in diabetes mellitus (1.78, SEM 0.04 m mol/l) than that in 15 control subjects (1.40, SEM 0.05 m mol/l). In those who recovered from hypoglycaemic coma, CSF lactate was markedly elevated to 2.45-4.43 m mol/l. CSF glucose concentrations, however, were substantially the same between treated hypoglycaemic and diabetes mellitus groups. These findings indicate that CSF lactate levels increase with glycaemic levels in diabetes mellitus owing to enhanced glucose influx into glycolytic pathway of the brain, and also increases in treated hypoglycaemic coma probably due to mitochondrial dysfunction or damage.

High resolution proton nuclear magnetic resonance studies of human cerebrospinal fluid.

One- and two-dimensional (correlated shift spectroscopy) high resolution proton n.m.r. spectra of human cerebrospinal fluid (CSF) are reported. The merits of water suppression by freeze drying or irradiation, and spectral simplification by spin-echo methods, are discussed. Well-resolved resonances for a range of low molecular weight metabolites such as lactate, 3-D-hydroxybutyrate, alanine, acetate, citrate, glucose, valine and formate were observed. Resonances for glutamine were observed only from freeze dried samples. Concentrations determined by n.m.r. were in reasonable agreement with those from conventional methods. The n.m.r. spectra of CSF were related to the clinical conditions of the subjects. No resonances for citrate were present in spectra of CSF from subjects (three infants) with bacterial meningitis; high lactate and lowered glucose levels were observed. Strong resonances for glucose and glycine were observed for mildly diabetic subjects. Both the aromatic and the aliphatic regions of the CSF spectra from subjects suffering from liver failure contained distinctive features characteristic for hepatic coma: Intense resonances for lactate, alanine, valine, methionine, tyrosine, phenylalanine and histidine. In some cases guanine was also present, which does not appear to have been reported previously. The two-dimensional spectrum suggested the presence of abnormally high levels of a number of endogenous metabolites. Such assignments were not possible using one-dimensional spectra alone because of signal overlap.

Catatonia with high CSF lactate in a case of diabetes with associated conditions.

A case of reversible catatonia in a well controlled insulin-dependent diabetic is described. The course of catatonia was characterized by very high CSF lactate values (serial semiautomatic determinations) during more than one month, beyond the clinical recovery. The CSF lactate elevations seem to reflect cerebral hypoxia. The uncommon coincidence of diabetes with cerebral atrophy, mental weakness, and perceptive deafness migh suggest the classification of this case of diabetes in the group 'associated with certain conditions and syndromes'.

Sorbitol and myoinositol levels in the cerebrospinal fluid of diabetic patients.

Sorbitol and myoinositol have been measured from human cerebrospinal fluid. The normal concentrations are very small (below 100 microM/l). The detection limit of the Gas Liquid Chromatographic method was 5 microM/l. The sensitive method provided a possibility to compare quantitatively the sugar alcohol concentrations in human cerebrospinal fluid. Sorbitol concentration was increased and myoinositol concentration decreased in the cerebrospinal fluid of diabetic patients.

Polyols in the cerebrospinal fluid and plasma of neurological, diabetic and uraemic patients.

Five polyols, arabinitol, anhydroglucitol, mannitol, sorbitol and myoinositol, normally present in the cerebrospinal fluid (CSF), were studied. Quantitative gas-liquid chromatographic analysis of 211 CSF and 112 plasma samples indicated significantly altered concentrations in several clinical conditions. All five polyols were decreased in the CSF of patients suffering from meningitis, cerebral atrophy, sepsis, and in patients receiving intrathecal cytostate therapy. Equilibration between plasma and CSF may explain the changes in sepsis and meningitis, while decreased total number of functioning cells may cause the decrease in cerebral atrophy. Intrathecal cytostates seem to have a destroying effect on the cell metabolism of the central nervous system. Renal failure causes accumulation of polyols in the plasma. Alterations in the metabolism of sorbitol, myoinositol and anhydroglucitol seem to be present in diabetes. The plasma concentration of anhydroglucitol is decreased in renal failure.

Accumulation of myoinositol in plasma and red cells of diabetic patients.

The concentration of myoinositol in plasma, cerebrospinal fluid and red cells and its elimination by the kidneys have been studied in 51 diabetic patients with normal or impaired kidney function, 16 non-diabetic patients with renal failure and 37 healthy controls. All diabetic patients who had a glomerular filtration rate considerably below normal, was the plasma concentration of myoinositol higher than in controls. The findings show that the rise in plasma concentration of myoinositol most probably results from a decreased glomerular filtration rate. In diabetic patients, urinary excretion of myoinositol correlated with an exponential increase in glucose excretion. That myoinositol accumulates in red cells of diabetic patients may be the result of its retention within these cells caused primarily by a transient, abnormal increase in the plasma concentration of myoinositol after an average meal.