Citations

The blood-nerve transfer of human plasma albumin glycated with D-glucose was investigated by measuring the permeability coefficient-surface area product (PS) of the blood-nerve barrier to radioiodinated albumin in normal adult rat sciatic nerve. Human albumin (ALB) from normal individuals, freshly isolated by CM-Affi-Gel Blue affinity chromatography, was glycated in vitro for 1, 3, 10, 19, and 30 weeks. Glycated ALB (gALB) was separated from the nonglycated form by boronate-affinity chromatography. The efficiency of this separation was assessed by chromatography of ALB glycated with [14C]glucose and by rechromatography of isolated ALB and gALB after radioiodination. The gALB was also shown to have a higher molecular weight and be completely separated from ALB after SDS/pore gradient electrophoresis in a Tris borate/EDTA buffer. After 1 week of glycation, the gALB PS was 2.2-fold greater than the ALB PS (0.724 +/- 0.063 x 10(-6) vs. 0.328 +/- 0.053 x 10(-6) ml.g-1.s-1; mean +/- SD; P less than 0.0001) and it increased with the time of glycation reaching a maximum value of 16.2-fold greater at 30 weeks (4.656 +/- 1.117 x 10(-6) vs. 0.288 +/- 0.042 x 10(-6) ml.g-1.s-1; mean +/- SD; P less than 0.0001). No change was observed in the residual endoneurial plasma volume. In addition, the PS of gALB isolated from patients with diabetic polyneuropathy was significantly increased (P less than 0.0001) compared to the PS for ALB isolated from the same patients. It is hypothesized that the increased permeability of gALB and presumably other glycated serum components across the blood-nerve barrier, as well as the observed quantitative increase in ALB, IgG, and IgM in sural nerve biopsies from patients with diabetic polyneuropathy contribute to the development of diabetic polyneuropathy over a prolonged period of time by mechanisms that might involve osmotic changes in the nerve microenvironment, direct toxic effects of glycated macromolecules on cells within the endoneurium, or nerve damage by classical immunological mechanisms due to trapping of glycated immunoglobulins within nerve.

The albumin (Alb), IgG, and IgM concentrations in the endoneurium of fascicular sural nerve biopsy samples were evaluated in controls (n = 9 or 10), diabetic patients without neuropathy (n = 6), and diabetic patients with polyneuropathy (n = 17 or 18). These values were significantly increased in diabetic patients with and without neuropathy when expressed both per endoneurial dry weight or endoneurial total protein compared to biopsy samples from healthy controls. When these concentrations, expressed per endoneurial total protein, were related to plasma concentrations similarly expressed, the resulting blood-nerve barrier (BNB) indices were significantly increased for Alb (6.1 times; P less than 0.00001), IgG (4.9 times; P = 0.00037), and IgM (2.7 times; P = 0.015). The diabetic patients without neuropathy (defined as having an index of pathology of greater than 0.65; a measure of the severity of the pathological abnormality based on morphological criteria) also had significant increases in two of these BNB indices that were intermediate between the diabetic neuropathy patients and controls (Alb, 3.9 times controls; P = 0.00002: IgG, 4.6 times controls; P = 0.00016: IgM, 1.8 times controls; not significant). No correlations were observed between the endoneurial concentrations of these plasma proteins or the BNB indices and the index of pathology, suggesting that these increases in endoneurial plasma proteins precede the pathologic alterations. The increased values for the diabetics in the absence of pathological abnormalities may prove useful in predicting neuropathic complications. The ratio of the IgG-BNB index to the Alb-BNB index was decreased 19%, and the ratio of the IgM-BNB index to the Alb-BNB index was decreased 56% in diabetic neuropathy patients compared to controls. Although the IgG and IgM concentrations are increased in the diabetic endoneurium, the Alb increase is greater and a mechanism other than size indiscriminate extravasation of plasma proteins, therefore, is suggested. Morphometric assessment of the endoneurial compartments, which would be expected to contain these plasma proteins, suggests that they are not altered in diabetic neuropathy; hence, it is hypothesized that the observed increase in endoneurial concentration of these plasma proteins results from altered transport through the endothelial or perineurial barrier, which supports an underlying vascular mechanism in the development of diabetic polyneuropathy.

Currently no definitive biomarker of Alzheimer's disease (AD) is available, and this impedes both clinical diagnosis in humans and drug discovery in transgenic animal models. Proton magnetic resonance spectroscopy ( 1 H MRS) provides a noninvasive way to investigate in vivo neurochemical abnormalities. Each observable metabolite can potentially provide information about unique in vivo pathological processes at the molecular or cellular level. In this study, the age-dependent 1 H MRS profile of transgenic AD mice was compared to that of wild-type mice. Twenty-seven APP-PS1 mice (which coexpress mutated human presenilin 1 and amyloid-β precursor protein) and 30 wild-type mice age 66-904 days were examined, some repeatedly. A reduction in the levels of N -acetylaspartate and glutamate, compared with total creatine levels, was found in APP-PS1 mice with advancing age. The most striking finding was a dramatic increase in the concentration of myo -inositol with age in APP-PS1 mice, which was not observed in wild-type mice. The age-dependent neurochemical changes observed in APP-PS1 mice agree with results obtained from in vivo human MRS studies. Among the different transgenic mouse models of AD that have been studied with 1 H MRS, APP-PS1 mice seem to best match the neurochemical profile exhibited in human AD. 1 H MRS could serve as a sensitive in vivo surrogate indicator of therapeutic efficacy in trials of agents designed to reduce neurotoxicity due to microglial activation. Because of its noninvasive and repeatable nature, MRS in transgenic models of AD could substantially accelerate drug discovery for this disease.

Purpose: To assess the neurocognitive effects of cranial radiotherapy on patients with low-grade gliomas, we analyzed cognitive performance data collected in a prospective, intergroup clinical trial. Methods: Patients included 203 adults with supratentorial low-grade gliomas randomly assigned to a lower dose (50.4 Gy in 28 fractions) or a higher dose (64.8 Gy in 36 fractions) of localized radiotherapy. Folstein Mini-Mental State Examination (MMSE) scores and neurologic function scores (NFS) at baseline and key evaluations were analyzed. Median follow-up was 7.4 years in 101 patients still alive. A change of more than three MMSE points was considered clinically significant. Results: In patients without tumor progression, significant deterioration from baseline occurred at years 1, 2, and 5 in 8.2%, 4.6%, and 5.3% of patients, respectively. Most patients with an abnormal baseline MMSE score (< 27) experienced significant increases. Baseline variables such as radiation dose, conformal versus conventional radiotherapy, number of radiation fields, age, sex, tumor size, NFS, seizures, and seizure medications did not predict cognitive function changes. Conclusion: In this population, most low-grade glioma patients maintained a stable neurocognitive status after focal radiotherapy as measured by the MMSE. Patients with an abnormal baseline MMSE were more likely to have an improvement in cognitive abilities than deterioration after receiving radiotherapy. Only a small percentage of patients had cognitive deterioration after radiotherapy. However, more discriminating neurocognitive assessment tools may identify cognitive decline not apparent with the use of the MMSE.