No abstract

The permeability of insulin (Ins), nerve growth factor (NGF), albumin (Alb), transferrin (Trf), and IgG across the blood-nerve barrier (BNB) and blood-brain barrier (BBB) in normal adult rats was quantified by measur-ing the (permeability coefficient X surface area) product (PS) with the L.v. bolus-injection technique in the canua brachial vein and artery using radionated proteins. The PS values of the BNB for IgG and Alb were low: 0.079 ± 0.029 x 10-6 and 0.101 ± 0.088 x 10-6 ml g-Ls-, (Xa ± SD, respectively). The PS values for NGF and Trf were 16.1-fold and 25.5-fold higher than for Alb. The PS for Ins across the BNB was 33.190 ± 2.053 X 10-6 mlg-'s-1--a remarkable 329-fold increase compared with Alb. The PS values of the BBB for IgG and Alb in different brain ri were all low, from O.O8± 0.017 to 0.151 ± 0.035 X 10-6 ml g'l-s'1 (X-± SD). NGF Van Bree et al. (4), the uptake values were of the same order of magnitude as that of the vascular marker and were, therefore, considered negligible, which leads to possible erroneous conclusions that the barrier was impermeable to proteins.The vascular-space marker chosen must meet several requirements which have been summarized (1). The closer "a vascular volume indicator approaches the biological, physical, and chemical properties of the test substance, the better the former is able to accurately model the intravascular distribution of the latter." In addition, Fenstermacher et al.(1) emphasized the need to determine a vascular-space correction for each individual animal rather than having a mean adjustment factor for a separate group of animals.In our experiments, the residual brain/endoneurial plasma volume (Vp) Abbreviations: BBB, blood-brain barrier; BNB, blood-nerve barrier; PS, (permeability coefficient x surface area) product; VP, residual brain/endoneurial plasma volume; Alb, albumin; NGF, nerve growth factor; Trf, transferrin; Ins, insulin. *To whom reprint requests should be addressed. 5705The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

One of the cardinal pathologic features of Alzheimer's disease (AD) is the formation of senile, or amyloid, plaques. Transgenic mice have been developed that express one or more of the genes responsible for familial AD in humans. Doubly transgenic mice develop "human-like" plaques, providing a mechanism to study amyloid plaque biology in a controlled manner. Imaging of labeled plaques has been accomplished with other modalities, but only MRI has sufficient spatial and contrast resolution to visualize individual plaques noninvasively. Methods to optimize visualization of plaques in vivo in transgenic mice at 9.4 T using a spin echo sequence based on adiabatic pulses are described. Preliminary results indicate that a spin echo acquisition more accurately reflects plaque size, while a T 2 * weighted gradient echo sequence reflects plaque iron content, not plaque size. In vivo MRI-ex vivo MRI-in vitro histologic correlations are provided. Histologically verified plaques as small as 50 m in diameter were visualized in living animals. To our knowledge this work represents the first demonstration of noninvasive in vivo visualization of individual AD plaques without the use of a contrast agent.

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-␤ 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.myo-inositol ͉ taurine ͉ drug discovery P roton magnetic resonance spectroscopy ( 1 H MRS) provides a noninvasive way to investigate in vivo neurochemical abnormalities of many brain disorders. In particular, MRS is particularly well suited for the study of neurodegenerative disorders, because no biomarkers for such disorders currently exist. Each observable metabolite can potentially provide unique information about the degenerative process, because metabolite levels are sensitive to different in vivo pathological processes at the molecular or cellular level. For example, N-acetylaspartate (NAA) is believed to be a marker for neuronal number and health, glutamate (Glu) acts as an excitatory neurotransmitter, and myo-inositol (mIns) is thought to be a marker for osmotic stress or astrogliosis.Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The primary risk factor for AD is age. As the population of virtually all modern industrialized societies ages, AD is poised to become a leading public health problem. The vast majority of prevalent cases of AD are sporadic. The remaining few percent of familial cases are attributed to specific mutations. Three known classes of mutations are associated with familial AD. Although statistically uncommon, the genetic associations with familial AD have shed insight into the origins of the disease. It is believed by many in the field that AD is ...

Since advanced glycosylation end products have been suggested to mediate hyperglycemia-induced microvascular atherogenesis and because aminoguanidine (AG) prevents their generation, we examined whether AG could prevent or ameliorate the physiologic and biochemical indices of streptozotocin (STZ)-induced experimental diabetic neuropathy. Four groups of adult Sprague-Dawley rats were studied: group I received STZ plus AG (25 mg kg'1 day-1), group II received STZ plus AG (50 mg-kg'1day-1), group HI received STZ alone, and group IV was a control. We monitored conduction and action potential amplitudes serially in sciatic-tibial and caudal nerves, nerve blood flow, oxygen free radical activity (conjugated dienes and hydroperoxides), and the product ofthe permeability coefficient and surface area to 125I-labeled albumin. STZ-induced diabetes (group HI) caused a 57% reduction in nerve blood flow and in abnormal nerve conduction and amplitudes and a 60% increase in conjugated dienes. Nerve blood flow was normalized by 8 weeks with AG (groups I and II) and conduction was significantly improved, in a dosedependent manner, by 16 and 24 weeks in sciatic-tibial and caudal nerves, respectively. The permeability coefficient was not impaired, suggesting a normal blood-nerve barrier function for albumin, and the oxygen free-radical indices were not ameliorated by AG. We suggest that AG reverses nerve ischemia and more gradually improves their electrophysiology by an action on nerve microvessels. AG may have potential in the treatment of diabetic neuropathy.In chronic experimental diabetic neuropathy, nerve blood flow (NBF) is reduced and the oxygen tension histogram is shifted into the hypoxic range (1). Nerve biosynthesis of 6-keto-prostaglandin Fia, the stable metabolite of prostacyclin, is significantly reduced in chronic, but not in acute, experimental diabetic neuropathy (2). Platelet thromboxane B2 is increased (3-6), resulting in a reduced prostacyclin/ thromboxane ratio and resultant vasoconstriction. Improvement in blood flow by chemical sympathectomy (7) or an increase in the oxygen supply by supplementation (8) or hyperbaric oxygenation (9) has been shown to improve nerve electrophysiology. Although these findings implicate perturbed microvascular physiology, the mechanism(s) by which chronic hyperglycemia results in a reduction in NBF is uncertain. It has been suggested that advanced glycosylation end products (AGE) may mediate hyperglycemiainduced microvascular atherogenesis (10, 11). Since aminoguanidine (AG) prevents AGE generation and has been reported to prevent basal lamina thickening in diabetic rats (10, 11), we examined whether AG could prevent or ameliorate the physiologic and biochemical indices of streptozotocin (STZ)-induced experimental diabetic neuropathy. METHODS Experimental Diabetic Neuropathy. We used male SpragueDawley rats weighing -250 g. They were separated into four groups of 16 animals each: group I or AG25 received STZ plus AG (25 mg kg-1-day-1), group II or AG50 received STZ plus AG...