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A 56-year-old man was seen with signs and symptoms consistent with orbital cellulitis. Computed tomographic scan showed a localized bony defect in the sphenoid wing, on which a biopsy was performed through a lateral orbitotomy. Pathologic examination of the surgical specimen revealed mucinous adenocarcinoma, and metastatic workup revealed an extensive lower esophageal malignant neoplasm. Arch Ophthalmol. 2000;118:986-988

Recent studies have shown that amyloid precursor protein (APP), which plays a central role in Alzheimer's disease (AD), protects against excitotoxic neuronal injuries by regulating the function of the glial glutamate transporters. The mechanisms underlying these effects and their relationship to the neurodegenerative process in AD are under intense scrutiny. In this context, the main objective of the present study was to determine if overexpression of mutant human APP in transgenic mouse brains results in altered functioning of the excitatory amino acid transporters (EAATs). Transgenic mice expressing the 695 amino acid form of the human APP from the Thy-1 promoter showed a significant decrease in B(max) and K(D) for aspartate uptake when compared to nontransgenic controls. This decrease in glutamate transporter activity was associated with decreased protein expression of glial specific glutamate transporters, EAAT1 and 2, but did not affect mRNA levels. These results suggest that expression of mutant forms of APP disturbs astroglial transport of excitatory amino acids at the posttranscriptional level leading, in turn, to increased susceptibility to glutamate toxicity., (Copyright 2000 Academic Press.)

Objective: To investigate the relationship between apolipoprotein E (APOE) genotype and both cholinergic dysfunction and synapse loss in AD., Background: A reduction in neocortical synapses and marked losses in the cholinergic system occur in AD. It has been suggested that the number of APOE epsilon4 alleles is inversely related to choline acetyltransferase (ChAT) activity, thereby influencing cholinergic function. Whether APOE genotype may influence neocortical synapse loss remains unclear., Methods: An autopsy series of 182 patients with AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria) and 16 normal controls (NC). APOE genotype was determined in blood samples or in postmortem brain tissue. Midfrontal synapse counts (AU/microg) were quantified by a dot-immunobinding assay for synaptophysin (Syn). Midfrontal ChAT activity (nmol/h/100 mg) was assessed using standard assays., Results: Mean midfrontal ChAT activity and Syn were both significantly reduced in patients with AD compared with NC. The relationship between ChAT activity and number of epsilon4 allele copies in AD was complex, with ChAT activity lower in patients with either two or no epsilon4 alleles compared with those with one epsilon4 allele. There was no relationship between APOE genotype and synapse loss in AD. Syn density was almost identical across the three genotypes., Conclusions: Unlike other studies, we failed to detect a linear relationship between ChAT activity and number of epsilon4 allele copies in the midfrontal cortex of this large sample of patients with AD. Our data also show that the presence of epsilon4 allele does not influence midfrontal synapse loss in AD. This suggests that factors other than APOE genotype may be operative in the decline in midfrontal cholinergic function and synapses seen in AD.

Objective: To evaluate cholinergic activity in diseases with Lewy bodies (LB; LB variant of AD [LBV], diffuse LB disease [DLBD], and Parkinson's disease [PD]) to determine if 1) AD changes are requisite to cholinergic dysfunction, 2) cholinergic activity declines to the same extent in neocortical and archicortical areas, and 3) cholinergic loss is influenced by APOE genotype., Background: Like AD, diseases with LB are associated with decreased choline acetyltransferase (ChAT) activity. Increased APOE epsilon4 allele frequency has been reported in LBV. Whether APOE genotype affects cholinergic function in LBV remains unclear., Methods: An autopsy series of 182 AD (National Institute on Aging and Consortium to Establish a Registry for Alzheimer's Disease criteria), 49 LBV, 11 PD, 6 DLBD, and 16 normal control (NC) subjects. APOE genotype and ChAT activity (nmol/h/100 mg) in the midfrontal and hippocampal cortices were determined., Results: Mean midfrontal ChAT activity was markedly reduced in diseases with LB (LBV: 53.3 +/- 39.0; PD: 54.8 +/- 35.7; DLBD: 41.3 +/- 24.8) compared to NC (255.4 +/- 134.6; p < 0.001) and AD (122.6 +/- 78.9; p < 0.05). Among diseases with LB, midfrontal ChAT activity was decreased to a similar extent in patients with (LBV) and without (DLBD and PD) AD pathology. Although mean ChAT activity for LBV was less than half that for AD in the midfrontal cortex, it was similar to that for AD in the hippocampus (LBV: 243.5 +/- 189.7; AD: 322.8 +/- 265.6; p > 0.05). However, hippocampal ChAT activity for both AD and LBV was lower than that for NC (666.5 +/- 360.3; p < 0.001). The epsilon4 allele dosage did not influence midfrontal ChAT activity in LBV., Conclusion: Marked losses in midfrontal ChAT activity occur in diseases with LB, independent of coexistent AD changes. A greater midfrontal, as opposed to hippocampal, cholinergic deficit may differentiate LBV from AD. The lack of a relationship between epsilon4 allele dosage and midfrontal ChAT activity suggests that other factors may play a role in its decline in LBV.

We present the dispersion relations for quasiparticle excitations about the color-flavor locked ground state of QCD at high baryon density. In the presence of condensates which pair light and strange quarks there need not be an energy gap in the quasiparticle spectrum. This raises the possibility of gapless color superconductivity, with a Meissner effect but no minimum excitation energy. Analysis within a toy model suggests that gapless color superconductivity may occur only as a metastable phase.

Neurodegenerative disorders are characterized by damage to selective neuronal populations (1) that could be followed or proceeded by synaptic injury (2). The mechanisms triggering cell death and synaptic damage in these disorders might be related to gain of a toxic property and/or loss of neuroprotective capacity of a specific neuronal protein (3). Many of these neuronal molecules play an important role in the maintenance and functioning of the synaptic apparatus (4,5). Therefore, specific mutations and other alterations of synaptic proteins might result in particular neurodegenerative diseases. In this regard, recent studies have shown that molecules involved in the pathogenesis of Alzheimer's disease (AD) in fact have a synaptic location. Examples of such proteins include amyloid precursor protein (APP) (6-8), nonamyloid-β component precursor (NACP) (9), and presenilin 1 and 2 (10-12). Furthermore, other neurodegenerative disorders such as Huntington's disease (HD) (13,14), Parkinson's disease (PD) (15-17), Creutzfeldt-Jakob disease (CJD) (18), and myotonic dystrophy (19) have turned out to be the result of mutations in proteins that concentrate at the synaptic site. Therefore, in order to better understand the mechanisms of central nervous system (CNS) dysfunction in neurodegenerative disorders, it is important to determine the concentrations of specific synaptic proteins at the synaptic site, as well as to determine overall synaptic density in specific brain regions. For example, in AD, memory deficits in early stages of the disease are associated with synaptic loss in the molecular layer of the hippocampal dentate gyrus, which reflects degeneration of the perforant pathway (2,20).

Recent studies have shown that deficient functioning of glutamate transporters (GTs) in Alzheimer disease (AD) might lead to neurodegeneration. The main objectives of the present study were to determine which GT subtype is most affected in AD and to asses to what extent altered GT function is associated with abnormal amyloid precursor protein (APP) expression. While EAAT2-immunoreactivity (IR) was decreased in AD frontal cortex, EAAT1- and EAAT3-IR were unaffected; mRNA levels for all 3 GTs were not affected. Decreased EAAT2-IR was associated with decreased GT activity. EAAT2-IR inversely correlated with EAAT2 mRNA levels, suggesting that in AD, GT expression alterations occur due to disturbance at the post-transcriptional level. EAAT2-IR was inversely correlated with APP770 mRNA. In addition, GT activity directly correlated with APP695 mRNA and total APP protein levels, and inversely correlated with APP751/770 mRNA levels. This study supports the notion that astroglial EAAT2 is affected in AD and abnormal functioning and/or processing of APP might play an important role in this process.

Dementia with Lewy bodies (DLB) is the second leading cause of cognitive impairment among the elderly. While it is usually accompanied by the neocortical neuritic plaques (NP) and entorhinal neurofibrillary tangles (NFT) characteristic of Alzheimer disease (AD), and so can be construed as a Lewy body variant of AD (LBV), it also occurs in pure form as diffuse Lewy body disease (DLBD). We assessed cognitive status in 17 DLB patients (12 with LBV and 5 with DLBD) and compared the results with 12 AD subjects and 5 controls. We then sought to determine which neuropathologic abnormalities correlated with cognitive impairment. Among DLB cases, neocortical Lewy body (LB) counts, modified Braak stages of NFT burden in the entorhinal cortex, neocortical NP counts, and loss of choline acetyltransferase (ChAT) activity all correlated with dementia severity. Unlike AD, neocortical NFT and anti-synaptophysin reactivity were uncorrelated with DLB dementia. Despite comparable LB counts and ChAT losses, the DLBD were significantly less demented than the LBV patients. We conclude that neocortical LB and ChAT depletion contribute to cognitive impairment in DLB and that concomitant AD pathology in LBV, represented by higher Braak stages and NP, promotes increased dementia severity compared with that encountered in DLBD.

Recent studies have suggested that neuronal populations that contain glutamate receptors are vulnerable to damage mediated by the human immunodeficiency virus 1 (HIV-1). Somatostatin-immunoreactive neurons contain, among other elements, glutamate receptors, and might therefore be susceptible to HIV-mediated damage. In order to test this hypothesis, we compared patterns of somatostatin immunoreactivity in the cortex and subcortex of autopsied AIDS cases with and without HIV encephalitis (HIVE). Somatostatin immunoreactivity in the frontal cortex interneurons, hippocampal pyramidal and nonpyramidal cells, and globus pallidus was significantly reduced in HIVE. Radioimmunoassay demonstrated a comparable decrease in somatostatin levels in the neocortex of HIVE cases. The decrease in somatostatin immunoreactivity in the neocortex was inversely correlated with the severity of HIVE and global cognitive performance, but not with the extent of the astroglial reaction. These findings indicate that somatostatin-immunoreactive neurons in the cortex are susceptible to damage mediated by HIV and that deficient functioning of this neuronal population might contribute to the cognitive dysfunction observed in AIDS patients.

The mechanisms of synapse damage in Alzheimer's disease (AD) are not fully understood. Deficient functioning of glutamate transporters might be involved in synaptic pathology and neurodegeneration by failing to clear excess glutamate at the synaptic cleft. In AD, glutamate transporter activity as assessed by D-[3H]aspartate binding is decreased; however, it is not clear to what extent it is associated with the neurodegenerative process and cognitive alterations. For this purpose, levels of D- and L-[3H]aspartate binding in midfrontal cortex were correlated with synaptophysin levels, brain spectrin degradation product levels, and clinical and neuropathological indicators of AD. Compared to control brains, AD brains displayed a 34% decrease in levels of D-[3H]aspartate binding, a 30% decrease in L-[3H]aspartate binding, and a 48% loss of synaptophysin immunoreactivity. Increased levels of brain spectrin degradation products correlated with a decrease in levels of D-[3H] and L-[3H]aspartate binding, and decreased levels of synaptophysin immunoreactivity. Levels of L-[3H]aspartate binding correlated with levels of synaptophysin immunoreactivity. These results suggest that decreased glutamate transporter activity in AD is associated with increased excitotoxicity and neurodegeneration, supporting the possibility that abnormal functioning of this system might be involved in the pathogenesis of synaptic damage in AD.

Apolipoprotein E (apoE) is involved in the development and regeneration of the central nervous system (CNS). ApoE may also be necessary to maintain the integrity of the synapto-dendritic complexity. We analyzed the synaptic alterations in the CNS of apoE-deficient (knockout) mice during the aging process. In apoE-deficient homozygous mice, there was an age-dependent 15 to 40% loss of synaptophysin-immunoreactive nerve terminals and microtubule-associated protein 2-immunoreactive dendrites in the neocortex and hippocampus, when compared to controls. Dendritic alterations were observed as early as 4 months of age. Ultrastructural analysis revealed extensive dendritic vacuolization and disruption of the endomembrane system and cytoskeleton in apoE-deficient homozygous mice. Further immunocytochemical studies of the neuronal cytoskeleton showed that in apoE-deficient mice there was a decrease in the immunoreactivity of alpha and beta tubulin (but not kinesin) in the cell bodies and processes. These results support the contention that apoE might play an important role in maintaining the stability of the synapto-dendritic apparatus and that altered or deficient functioning of this molecule could underlie the synaptic and cytoskeletal alterations in Alzheimer's disease.

Both genetic and environmental factors affect the progression of Alzheimer's disease (AD). The presence of cortical Lewy bodies in AD patients is associated with an altered presentation of AD pathology suggestive of an interaction between the pathogenesis of Lewy bodies and AD lesions. Since the CYP2D6B mutant allele is often present in patients with Lewy body diseases (Parkinson's disease and Lewy body variant of AD), we extended these prior observations by studying the neuropathology associated with the presence of the CYP2D6B mutant allele in a pure AD population without Lewy bodies. AD patients who possessed the CYP2D6B mutant allele, in comparison with those without the CYP2D6B allele, were found to have a smaller decline in two synaptic markers, choline acetyltransferase and synaptophysin, in the frontal cortex relative to normal control values. On the other hand, senile plaques and neurofibrillary tangles were not significantly affected by the presence of the CYP2D6B mutant allele in the frontal cortex of AD patients. Association of the CYP2D6B mutant allele with Lewy body formation in both Parkinson's disease and the Lewy body variant of AD and with the milder synaptic pathology in pure AD without Lewy bodies suggest that depending on the contribution of other genetic and environmental factors, this mutant allele may be involved with different aspects of neurodegeneration.

In the present study we observed that while platelet-derived growth factor (PDGF)-BB is exclusively expressed by neurons in the human brain, PDGF-AA is expressed in neurons and blood vessels. In Alzheimer's disease (AD), antibodies against PDGF-BB (but not PDGF-AA) recognized the neurofibrillary alterations of this disease. The levels of PDGF-BB correlated with the patterns of synaptic loss and sprouting while PDGF-AA immunostaining of the vessels was correlated with glial proliferation. Immunostaining was completely abolished when the antibodies were preincubated with their respective purified recombinant PDGF. Western blot analysis showed that antibodies against PDGF recognized a 31 kDa protein that was mildly increased in AD. These data suggest that PDGF, as well as other neurotrophic factors, play an important role in the mechanisms of neurofibrillary pathology in AD.

Expression of the HIV-1 envelope protein gp120 in brains of transgenic (tg) mice induces extensive neurodegeneration (Toggas, S. M., E. Masliah, E. M. Rockenstein, G. F. Rall, C. R. Abraham, and L. Mucke. 1994. Nature [Lond.]. 367:188-193.). To further analyze the pathogenesis of gp120-induced neurotoxicity and to assess the neuroprotective potential of human amyloid precursor proteins (hAPPs) in vivo, different hAPP isoforms were expressed in neurons of gp120/hAPP-bigenic mice: hAPP751, which contains a Kunitz-type protease inhibitor domain, or hAPP695, which lacks this domain. Bigenic mice overexpressing hAPP751 at moderate levels showed significantly less neuronal loss, synapto-dendritic degeneration, and gliosis than singly tg mice expressing gp120 alone. In contrast, higher levels of hAPP695 expression in bigenic mice failed to prevent gp120-induced brain damage. These data indicate that hAPP can exert important neuroprotective functions in vivo and that the efficiency of this protection may depend on the hAPP isoform expressed and/or on the level of neuronal hAPP expression. Hence, molecules that mimic beneficial APP activities may be useful in the prevention/treatment of HIV-1-associated nervous system damage and, perhaps, also of other types of neural injury.

The amyloid precursor protein (APP) is involved in Alzheimer's disease (AD) because its degradation products accumulate abnormally in AD brains and APP mutations are associated with early onset AD. However, its role in health and disease appears to be complex, with different APP derivatives showing either neurotoxic or neurotrophic effects in vitro. To elucidate the effects APP has on the brain in vivo, cDNAs encoding different forms of human APP (hAPP) were placed downstream of the neuron-specific enolase (NSE) promoter. In multiple lines of NSE-hAPP transgenic mice neuronal overexpression of hAPP was accompanied by an increase in the number of synaptophysin immunoreactive (SYN-IR) presynaptic terminals and in the expression of the growth-associated marker GAP-43. In lines expressing moderate levels of hAPP751 or hAPP695, this effect was more prominent in homozygous than in heterozygous transgenic mice. In contrast, a line with several-fold higher levels of hAPP695 expression showed less increase in SYN-IR presynaptic terminals per amount of hAPP expressed than the lower expressor lines and a decrease in synaptotrophic effects in homozygous compared with heterozygous offspring. Transgenic mice (2-24 months of age) showed no evidence for amyloid deposits or neurodegeneration. These findings suggest that APP may be important for the formation/maintenance of synapses in vivo and that its synaptotrophic effects may be critically dependent on the expression levels of different APP isoforms. Alterations in APP expression, processing or function could contribute to the synaptic pathology seen in AD.

Extensive synaptic and neuritic alterations in the neocortex and limbic system are characteristically found in Alzheimer's disease (AD). However, it is not known how early in the development of the disease these alterations occur. For the present study, we compared the synaptic and neuritic alterations among cases classified clinically and neuropathologically as early, mild and advanced AD. In early AD there was a 20% loss of synaptophysin-immunoreactive presynaptic terminals in the outer molecular layer of the hippocampal dentate gyrus (but not in the neocortex and entorhinal cortex), accompanied by increased amyloid precursor protein (APP) and Alz50 immunoreactivity in hippocampal and entorhinal cortex pyramidal neurons. These results suggest that abnormal neuronal expression of APP and cytoskeletal proteins in early stages might be involved in the mechanisms of synaptic pathology in AD.

Background: The protein p105 is a nuclear antigen associated with cell proliferation. Recent investigations have indicated that many molecules previously considered to be growth-associated are actually involved in plasticity of the central nervous system., Experimental Design: For the present study, using immunohistochemical and immunochemical techniques in control and Alzheimer's disease (AD) brain, we explored the possibility that p105 could be involved in the aberrant sprouting response. AD tissue was used because in this disorder, the neuronal sprouting processes display a disruption in their cytoskeleton and the microtubule-associated protein, tau is abnormally phosphorylated. Control experiments were performed with the p105 antibody from an independent source, and with an antibody against Ki-67., Results: The antibody against p105 (but not against Ki-67) immunolabeled the tangles, neuropil threads, and a subpopulation of fusiform neurites in the plaque. The p105 immunoreactivity was colocalized with tau and the numbers of tangles immunostained with p105 antibody correlated with the number of tangles immunolabeled with an antibody against tau. Western blot analysis of human brain homogenates showed that the antibody against p105 immunostained a major band at an estimated molecular weight of 105 kilodaltons and a secondary band at 84 kilodaltons. In AD frontal cortex, there was a significant increase in the 84 kilodalton band in the particulate, but not in the cytosolic fraction., Conclusions: The characterization of the patterns of expression of this class of nuclear antigen in the brain might provide important clues as to the mechanisms of plasticity and abnormal growth under normal conditions, as well as in AD.

We measured the concentrations of the monoamines, their precursors, and their metabolites, and the activity of choline acetyltransferase (ChAT) in basal ganglia and cortical regions of postmortem brains from cases with histologically verified pure Alzheimer's disease (AD), AD with diffusely distributed Lewy bodies (Lewy body variant [LBV]), and normal controls. Dopamine and homovanillic acid (HVA) were severely depleted in basal ganglia of the LBV cases but were not significantly altered in pure AD cases; tyrosine hydroxylase levels in putamen were also significantly reduced in LBV but not AD cases. These reductions in basal ganglia dopamine and HVA suggest that LBV cases have a level of dopamine depletion similar to Parkinson's disease (PD). Additionally, ChAT activity in caudate and norepinephrine concentration in putamen were significantly reduced in the LBV group, which may have contributed to the absence of resting tremor and the milder presentation of parkinsonian features in this group compared with classic PD. In frontal, parietal, and temporal cortex, activity of ChAT in the LBV group was significantly reduced compared with controls and lower than in pure AD.

About one quarter of Alzheimer's disease patients have been found to have concomitant subcortical and neocortical Lewy bodies (LBs). We compared the aberrant neuronal sprouting and the extent of neuritic and synaptic damage in these Lewy body variants of Alzheimer's disease (LBV), with the same pathologic alterations in Alzheimer's disease without LBs (AD). More of the thioflavine-S-positive senile plaques of the LBVs contained growth associated protein 43 (GAP-43), a marker of neuritic growth and sprouting. Compared to AD, the LBVs had 39% more GAP-43-positive plaques in the frontal cortex, and 53% more in the hippocampus. These neuritic alterations were accompanied by an accumulation of amyloid precursor protein and phosphorylated neurofilaments. Synapse loss was the same in LBV and AD. These results suggest more extensive aberrant neuronal sprouting in LBV than in AD.

We studied axonal damage in Alzheimer's disease frontal cortex and hippocampus with a novel monoclonal antibody (SMI 312) against phosphorylated neurofilaments. This antibody immunolabeled, with great detail, the neuropil axonal network. In aged normal cases only a few pyramidal cell perikarya were immunostained. In Alzheimer's disease there was a two- to four-fold increase in neuronal SMI 312 immunolabeling, and neuropil neuritic processes were severely disrupted. Double-immunolabeling analysis showed that 88% of SMI 312-immunolabeled abnormal neuritic clusters were associated with amyloid, whereas the remaining 12% were not. Serial section analysis and 3-D reconstructions suggested that dystrophic neurites of classical plaques were derived from long axons. These abnormal neurites were also growth-associated protein 43 positive and occasionally tau positive. The present study supports the contention that a subpopulation of aberrantly sprouting axons in the neuritic plaque is derived from cortico-cortico fibers. This disruption of the neocortical association fibers and neuritic microcircuitry could underlie the cognitive impairment of Alzheimer's disease.

Previous in vitro studies have suggested that amyloid precursor protein (APP) could be involved in cell surface adhesion, neuritic growth and survival of hippocampal neurons. In the present study, involvement of APP in aberrant sprouting in Alzheimer's disease (AD) was studied by comparing immunolabeling patterns of anti-APP and anti-growth-associated protein 43 (anti-GAP43). Confocal laser imaging of frontal cortex sections double-immunolabeled for APP and GAP43 showed an increase, in AD, of presynaptic boutons immunostained with anti-GAP43 that contained anti-APP immunoreactivity. The neuritic plaques in AD cases presented intense anti-GAP43 immunoreactive abnormal neurites colocalized with anti-APP. Three-dimensional reconstruction of the plaques showed that anti-APP was colocalized with anti-GAP43 in 57.5% of the aberrant sprouting neurites. We conclude that co-expression of APP with GAP43 in the plaque might be involved in the aberrant sprouting response observed in AD.

Alzheimer's disease (AD) is characterized by extensive synaptic and neuronal loss and by plaque formation in the cortex, but the mechanisms responsible for synaptic plasticity in the neocortex are still not completely understood. To analyze the sprouting response in AD cortex, we compared the patterns of GAP-43 with synaptophysin immunoreactivity. In AD, GAP-43 immunohistochemistry revealed extensive sprouting in the hippocampal molecular layer, stratum polymorphous, CA1 region, and prosubiculum. These regions presented abundant anti-GAP-43-immunoreactive coiled fibers and dystrophic neurites in association with plaques. Some of these sprouting structures were colocalized with anti-synapto-physin- and anti-neurofilament-positive neurites. The AD neocortex was characterized by an overall decrease in GAP-43 immunoreactivity accompanied by sprouting neurites in the areas of synaptic pathology. We conclude that GAP-43 might be involved in the mechanisms of synaptic plasticity in the AD cortex, as well as in the process of aberrant sprouting in the neuritic plaques.

Most clinically demented elderly patients are found at autopsy to have Alzheimer's disease, multi-infarct dementia, Parkinson's disease, Pick's disease, or Creutzfeldt-Jakob disease. We studied 5 patients clinically characterized by late onset dementia whose brains showed no pathological evidence of Alzheimer's disease, or any other specific neuropathological diagnosis. We found argyrophilic grains, coiled bodies, abundant Alz-50-positive and thioflavine S-negative neurofibrillary tangles, and neuropil threads in the hippocampus, entorhinal cortex, locus ceruleus, substantia nigra, subthalamic nucleus, and inferior olives. Ultrastructurally, the grains, threads, and tangles were composed of straight tubulofilamentous structures, 25 nm in diameter, similar to those found in patients with progressive supranuclear palsy but different from the paired helical filaments of patients with Alzheimer's disease. These findings suggest that the late onset dementia with argyrophilic grains syndrome is also characterized by the presence of tangles and threads with the topographical distribution of progressive supranuclear palsy.

Quantification of synaptophysinlike immunoreactivity is a valuable method for studying the presynaptic terminals in the normal and damaged nervous system. The present report shows that in the control brain, the predominant pattern of synaptic immunostaining in the neocortex was that of an evenly distributed densely granular immunolabeling of the neuropil, while in the paleocortex and in subcortical areas of the brain most of the presynaptic terminals were distributed along the dendritic arborizations or around the neuronal somata. The immunochemical and the immunohistochemical analysis of the Alzheimer's disease tissue showed that the frontal and parietal cortex presented the most severe and widespread loss, with a 45% loss in synaptophysin immunoreactivity. These areas showed an average 35% loss of large neurons. The visual cortex, hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus ceruleus displayed some degree of loss, but to a lesser extent. In addition to this loss, the basic patterns of organization of the presynaptic terminals were altered, with the presence of abundant, enlarged synaptophysin-labeled terminals. This study further supports the role of synaptic pathology in Alzheimer's disease.

Both protein kinases and phosphoprotein phosphatases are important components of signal transduction systems in cells. Recent studies in Alzheimer's disease (AD) have shown abnormal protein phosphorylation in the cortex suggesting an alteration in these enzymes. In the present study, an antibody against CD45 was used to analyze the status of this protein phosphotyrosine phosphatase in AD. We studied and quantified the immunohistochemical and immunochemical distribution of this integral membrane protein in control and AD brain. We found that anti-CD45 immunostained the great majority of microglia, both resting and activated. These cells were Ricinus communis agglutinin I positive and glial fibrillary acidic protein and neurofilament negative. The AD frontal cortex showed a 35% (P less than 0.01) increase in the number of anti-CD45 immunoreactive microglia as compared with controls. These results were consistent with the immunoblot quantification of CD45 immunoreactivity following native gel electrophoresis. In AD, 30% of the CD45-immunostained microglia were clustered in the neuritic plaques (about six per plaque) while the remaining 70% were scattered in the neuropil. The AD hippocampus showed an increase in CD45-immunoreactive microglia in the molecular layer of the dentate gyrus. At the ultrastructural level, CD45 immunoreactivity was localized exclusively to the plasma membrane of the microglia. The presence of the anti-CD45 immunoreactivity in microglia suggests the possibility that they may require the presence of CD45 as a cell surface receptor which may regulate cell function through modulation of intracellular signaling.

Applying the relatively new technique of laser confocal imaging, vibratome sections which were double immunolabeled for amyloid beta protein and the presynaptic terminal marker synaptophysin were examined. It was found that while synaptic density was generally diminished in Alzheimer's disease (AD) cortical neuropil as compared to controls, the reduction was no greater within the diffuse plaques than outside them. Synapse loss was accentuated, however, within immature and mature plaques. These findings suggest that the pathogenetic process in AD might commence with synapse loss and neurodegeneration rather than with deposition of amyloid beta protein.

Currently available specific synaptic markers have made it possible to estimate the synaptic density by immunochemical techniques. In the present study we labeled the neocortical presynaptic terminals in histological sections of human autopsy tissue with a monoclonal antibody against synaptophysin. The characteristic granular neuropil reaction was quantified by measuring the average optical density (OD) in the different layers of the parietal cortex with the aid of image analysis equipment. The raw neuropil OD was corrected by subtracting the OD of the white matter in the same section. Our study showed that consistent microdensitometric results can be obtained on 5-microns paraffin sections from specimens with less than 8 hr of post-mortem time before fixation, incubated with 5 micrograms/ml of anti-synaptophysin. The corrected OD measurements were slightly larger in neocortical layers II, III, and V than in layers I, IV, and VI, but the differences were not statistically significant. In area 17, layer IV was denser than the others. We conclude that with certain precautions this method can be used to measure relative amounts of synaptophysin-like immunoreactivity and to infer the density of presynaptic boutons in human situations and in animal models.

Because glucose-stimulated insulin secretion is selectively impaired during the development of insulin-dependent diabetes mellitus (IDDM), we tested the possibility that the glucose transporter of pancreatic islet beta cells is a target of the autoimmune process in patients with IDDM. We measured the uptake of 3-O-methyl-beta-D-glucose by dispersed islet cells from rats after a 15-minute incubation with purified IgG from 27 patients with newly diagnosed IDDM, 28 normal subjects, and 5 patients with non-insulin-dependent diabetes mellitus (NIDDM). The IgG fractions from 26 of the 27 patients with IDDM (96 percent), but from none of the 5 patients with NIDDM, reduced the initial rates of 3-O-methyl-beta-D-glucose uptake to at least 1 SD below the mean of the rates observed in the presence of IgG fractions from normal subjects (P less than 0.001). In contrast, the uptake of L-leucine by islet cells was not affected by any of the IgG fractions. The inhibitory activity of IgG from the patients with IDDM was abolished by preincubation with islet cells and membranes from hepatocytes, which contain the same glucose transporter as beta cells, but not with erythrocytes, which do not contain this transporter. We conclude that IgG from patients with IDDM of recent onset, but not from those with NIDDM, inhibits glucose uptake by rat islet cells. The results are consistent with the presence of an antibody against a protein involved in glucose transport by beta cells that would thereby impair glucose-stimulated insulin secretion.

With a computerized image-analysis apparatus for neocortical morphometry and chemical methods for evaluation of the cholinergic system, five brain specimens of Pick's disease (PD) were studied and the results compared to those from specimens of age-matched normal subjects and Alzheimer's disease (AD). The PD specimens showed major reductions in brain weight, frontal and temporal cortical thickness, and large neuron populations, compared with controls. Lesser reductions were seen in small neurons and thickness of the inferior parietal cortex. The authors found no relationship between age of onset or disease duration and either the degree of cortical thinning or neuron loss or the number of Pick bodies in the neocortex and hippocampus. PD specimens were more atrophic than AD brains, having lower brain weights and more fronto-temporal thinning. Large neurons were comparably reduced in the two conditions in the frontal and temporal lobes, but small neuron losses were greater in the PD midfrontal area. Only the AD cases showed loss of large neurons in the inferior parietal region. Levels of choline acetyltransferase were normal in PD and reduced in AD, whereas muscarinic receptor binding was decreased in both.

In an attempt to elucidate possible mechanisms for the success of continuous subcutaneous insulin infusion (CSII), we evaluated the C-peptide response to a standard breakfast in seven type I diabetic patients while they were on conventional insulin treatment and again after 4 wk of near-normal glycemia achieved with CSII. While on conventional therapy their 24-h mean blood glucose level was 211 +/- 12 mg/dl and their glycosylated hemoglobin level was 10.6 +/- 0.6%. After 4 wk of CSII their 24-h mean blood glucose level fell to 95 +/- 7 mg/dl and their glycosylated hemoglobin level fell to 6.5 +/- 0.4%. Plasma C-peptide levels were undetectable in all seven patients both while on conventional therapy and after 4 wk of CSII. We conclude that the success of CSII is related to an improved method of insulin delivery and not to either the selection of type I diabetic patients who have some residual insulin secretory capacity or to some change in endogenous insulin secretion produced by the treatment itself.