Showing papers by "Patrick L. McGeer published in 1995"
TL;DR: Multiple epidemiological studies indicate that patients taking anti-inflammatory drugs or suffering from conditions in which such drugs are routinely used, have a decreased risk of developing Alzheimer disease.
1,329 citations
TL;DR: The number of cases in this study was too small to permit evaluation of microglial response according to the disease state, but the results demonstrate the potential for such studies in the future.
Abstract: Microglia were successfully cultured from human brain tissue from normal and neurologically diseased cases obtained 3.5-10 hours postmortem. Final cell preparations were more than 99% pure as judged by latex bead phagocytosis, expression of microglial phenotypic markers, and absence of astrocytic markers. The expression of complement genes C1qB, C3, and C4 as well as genes for interleukin-(IL-)1 alpha, IL-1 beta, IL-6, tumor necrosis factor (TNF)alpha, IL-1 receptor antagonist, and transforming growth factor beta, but not inducible nitric oxide synthase, by these cells was detected by polymerase chain reaction (PCR) analysis. The pattern of gene expression was evaluated following stimulation of the cells with lipopolysaccharide, phorbol myristate acetate, gamma interferon, and beta amyloid peptide. There was considerable variation in gene response to these activating agents. However, it was of interest that beta-amyloid peptide (1-40) increased the expression of IL-1 beta mRNA in these cells. The number of cases in this study was too small to permit evaluation of microglial response according to the disease state, but the results demonstrate the potential for such studies in the future.
259 citations
TL;DR: Data indicate that C1 inhibitor, a regulatory molecule controlling multiple inflammatory proteolytic cascades, is produced in normal brain.
90 citations
TL;DR: The results suggest that LRP may have a function, particularly in neurons, of receptor-mediated endocytosis with subsequent lysosomal uptake and degradation of ligands such as alpha 2-macroglobulin proteinase complexes and apolipoprotein E.
54 citations
TL;DR: Patients with parkinsonism, fasciculations, hyperreflexia and mild atrophy are unlikely to demonstrate active denervation on EMG; their prognosis is better than for classical MND.
40 citations
Patent•
28 Aug 1995TL;DR: In this paper, a method for identifying compounds that are therapeutically effective for treating inflammatory conditions is provided. And a method of treating an inflammatory condition in a mammal with such compounds, such as isoquinoline and benzodiazepine derivatives, was provided.
Abstract: Compounds which bind with high affinity to peripheral benzodiazepine receptors are useful as antiinflammatory agents. Such compounds include isoquinoline and benzodiazepine derivatives, such as PK 11195. A method of treating an inflammatory condition in a mammal with such compounds is provided. Pharmaceutical compositions comprising such compounds are provided. A method is provided for identifying compounds that are therapeutically effective for treating inflammatory conditions.
38 citations
TL;DR: Pick's disease brains were examined immunohistochemically for the expression of antigens known to be associated with Alzheimer's disease lesions and two glial abnormalities in PD are described: glial fibrillary tangles and clusters of granules positive for the complement protein C4d in the hippocampal dentate fascia.
Abstract: Pick's disease (PD) brains were examined immunohistochemically for the expression of antigens known to be associated with Alzheimer's disease (AD) lesions. Most antibodies which label intracellular neurofibrillary tangles (NFTs) in AD were found to stain Pick bodies (PBs). Among them was the monoclonal antibody A2B5, which is known to recognize neuronal surface gangliosides. This result indicates that membrane proteins are probably incorporated into PBs as into NFTs. However, PBs, in contrast to NFTs, showed a paucity of staining for heparan sulfate glycosaminoglycan and basic fibroblast growth factor (bFGF). Staining for midline, seen in senile plaques in AD, was not seen in PD. The relative lack of staining for these two neurotrophic factors in PD brain may reflect underlying mechanisms which are distinct from those in AD. We also describe two glial abnormalities in PD: glial fibrillary tangles and clusters of granules positive for the complement protein C4d in the hippocampal dentate fascia. These are presumably related to complement-activated oligodendroglia, and both pathological structures are more abundant in advanced cases, suggesting that they may be hallmarks of the disease progression.
35 citations
TL;DR: The fact that extracellular tangle material can act as a nidus for BAP build-up in LB suggests that further consideration needs to be given to the ways in which extracllular BAP deposits are formed.
Abstract: The Chamorro population of the island of Guam is highly susceptible to a disease called lytico-bodig (LB), wich clinically resembles a mixture of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and Alzheimer disease (AD). The disease is characterized by the widespread development of neurofibrillary tangles in the central nervous system. These tangles have an immuno-histochemical profile indistinguishable from that seen in AD. We studied by immunohistochemistry the occurrence of intracellular and extracellular neurofibrillary tangles in LB in the entorhinal cortex, hippocampus and substantia nigra using antibodies to tau protein and ubiquitin. We also studied the relationship of these tangles to amyloid precursor protein (APP) and its β-amyloid fragment (BAP), using multiple antibodies to BAP and other APP sequences. In advanced cases of LB, the development of neurofibrillary tangles was far more severe than in advanced cases of AD. Virtually all neurons of CA-1 and the subiculum were lost and only ghost tangles remained. In areas dominated by such extracellular tangles, BAP deposits were frequently observed developing around the fibers of ghost tangles. In some cases, the deposits covered only a few of the fibers, but in others, they seemed to envelope the complete tangle. The deposits were thiolavin S and Congo red positive, indicating that the BAP was in a consolidated form. We describe these entities as tangle-associated amyloid deposits”. Such BAP deposits have previously eeen described in some cases of AD, dementia pugilistica and LB. However, we found them in all cases of LB with dementia in the hippocampal-entorhinal areas and in most cases in the substantia nigra. They do not evolve from diffuse BAP deposits since they are remote from them, and they do not trap dystrophic neurites. The fact that extracellular tangle material can act as a nidus for BAP build-up in LB suggests that further consideration needs to be given to the ways in which extracellular BAP deposits are formed.
29 citations
TL;DR: It is reasonable to propose that administration of antiinflammatory drugs may be of therapeutic use in the treatment of or may delay the onset of Pick's disease, and nonsteroidalantiinflammatory drugs (NSAIDs) were considered for therapy of Alzheimer's.
Abstract: TOTHE EDITOR: Pick's disease is a progressiveand fatal dementia for which there is no known treatment. Although its prevalence is much lower than that of Alzheimer'sdisease,it alwaysshouldbe includedin a differential diagnosis when Alzheimer's is suspected. Because of the sharp demarcationlines separatingatrophiedportionsof the frontal and temporal lobes from the rest of the brain, Pick's disease can be readily diagnosed premortemthroughcomputed axial tomography,single photon emissioncomputertomography, or positionemissiontomography. Pick's and Alzheimer's diseases have neuropathologic similarities. These include neurofibrillary tangles, accumulations of beta-amyloid precursorprotein,and an apparentchronicinflammatory response. There is activation of severalcomponentsof the classicalcomplementpathway of the immunesystem,includingthe membraneattackcomplex (MAC), and upregulation of 3 of its inhibiting proteins: c1usterin, vitronectin, and protectin.' A somewhat similar distributionof the MAC and 3 of its inhibiting proteins' has been found in Alzheimer's. An autodestructive processhas been hypothesized to accountfor the presenceof the MACJ The apparentrelationship of the pathologyof Pick's and Alzheimer's diseases suggests that drugs therapeutically and prophylacticallyeffectiveagainstAlzheimer'salso mightbe efficacious againstPick's disease. On the basisof the inflammatory pathologyevident in Alzheimer's,nonsteroidalantiinflammatory drugs (NSAIDs)were consideredfor therapy of Alzheimer's.' Indomethacin, an NSAID that crosses the blood-brain barrier rapidly and efficiently,was chosen for a pilot study. Indomethacin proved effective in arresting the progression'of Alzheimer's in a 6month,double-blind, placebo-controlled clinical trial,' stronglysupporting the earlier hypothesis. Further,a cotwin study by Breitneret al. suggested that NSAIDs or steroids might be effective in preventing or delayingthe onsetof Alzheimer'sdisease/ Thus, it is reasonableto propose that administration of antiinflammatory drugs may be of therapeutic use in the treatmentof or may delay the onsetof Pick's disease.Steroids,however,are notoriousfor causingrnajor.Jife-threateningadverse effects, for which there is no remedy.They are, therefore, deemed inappropriatefor the purposes described herein. NSAIDsalso have adverseeffects,the most seriousof which is gastrointestinal ulceration. However, protection against this effect is possible with misoprostol or other gastroprotective agents.The infrequentoccurrence of Pick's disease precludes the organizationof controlledclinical trials comparable with those carried out for Alzheimer's disease. Information,at least initially, is most likelyto be gainedfrom physicians who are treatingpatientsusing the same methodsused to treatAlzheimer's.\