Alzheimer Disease: Mirra SS

Mirra SS. · No affiliation provided · Hum Pathol. · Pubmed #10534156 No free full text.

This publication has no abstract.

Gearing M, Lynn M, Mirra SS. · Veterans Affairs Medical Center and the Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. · Arch Neurol. · Pubmed #10025425 links to  free full text

Abstract: BACKGROUND: While NFT frequency is reportedly reduced in AD+DLB, we often encounter abundant neocortical NFTs in such cases and decided to investigate this discrepancy. OBJECTIVE: To compare neurofibrillary tangle (NFT) frequency in Alzheimer disease with concomitant dementia with Lewy bodies (AD+DLB) with NFT frequency in "pure" AD. METHODS: Neurofibrillary tangle frequency, as well as regional staging of neurofibrillary degeneration modified from Braak, was scored in 160 autopsy cases of primary dementia (80 AD+DLB cases and 80 pure AD cases). RESULTS: Neurofibrillary tangle and modified Braak scores were lower in AD+DLB, as reported previously. Yet, neocortical NFT scores assumed markedly different patterns in the 2 groups (P = .001). In pure AD, NFT scores of "frequent" were predominant: more cases exhibited frequent than moderate or sparse NFTs. In AD+DLB, the distribution of NFT scores was bimodal: NFTs were either frequent or few to absent. Neocortical NFT scores in the AD+DLB group tended to parallel the severity of other types of tau cytopathology (neuropil threads and tau-positive plaque neurites). CONCLUSIONS: Cases of AD+DLB may be divided into 2 subgroups based on the extent of neocortical neurofibrillary pathology. These findings could have implications for disease pathogenesis and treatment.

Fillenbaum GG, van Belle G, Morris JC, Mohs RC, Mirra SS, Davis PC, Tariot PN, Silverman JM, Clark CM, Welsh-Bohmer KA, Heyman A. · Center for the Study of Aging and Human Development, Duke University Medical Center, Durham, NC, USA. · Alzheimers Dement. · Pubmed #18631955 No free full text.

Abstract: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) was funded by the National Institute on Aging in 1986 to develop standardized, validated measures for the assessment of Alzheimer's disease (AD). The present report describes the measures that CERAD developed during its first decade and their continued use in their original and translated forms. These measures include clinical, neuropsychological, neuropathologic, and behavioral assessments of AD and also assessment of family history and parkinsonism in AD. An approach to evaluating neuroimages did not meet the standards desired. Further evaluations that could not be completed because of lack of funding (but where some materials are available) include evaluation of very severe AD and of service use and need by patient and caregiver. The information that was developed in the U.S. and abroad permits standardized assessment of AD in clinical practice, facilitates epidemiologic studies, and provides information valuable for individual and public health planning. CERAD materials and data remain available for those wishing to use them.

Shao CY, Crary JF, Rao C, Sacktor TC, Mirra SS. · Department of Pathology , State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA. · J Neuropathol Exp Neurol. · Pubmed #16691114 No free full text.

Abstract: To study the role of atypical protein kinase C (aPKC) in neurodegenerative disease, we investigated the distribution of PKCiota/lambda, an aPKC isoform, in a variety of tauopathies and alpha-synucleinopathies. Immunohistochemical study revealed PKCiota/lambda within tau-positive neurofibrillary inclusions in Alzheimer disease (AD), progressive supranuclear palsy, corticobasal degeneration (CBD), and Pick disease (PiD), within alpha-synuclein-positive Lewy bodies in idiopathic Parkinson disease and dementia with Lewy bodies, as well as within glial inclusions in multisystem atrophy. We also observed PKCiota/lambda label of actin-rich Hirano bodies in AD, PiD, and elderly individuals. Double immunolabeling and fluorescence resonance energy transfer demonstrated close physical association between PKCiota/lambda and phospho-tau or alpha-synuclein in some neurofibrillary tangles and Lewy bodies. Furthermore, PKCiota/lambda colocalized with p62, a chaperone protein that binds to both aPKC and ubiquitin, in most of these inclusions. PKCiota/lambda also closely associated with the inactivated form of glycogen synthase kinase-3beta, GSK-3beta[ser9]. Together, these findings suggest that PKCiota/lambda may play a role in common mechanisms involving the pathogenesis of neurodegenerative disease.

Crary JF, Shao CY, Mirra SS, Hernandez AI, Sacktor TC. · Graduate Program in Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA. · J Neuropathol Exp Neurol. · Pubmed #16691113 No free full text.

Abstract: Protein kinase Mzeta (PKMzeta), an atypical protein kinase C (PKC) isoform, plays a key role in the maintenance of long-term potentiation (LTP), a persistent enhancement of AMPA receptor-mediated synaptic transmission, as well as in the persistence of memory in Drosophila. Because memory impairment in Alzheimer disease (AD) has been attributed to disruption of synaptic plasticity, we investigated the expression and distribution of PKMzeta in this disorder. We found that PKMzeta accumulated in neurofibrillary tangles (NFTs), whereas conventional and novel PKC isoforms did not. Unlike tau, which is present in all NFTs regardless of location, PKMzeta was found in a subset of NFTs restricted to limbic or medial temporal lobe structures (i.e. hippocampal formation, entorhinal cortex, and amygdala), areas implicated in memory loss in AD. Interestingly, PKMzeta was not identified in any NFTs in control brains derived from 6 elderly individuals without known cognitive impairment. In medial temporal lobe structures in AD, PKMzeta also occurred within abnormal neurites expressing MAP2, GluR1 and GluR2 as well as in perisomatic granules expressing GluR1 and GluR2, suggesting that aggregation of PKMzeta disrupts glutamatergic synaptic transmission. Together, these findings suggest a link between PKMzeta-mediated synaptic plasticity and memory impairment in AD.

Sheffield LG, Miskiewicz HB, Tannenbaum LB, Mirra SS. · Department of Pathology, SUNY Downstate Medical Center, Brooklyn, New York, NY 11203, USA. · J Neuropathol Exp Neurol. · Pubmed #16410748 No free full text.

Abstract: Ultrastructural studies of neurofibrillary tangles in Alzheimer disease (AD) have demonstrated a close relationship between nuclear pores and the cytoplasmic paired helical filaments comprising the tangles, as well as nuclear irregularity in many tangle-bearing neurons; nuclear pore aggregation has been observed in nearby neurons. These observations prompted examination of the nuclear pore complex (NPC) and proteins critical to nucleocytoplasmic transport in neurons with and without tangles in AD and control cases. Light microscopic study of hippocampus and neocortex in AD and controls revealed that all nuclei were labeled by antibodies to NPC proteins, including the central transporter nucleoporin Nup62. Nucleoporin and tau label revealed significantly more nuclear irregularity in AD, often associated with neurofibrillary tangles. Double label of Nup62 with apoptotic markers (TUNEL and active caspase-3) and a cell-cycle protein (cyclin B1) revealed no clear relationship of nuclear irregularity to apoptosis or cell-cycle protein expression. However, cytoplasmic accumulation of nuclear transport factor 2 (NTF2), a protein that transports cargo from the cytoplasm into the nucleus, was observed in a subset of hippocampal neurons with and without tangles in AD but not control cases. Further investigation of the NPC and nucleocytoplasmic transport in AD is warranted.

Atzori C, Ghetti B, Piva R, Srinivasan AN, Zolo P, Delisle MB, Mirra SS, Migheli A. · Department of Neuroscience, University of Turin, Italy. · J Neuropathol Exp Neurol. · Pubmed #11764091 No free full text.

Abstract: JNK and p38, two members of the MAP kinase family, are strongly induced by various stresses including oxidative stress and have been involved in regulation of apoptosis. As both kinases phosphorylate tau protein in vitro, we have investigated their immunohistochemical localization in a group of neurodegenerative diseases characterized by intracellular deposits of hyperphosphorylated tau. Cases included Alzheimer disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Gerstmann-Sträussler-Scheinker disease-Indiana kindred, and frontotemporal dementia with parkinsonism linked to chromosome 17. In all tissue samples, strong immunoreactivity for both MAP kinases was found in the same neuronal or glial cells that contained tau-positive deposits. By double immunohistochemistry, JNK and p38 colocalized with tau in the inclusions. Analysis of apoptosis-related changes (DNA fragmentation, activated caspase-3) showed that the expression of JNK and p38 was unrelated to activation of an apoptotic cascade. Our data indicate that phospho-JNK and phospho-p38 are associated with hyperphosphorylated tau in a variety of abnormal tau inclusions, suggesting that these kinases may play a role in the development of degenerative diseases with tau pathology.

Wolf DS, Gearing M, Snowdon DA, Mori H, Markesbery WR, Mirra SS. · Department of Pathology and Laboratory Medicine, VA Medical Center and Emory University School of Medicine, Atlanta, Georgia, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10609672 No free full text.

Abstract: Although diffuse plaques in the neocortex may represent an early stage in the evolution of neuritic plaques, plaques in the striatum and cerebellum retain their predominantly diffuse nature in Alzheimer disease (AD), regardless of disease duration. We had the opportunity to explore the progression of these regional features by using autopsy brain specimens from 15 cognitively normal and five AD subjects, all Catholic sisters enrolled in the Nun Study, a longitudinal study on aging and AD. Neuropathologic changes were assessed in the temporal cortex, striatum, and cerebellum without knowledge of clinical status. We found diffuse plaques in the striatum in six (40%) and cerebellar plaques in none of the brains from the non-demented subjects. Striatal plaques were present in all five and cerebellar plaques in four of the five AD cases. In the 20 cases overall, the presence of striatal plaques generally paralleled the occurrence of neuritic plaques in neocortex and correlated with lower scores on several neuropsychologic tests assessing memory. Our findings suggest that striatal diffuse plaques occur relatively early in the progression of AD pathology and coincide with neocortical pathology and cognitive changes. Thus, it is unlikely that temporal factors alone account for regional differences in progression of AD neuropathology.

Tsuang D, Larson EB, Bowen J, McCormick W, Teri L, Nochlin D, Leverenz JB, Peskind ER, Lim A, Raskind MA, Thompson ML, Mirra SS, Gearing M, Schellenberg GD, Kukull W. · Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, USA. · Arch Neurol. · Pubmed #10593304 links to  free full text

Abstract: CONTEXT: A recent collaborative study found that apolipoprotein E (APOE) genotype, in conjunction with the clinical diagnosis of Alzheimer disease (AD), was useful in improving diagnostic specificity (correctly not diagnosing AD) relative to the clinical diagnosis alone. Since these samples are particularly enriched with patients with AD and the APOE epsilon4 allele, results may not be generalizable to patients seen in the general medical community. OBJECTIVE: To evaluate the diagnostic utility of the APOE genotype in diagnosing AD in a community-based case series from the largest health maintenance organization in an urban area. DESIGN: We examined the effect of including APOE genotype on the diagnosis of AD in a community-based case series of patients presenting with memory complaints. PATIENTS: Clinical and neuropathologic diagnoses and APOE genotype were obtained from 132 patients who underwent evaluation for dementia and subsequent autopsy. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values given various combinations of clinical diagnoses and the presence of an APOE epsilon4 allele. RESULTS: Of the 132 patients, 94 had neuropathologically confirmed AD, yielding a prevalence of 71%. The clinical diagnosis alone yielded a sensitivity of 84%, an estimated specificity of 50%, and positive and negative predictive values of 81% and 56%, respectively. The presence of an epsilon4 allele alone was associated with an estimated sensitivity of 59%, specificity of 71%, and positive and negative predictive values of 83% and 41%, respectively. Using the presence of clinical AD and an epsilon4 allele decreased the sensitivity to 49% and increased the specificity to 84%. The positive and negative predictive values were 88% and 40%, respectively. Alternatively, the clinical diagnosis of AD or the presence of an epsilon4 allele in individuals not meeting clinical criteria for AD increases the estimated sensitivity to 94% but decreases the specificity to 37%. The positive and negative predictive values were 79% and 70%, respectively. The changes in the sensitivity and specificity for the combined tests relative to clinical diagnosis alone offset each other. For lower prevalence communities, the positive predictive value will be much lower than those observed herein. CONCLUSIONS: Our findings do not support the use of APOE genotyping alone in the diagnosis of AD in the general medical community. Although the presence of an epsilon4 allele in older persons with clinical AD increased the probability of having AD and the absence of an epsilon4 allele in this group decreased the probability of having AD, the association is not strong enough in the differential diagnosis of non-Alzheimer dementia and AD.

Heyman A, Fillenbaum GG, Gearing M, Mirra SS, Welsh-Bohmer KA, Peterson B, Pieper C. · Division of Neurology, Duke University, Durham, NC, USA. · Neurology. · Pubmed #10371532 No free full text.

Abstract: OBJECTIVE: To compare the clinical, neuropsychological, and neuropathologic findings in patients with AD alone with those in patients with the Lewy body variant of AD (LBV). BACKGROUND: Prior studies indicate that patients with LBV not only have distinct clinical and neuropsychological differences from those with AD alone, but have a poorer prognosis with shorter survival time. METHODS: The authors evaluated 74 patients with autopsy-confirmed AD alone and 27 patients with LBV, and compared demographic characteristics and clinical, neuropsychological, and neuropathologic findings. RESULTS: The two groups of patients were equivalent with respect to age at time of entry into the study, years of education, and sex. Two or more extrapyramidal clinical manifestations were found in 44% of patients with LBV, compared with 16% of patients with AD alone (p = 0.02). Duration of survival after entry into the study was similar in both groups, with a mean survival of 3.6 (+/-2.1) years for AD alone versus 3.8 (+/-1.9) years for LBV. Of the various neuropsychological tests administered at the last Consortium to Establish a Registry for Alzheimer's Disease evaluation, only delayed recall of a learned word list was significantly different in the two groups, with 32% of patients with LBV versus 15% of patients with AD alone recalling any items (p = 0.04). Neuropathologic findings confirmed those of previous studies and showed that neurofibrillary tangles were significantly less frequent in the neocortex of patients with LBV than in those with AD alone. CONCLUSION: Compared with patients with AD alone, those with LBV had a greater frequency of extrapyramidal manifestations, somewhat better recall on a selected memory task at their final evaluation, and a significantly lower frequency of neocortical neurofibrillary tangles at autopsy. There were no differences between the two groups, however, in survival time from entry into the study.

Mirra SS, Murrell JR, Gearing M, Spillantini MG, Goedert M, Crowther RA, Levey AI, Jones R, Green J, Shoffner JM, Wainer BH, Schmidt ML, Trojanowski JQ, Ghetti B. · Department of Pathology, State University of New York, Health Science Center at Brooklyn, 11203, USA. · J Neuropathol Exp Neurol. · Pubmed #10218629 No free full text.

Abstract: Familial forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) have recently been associated with coding region and intronic mutations in the tau gene. Here we report our findings on 2 affected siblings from a family with early-onset dementia, characterized by extensive tau pathology and a Pro to Leu mutation at codon 301 of tau. The proband, a 55-year-old woman, and her 63-year-old brother died after a progressive dementing illness clinically diagnosed as Alzheimer disease. Their mother, 2 sisters, maternal aunt and uncle, and several cousins were also affected. Autopsy in both cases revealed frontotemporal atrophy and degeneration of basal ganglia and substantia nigra. Sequencing of exon 10 of the tau gene revealed a C to T transition at codon 301, resulting in a Pro to Leu substitution. Widespread neuronal and glial inclusions, neuropil threads, and astrocytic plaques similar to those seen in corticobasal degeneration were labeled with a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes spanning the entire tau sequence. Isolated tau filaments had the morphology of narrow twisted ribbons. Sarkosyl-insoluble tau exhibited 2 major bands of 64 and 68 kDa and a minor 72 kDa band, similar to the pattern seen in a familial tauopathy associated with an intronic tau mutation. These pathological tau bands predominantly contained the subset of tau isoforms with 4 microtubule-binding repeats selectively affected by the P301L missense mutation. Our findings emphasize the phenotypic and genetic heterogeneity of tauopathies and highlight intriguing links between FTDP-17 and other neurodegenerative diseases.