13 results on '"Kryscio, Richard J."'
Search Results
2. ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology
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Nelson, Peter T, Estus, Steven, Abner, Erin L, Parikh, Ishita, Malik, Manasi, Neltner, Janna H, Ighodaro, Eseosa, Wang, Wang-Xia, Wilfred, Bernard R, Wang, Li-San, Kukull, Walter A, Nandakumar, Kannabiran, Farman, Mark L, Poon, Wayne W, Corrada, Maria M, Kawas, Claudia H, Cribbs, David H, Bennett, David A, Schneider, Julie A, Larson, Eric B, Crane, Paul K, Valladares, Otto, Schmitt, Frederick A, Kryscio, Richard J, Jicha, Gregory A, Smith, Charles D, Scheff, Stephen W, Sonnen, Joshua A, Haines, Jonathan L, Pericak-Vance, Margaret A, Mayeux, Richard, Farrer, Lindsay A, Van Eldik, Linda J, Horbinski, Craig, Green, Robert C, Gearing, Marla, Poon, Leonard W, Kramer, Patricia L, Woltjer, Randall L, Montine, Thomas J, Partch, Amanda B, Rajic, Alexander J, Richmire, KatieRose, Monsell, Sarah E, Alzheimer’ Disease Genetic Consortium, Schellenberg, Gerard D, and Fardo, David W
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Biomedical and Clinical Sciences ,Neurosciences ,Neurodegenerative ,Aging ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Genetics ,Alzheimer's Disease ,Dementia ,Human Genome ,Prevention ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Neurological ,Good Health and Well Being ,Aged ,80 and over ,Cohort Studies ,Databases as Topic ,Endophenotypes ,Genome-Wide Association Study ,Hippocampus ,Humans ,Polymorphism ,Single Nucleotide ,Sclerosis ,Sulfonylurea Compounds ,Sulfonylurea Receptors ,Oldest old ,Neuropathology ,KATP ,CTAGE5 ,ADGC ,Potassium channel ,Alzheimer’ Disease Genetic Consortium ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer's Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer's Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer's Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1-3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4-5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10(-9)), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.
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- 2014
3. Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease
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Nelson, Peter T., Smith, Charles D., Abner, Erin L., Wilfred, Bernard J., Wang, Wang-Xia, Neltner, Janna H., Baker, Michael, Fardo, David W., Kryscio, Richard J., Scheff, Stephen W., Jicha, Gregory A., Jellinger, Kurt A., Van Eldik, Linda J., and Schmitt, Frederick A.
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- 2013
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4. Association between male gender and cortical Lewy body pathology in large autopsy series
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Nelson, Peter T., Schmitt, Frederick A., Jicha, Gregory A., Kryscio, Richard J., Abner, Erin L., Smith, Charles D., Van Eldik, Linda J., and Markesbery, William R.
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- 2010
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5. Cancer diagnosis is associated with a lower burden of dementia and less Alzheimer's-type neuropathology.
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Karanth, Shama D, Katsumata, Yuriko, Nelson, Peter T, Fardo, David W, McDowell, Jaclyn K, Schmitt, Frederick A, Kryscio, Richard J, Browning, Steven R, Braithwaite, Dejana, Arnold, Susanne M, and Abner, Erin L
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TUMOR diagnosis ,ALZHEIMER'S disease diagnosis ,ALZHEIMER'S disease ,NEURONS ,RESEARCH funding ,TUMORS ,LONGITUDINAL method - Abstract
Cancer and Alzheimer's disease are common diseases in ageing populations. Previous research has reported a lower incidence of Alzheimer's disease-type (amnestic) dementia among individuals with a diagnosis of cancer. Both cancer and amnestic dementia are prevalent and potentially lethal clinical syndromes. The current study was conducted to investigate the association of cancer diagnosis with neuropathological and cognitive features of dementia. Data were analysed from longitudinally evaluated participants in a community-based cohort study of brain ageing who came to autopsy at the University of Kentucky Alzheimer's Disease Research Center. These data were linked to the Kentucky Cancer Registry, a population-based state cancer surveillance system, to obtain cancer-related data. We examined the relationship between cancer diagnosis, clinical dementia diagnosis, Mini-Mental State Examination scores and neuropathological features using inverse probability weighting to address bias due to confounding and missing data. To address bias due to inclusion of participants with dementia at cohort baseline, we repeated all analyses restricted to the participants who were cognitively normal at baseline. Included participants (n = 785) had a mean ± standard deviation age of death of 83.8 ± 8.6 years; 60.1% were female. Cancer diagnosis was determined in 190 (24.2%) participants, and a diagnosis of mild cognitive impairment or dementia was determined in 539 (68.7%). APOE ɛ4 allele dosage was lower among participants with cancer diagnosis compared to cancer-free participants overall (P = 0.0072); however, this association was not observed among those who were cognitively normal at baseline. Participants with cancer diagnosis had lower odds of mild cognitive impairment or dementia, and higher cognitive test scores (e.g. Mini-Mental State Examination scores evaluated 6 and ≤2 years ante-mortem, P < 0.001 for both comparisons). Cancer diagnosis also associated with lower odds of higher Braak neurofibrillary tangle stages (III/IV) or (V/VI), moderate/frequent neuritic plaques, moderate/frequent diffuse plaques and moderate/severe cerebral amyloid angiopathy (all P < 0.05). By contrast, TDP-43, α-synuclein and cerebrovascular pathologies were not associated with cancer diagnosis. Cancer diagnosis was associated with a lower burden of Alzheimer's disease pathology and less cognitive impairment. These findings from a community-based cohort with neuropathological confirmation of substrates support the hypothesis that there is an inverse relationship between cancer and Alzheimer's disease. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Diabetes is associated with cerebrovascular but not Alzheimer's disease neuropathology.
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Abner, Erin L., Nelson, Peter T., Kryscio, Richard J., Schmitt, Frederick A., Fardo, David W., Woltjer, Randall L., Cairns, Nigel J., Yu, Lei, Dodge, Hiroko H., Xiong, Chengjie, Masaki, Kamal, Tyas, Suzanne L., Bennett, David A., Schneider, Julie A., and Arvanitakis, Zoe
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Introduction The relationship of diabetes to specific neuropathologic causes of dementia is incompletely understood. Methods We used logistic regression to evaluate the association between diabetes and infarcts, Braak neurofibrillary tangle stage, and neuritic plaque score in 2365 autopsied persons. In a subset of >1300 persons with available cognitive data, we examined the association between diabetes and cognition using Poisson regression. Results Diabetes increased odds of brain infarcts (odds ratio [OR] = 1.57, P < .0001), specifically lacunes (OR = 1.71, P < .0001), but not Alzheimer's disease neuropathology. Diabetes plus infarcts was associated with lower cognitive scores at end of life than infarcts or diabetes alone, and diabetes plus high level of Alzheimer's neuropathologic changes was associated with lower mini-mental state examination scores than the pathology alone. Discussion This study supports the conclusions that diabetes increases the risk of cerebrovascular but not Alzheimer's disease pathology, and at least some of diabetes' relationship to cognitive impairment may be modified by neuropathology. [ABSTRACT FROM AUTHOR]
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- 2016
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7. Disease-related microglia heterogeneity in the hippocampus of Alzheimer's disease, dementia with Lewy bodies, and hippocampal sclerosis of aging.
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Bachstetter, Adam D., Van Eldik, Linda J., Schmitt, Frederick A., Neltner, Janna H., Ighodaro, Eseosa T., Webster, Scott J., Patel, Ela, Abner, Erin L., Kryscio, Richard J., and Nelson, Peter T.
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MICROGLIA ,ALZHEIMER'S disease ,LEWY body dementia - Abstract
Introduction: Neuropathological, genetic, and biochemical studies have provided support for the hypothesis that microglia participate in Alzheimer's disease (AD) pathogenesis. Despite the extensive characterization of AD microglia, there are still many unanswered questions, and little is known about microglial morphology in other common forms of age-related dementia: particularly, dementia with Lewy bodies (DLB) and hippocampal sclerosis of aging (HS-Aging). In addition, no prior studies have attempted to compare and contrast the microglia morphology in the hippocampus of various neurodegenerative conditions. Results: Here we studied cases with pathologically-confirmed AD (n =7), HS-Aging (n = 7), AD + HS-aging (n = 4), DLB (n = 12), and normal (cognitively intact) controls (NC) (n = 9) from the University of Kentucky Alzheimer's Disease Center autopsy cohort. We defined five microglia morphological phenotypes in the autopsy samples: ramified, hypertrophic, dystrophic, rod-shaped, and amoeboid. The Aperio ScanScope digital neuropathological tool was used along with two well-known microglial markers: IBA1 (a marker for both resting and activated microglia) and CD68 (a lysosomal marker in macrophages/microglia associated with phagocytic cells). Hippocampal staining analyses included studies of subregions within the hippocampal formation and nearby white matter. Using these tools and methods, we describe variation in microglial characteristics that show some degree of disease specificity, including, (1) increased microglia density and number in HS-aging and AD + HS-aging; (2) low microglia density in DLB; (3) increased number of dystrophic microglia in HS-aging; and (4) increased proportion of dystrophic to all microglia in DLB. Conclusions: We conclude that variations in morphologies among microglial cells, and cells of macrophage lineage, can help guide future work connecting neuroinflammatory mechanisms with specific neurodegenerative disease subtypes. [ABSTRACT FROM AUTHOR]
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- 2015
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8. Self-Reported Head Injury and Risk of Late-Life Impairment and AD Pathology in an AD Center Cohort.
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Abner, Erin L., Nelson, Peter T., Schmitt, Frederick A., Browning, Steven R., Fardo, David W., Wan, Lijie, Jicha, Gregory A., Cooper, Gregory E., Smith, Charles D., Caban-Holt, Allison M., Van Eldik, Linda J., and Kryscio, Richard J.
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COGNITION disorder risk factors ,DEMENTIA risk factors ,HYPOTHESIS ,AGE factors in disease ,ALZHEIMER'S disease ,ANALYSIS of covariance ,APOLIPOPROTEINS ,AUTOPSY ,CHI-squared test ,CLINICAL medicine ,COMPUTER simulation ,CONFIDENCE intervals ,DEATH ,LONGITUDINAL method ,MULTIVARIATE analysis ,RESEARCH funding ,STATISTICAL sampling ,SELF-evaluation ,SEX distribution ,LOGISTIC regression analysis ,SECONDARY analysis ,SYMPTOMS ,KEY performance indicators (Management) ,HEAD injuries ,PREDICTIVE validity ,REPEATED measures design ,SEVERITY of illness index ,DISEASE progression ,DESCRIPTIVE statistics ,ODDS ratio - Abstract
Aims: To evaluate the relationship between self-reported head injury and cognitive impairment, dementia, mortality, and Alzheimer's disease (AD)-type pathological changes. Methods: Clinical and neuropathological data from participants enrolled in a longitudinal study of aging and cognition (n = 649) were analyzed to assess the chronic effects of self-reported head injury. Results: The effect of self-reported head injury on the clinical state depended on the age at assessment: for a 1-year increase in age, the OR for the transition to clinical mild cognitive impairment (MCI) at the next visit for participants with a history of head injury was 1.21 and 1.34 for the transition from MCI to dementia. Without respect to age, head injury increased the odds of mortality (OR = 1.54). Moreover, it increased the odds of a pathological diagnosis of AD for men (OR = 1.47) but not women (OR = 1.18). Men with a head injury had higher mean amyloid plaque counts in the neocortex and entorhinal cortex than men without. Conclusions: Self-reported head injury is associated with earlier onset, increased risk of cognitive impairment and dementia, increased risk of mortality, and AD-type pathological changes. © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
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- 2014
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9. 'End-Stage' Neurofibrillary Tangle Pathology in Preclinical Alzheimer's Disease: Fact or Fiction?
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Abner, Erin L., Kryscio, Richard J., Schmitt, Frederick A., SantaCruz, Karen S., Jicha, Gregory A., Lin, Yushun, Neltner, Janna M., Smith, Charles D., Van Eldik, Linda J., and Nelson, Peter T.
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ALZHEIMER'S disease , *NEUROLOGICAL disorders , *NEUROFIBRILLARY tangles , *PATHOLOGY , *DISEASES in older people - Abstract
Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores (MMSE) and clinical 'dementia' status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition. [ABSTRACT FROM AUTHOR]
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- 2011
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10. Acetylcholinesterase Inhibitor Treatment is Associated with Relatively Slow Cognitive Decline in Patients with Alzheimer's Disease and AD + DLB.
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Nelson, Peter T., Kryscio, Richard J., Abner, Erin L., Schmitt, Frederick A., Jicha, Gregory A., Mendiondo, Marta S., Cooper, Greg, Smith, Charles B., and Markesbery, William R.
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DEMENTIA , *DISEASES , *ALZHEIMER'S disease , *LEWY body dementia , *PATHOLOGY - Abstract
Dementia can be caused by different diseases including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or both (AD + DLB). University of Kentucky AD Center pathologically-diagnosed AD and AD + DLB cases were evaluated who had three or more longitudinal antemortem mental status examinations (n = 156). Patients with important concomitant pathology (n = 5) or patients that were profoundly demented at recruitment (intake MMSE < 20; n = 86) were excluded to strengthen our ability to test the association of specific clinical and pathological indices. Patients with pathologically-diagnosed AD + DLB (n = 25) lost cognitive capacity faster than patients with AD alone (n = 40). In both diseases, treatment with acetylcholinesterase inhibitors was associated with a slower rate of cognitive decline. [ABSTRACT FROM AUTHOR]
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- 2009
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11. Brain pathologies in extreme old age.
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Neltner, Janna H., Abner, Erin L., Jicha, Gregory A., Schmitt, Frederick A., Patel, Ela, Poon, Leonard W., Marla, Gearing, Green, Robert C., Davey, Adam, Johnson, Mary Ann, Jazwinski, S. Michal, Sangkyu Kim, Davis, Daron, Woodard, John L., Kryscio, Richard J., Van Eldik, Linda J., and Nelson, Peter T.
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BRAIN diseases , *DISEASES in older people , *COHORT analysis , *ACQUISITION of data , *NEUROFIBRILLARY tangles , *ALZHEIMER'S disease - Abstract
With an emphasis on evolving concepts in the field, we evaluated neuropathologic data from very old research volunteers whose brain autopsies were performed at the University of Kentucky Alzheimer's Disease Center, incorporating data from the Georgia Centenarian Study (n = 49 cases included), Nun Study (n = 17), and University of Kentucky Alzheimer's Disease Center (n = 11) cohorts. Average age of death was 102.0 (range: 98-107) years overall. Alzheimer's disease pathology was not universal (62% with "moderate" or "frequent" neuritic amyloid plaque densities), whereas frontotemporal lobar degeneration was absent. By contrast, some hippocampal neurofibrillary tangles (including primary age-related tauopathy) were observed in every case. Lewy body pathology was seen in 16.9% of subjects and hippocampal sclerosis of aging in 20.8%. We describe anatomic distributions of pigment-laden macrophages, expanded Virchow-Robin spaces, and arteriolosclerosis among Georgia Centenarians. Moderate or severe arteriolosclerosis pathology, throughout the brain, was associated with both hippocampal sclerosis of aging pathology and an ABCC9 gene variant. These results provide fresh insights into the complex cerebral multimorbidity, and a novel genetic risk factor, at the far end of the human aging spectrum. [ABSTRACT FROM AUTHOR]
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- 2016
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12. Alzheimer's-type neuropathology in the precuneus is not increased relative to other areas of neocortex across a range of cognitive impairment
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Nelson, Peter T., Abner, Erin L., Scheff, Stephen W., Schmitt, Frederick A., Kryscio, Richard J., Jicha, Gregory A., Smith, Charles D., Patel, Ela, and Markesbery, William R.
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ALZHEIMER'S disease , *NEUROLOGICAL disorders , *NERVE fibers , *COGNITION disorders , *AUTOPSY , *AMYGDALOID body - Abstract
Abstract: We studied Alzheimer''s disease (AD) pathology in the precuneus and surrounding brain areas. Anatomically, the precuneus corresponds to the medial portion of human cerebral cortical Brodmann Area 7. This study utilized patients from the University of Kentucky Alzheimer''s Disease Center autopsy cohort. Data from 47 brains were used comprising patients of differing antemortem cognitive impairment severities, each with longitudinal clinical data and extensive neuropathological data. We assessed whether the precuneus and surrounding areas are differentially vulnerable to AD-type pathological lesions (diffuse amyloid plaques, neuritic amyloid plaques, and neurofibrillary tangles). Eleven areas of brain were evaluated for each case: amygdala, hippocampal CA1, subiculum, entorhinal cortex, frontal cortex, superior and middle temporal gyri, inferior parietal lobule, occipital cortex, posterior cingulate gyrus, Brodmann Area 31, and the precuneus proper. Like other areas of neocortex, the precuneus demonstrated increased diffuse and neuritic amyloid plaques early in the evolution in AD, and increased neurofibrillary tangles late in AD. Correcting for the antemortem cognitive status of the patients, there was no evidence of an increase in the density of AD-type pathology in the precuneus or neighboring areas relative to other areas of cerebral neocortex. Our results are not consistent with the idea that the precuneus is involved in a special way with plaques or tangles relative to other areas of neocortex. [Copyright &y& Elsevier]
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- 2009
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13. Preclinical AD Workgroup staging: pathological correlates and potential challenges
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Jicha, Gregory A., Abner, Erin L., Schmitt, Frederick A., Kryscio, Richard J., Riley, Kathryn P., Cooper, Gregory E., Stiles, Nancy, Mendiondo, Marta S., Smith, Charles D., Van Eldik, Linda J., and Nelson, Peter T.
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NEUROLOGICAL disorders , *MILD cognitive impairment , *ALZHEIMER'S disease , *MEDICAL sciences , *COGNITIVE testing , *BIOMARKERS , *MEDICAL statistics - Abstract
Abstract: The National Institute on Aging Preclinical Alzheimer''s disease Workgroup (PADW) has issued a preliminary report with recommendations for classifying preclinical Alzheimer''s disease (pAD) according to 3 early disease stages. Here we examine the PADW recommendations in relation to neuropathological features in a large, consecutive series of cognitively intact elderly persons, autopsied within a year after cognitive testing (n = 126 cognitively intact patients with mean age 83.7 years at death). Subjects were grouped based on a hypothetical construct correlating pathological features with PADW stages. Many cognitively intact individuals were classifiable as pAD (53/126 or 43%), as expected based on epidemiological and biomarker studies. Of these, most (48%) were in “stage 3”, which corresponds to amyloid pathology with early neurodegeneration. As with prior studies, our data indicate that the development of neocortical neurofibrillary tangles is the key pathological event that is not observed in pAD cases: Braak stages III or IV pathology are hence not truly a substrate for “intermediate likelihood” that cognitive impairment is due to Alzheimer''s disease (AD). We also stress the importance of comorbid non-Alzheimer''s disease brain pathologies (hippocampal sclerosis, neocortical alpha-synucleinopathy, cerebrovascular disease, and brains with hippocampal neurofibrillary tangles but no cortical amyloid plaques) that can contribute to the development of cognitive impairment, or which may serve as confounds in the application of the PADW recommendations. While the final recommendations from the PADW working group have not yet been released, this preliminary analysis provides a perspective on those recommendations from a neuropathological point of view. [Copyright &y& Elsevier]
- Published
- 2012
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