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John Q. Trojanowski

Bio: John Q. Trojanowski is an academic researcher from University of Pennsylvania. The author has contributed to research in topics: Alzheimer's disease & Dementia. The author has an hindex of 226, co-authored 1467 publications receiving 213948 citations. Previous affiliations of John Q. Trojanowski include Vanderbilt University & University of California, San Francisco.


Papers
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Journal ArticleDOI
TL;DR: These data provide the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases is suggested.
Abstract: Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.

197 citations

Journal ArticleDOI
TL;DR: Among several potential antemortem biomarkers in the diagnosis of DLB, measures of the glucose metabolism in the occipital cortex may be an informative diagnostic aid to distinguish DLB from AD; and a pathological process that generates widespread spongiform change and gliosis in long projection fibers may contribute, at least in part, to the characteristic imaging features ofDLB.

195 citations

Journal ArticleDOI
TL;DR: The areal and laminar distribution of the cortical efferents of the medial, lateral and inferior pulvinar nuclei (PM, PL and PI) were determined in rhesus monkey using autoradiography and Horseradish Peroxidase.
Abstract: The areal and laminar distribution of the cortical efferents of the medial, lateral and inferior pulvinar nuclei (PM, PL and PI respectively) were determined in rhesus monkey using autoradiography and Horseradish Peroxidase (HRP). The autoradiographic data indicated that: areas 8a, 45 and 46 on the convexity and 11 and 12 on the orbital surface of the frontal lobe received projections from PM; areas 20, 21 and 22 in temporal lobe received projections from PM primarily with caudal-medial parts of PM projecting to more rostral-dorsal parts of temporal lobe and rostral-lateral parts of PM projecting to more caudal-ventral parts of temporal lobe but PL also sends some efferents to caudal temporal lobe; areas 5 and 7 in parietal lobe and 18 and 19 in occipital lobe received projections primarily from the region in pulvinar comprising PL and PI with the more ventral parts of this region porsal parts of this region projecting to the more dorsal-lateral and medial parts of parieto-occipital cortex and with PM comtributing slightly to these projections rostrally. The autoradiographic information on the pulvinar projections to frontal lobe and temporal pole was supplemented by data derived from cortical HRP injections. These indicated that although only PM of the pulvinar subnuclei projected to these regions, three other caudal thalamic structures, i.e., medial dorsal nucleus, nucleus limitans and suprageniculate nucleus also projected to these regions raising some questions about the identity of the densocellular part of the medial dorsal nucleus which has also been considered to be part of pulvinar. The laminar distribution of pulvinar cortical efferents was uniformly similar regardless of the pulvinar recipient area examined. Elevated numbers of silver grains were observed over all cortical layers, but the silver grains were densest over the deep parts of layer III. The thalamic reticular nucleus was the only diencephalic structure observed to receive projections from pulvinar and it did so from PM, PL and PI. The pulvinar's efferents are to homotypical rather than heterotypical cortex and its connections are most extensive with cortex rather than with subcortical structures.

195 citations

Journal ArticleDOI
14 Jun 2012-PLOS ONE
TL;DR: This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits.
Abstract: Background/Aims: We evaluated clinicopathological correlates of upper motor neuron (UMN) damage in amyotrophic lateral sclerosis (ALS), and analyzed if the presence of the C9ORF72 repeat expansion was associated with alterations in microglial inflammatory activity. Methods: Microglial pathology was assessed by IHC with 2 different antibodies (CD68, Iba1), myelin loss by Kluver-Barrera staining and myelin basic protein (MBP) IHC, and axonal loss by neurofilament protein (TA51) IHC, performed on 59 autopsy cases of ALS including 9 cases with C9ORF72 repeat expansion. Results: Microglial pathology as depicted by CD68 and Iba1 was significantly more extensive in the corticospinal tract (CST) of ALS cases with a rapid progression of disease. Cases with C9ORF72 repeat expansion showed more extensive microglial pathology in the medulla and motor cortex which persisted after adjusting for disease duration in a logistic regression model. Higher scores on the clinical UMN scale correlated with increasing microglial pathology in the cervical CST. TDP-43 pathology was more extensive in the motor cortex of cases with rapid progression of disease. Conclusions: This study demonstrates that microglial pathology in the CST of ALS correlates with disease progression and is linked to severity of UMN deficits.

195 citations

Journal ArticleDOI
TL;DR: No significant evidence of neurodegeneration or ongoing neural injury in the cerebral cortex was found in this sample of elderly persons with schizophrenia, and the behavioral and cognitive deterioration observed in late life did not correlate with age-related degenerative phenomena.
Abstract: Background The cognitive and functional deterioration that is observed in many "poor-outcome" patients with schizophrenia suggests a neurodegenerative process extending into late life Previous diagnostic studies have excluded known neurodegenerative diseases as explanations for this dementia However, we hypothesized that relatively small accumulations of age- or disease-related neurodegenerative lesions occurring in an otherwise abnormal brain could result in deterioration in schizophrenia Methods Postmortem studies were conducted using 23 prospectively accrued elderly persons with chronic schizophrenia for whom clinical ratings had been determined before death, 14 elderly control patients with no neuropsychiatric disease, and 10 control patients with Alzheimer disease Immunohistochemistry and unbiased stereological counting methods were used to quantify common neurodegenerative lesions (ie, neurofibrillary tangles, amyloid plaques, and Lewy bodies) and cellular reactions to a variety of noxious stimuli (ubiquitinated dystrophic neurites, astrocytosis, and microglial infiltrates) in the ventromedial temporal lobe and the frontal and the calcarine (primary visual) cortices Results No statistically significant differences were found between the patients with schizophrenia and the control patients without neuropsychiatric disease for the densities of any of the markers, while both groups exhibited fewer lesions than did the control group with Alzheimer disease Correlation analyses in the schizophrenia sample failed to identify significant correlations between cognitive and psychiatric ratings and densities of any of the neuropathologic markers Conclusions No significant evidence of neurodegeneration or ongoing neural injury in the cerebral cortex was found in this sample of elderly persons with schizophrenia Furthermore, the behavioral and cognitive deterioration observed in late life did not correlate with age-related degenerative phenomena

194 citations


Cited by
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28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

18,940 citations

Journal ArticleDOI
TL;DR: The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available.
Abstract: The National Institute on Aging and the Alzheimer's Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer's disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Biomarker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.

13,710 citations

Journal ArticleDOI
19 Jul 2002-Science
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
Abstract: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer9s disease (AD) may be caused by deposition of amyloid β-peptide (Aβ) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Aβ in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Aβ production and Aβ clearance.

12,652 citations

Journal ArticleDOI
TL;DR: There is growing evidence that aging involves, in addition, progressive changes in free radical-mediated regulatory processes that result in altered gene expression.
Abstract: At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

9,131 citations