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.

Amyloid β-Protein (Aβ) 1–40 But Not Aβ1–42 Contributes to the Experimental Formation of Alzheimer Disease Amyloid Fibrils in Rat Brain

Abstract: Two major C-terminal variants ending at Val40 and Ala42 constitute the majority of amyloid beta-protein (Abeta), which undergoes postsecretory aggregation and deposition in the Alzheimer disease (AD) brain. To probe the differential pathobiology of the two Abeta variants, we used an in vivo paradigm in which freshly solubilized Abeta1-40 or Abeta1-42 was injected into rat brains, followed by examination using Congo red birefringence, Abeta immunohistochemistry, and electron microscopy. In the rat brain, soluble Abeta 1-40 and Abeta1-42 formed aggregates, and the Abeta1-40 but not the Abeta1-42 aggregates showed Congo red birefringence. Electron microscopy revealed that the Abeta1-40 aggregates contained fibrillar structures similar to the amyloid fibrils of AD, whereas the Abeta1-42 aggregates contained nonfibrillar amorphous material. Preincubation of Abeta1-42 solution in vitro led to the formation of birefringent aggregates, and after injection of the preincubated Abeta1-42, the aggregates remained birefringent in the rat brain. Thus, a factor or factors might exist in the rat brain that inhibit the fibrillar assembly of soluble Abeta1-42. To analyze the postsecretory processing of Abeta, we used the same in vivo paradigm and showed that Abeta1-40 and Abeta1-42 were processed at their N termini to yield variants starting at pyroglutamate, and at their C termini to yield variants ending at Val40 and at Val39. Thus the normal rat brain could produce enzymes that mediate the conversion of Abeta 1-40/1-42 into processed variants similar to those in AD. This experimental paradigm may facilitate efforts to elucidate mechanisms of Abeta deposition evolving into amyloid plaques in AD.

Reduced CSF p-Tau181 to Tau ratio is a biomarker for FTLD-TDP

Abstract: Objectives: To validate the ability of candidate CSF biomarkers to distinguish between the 2 main forms of frontotemporal lobar degeneration (FTLD), FTLD with TAR DNA-binding protein 43 (TDP-43) inclusions (FTLD-TDP) and FTLD with Tau inclusions (FTLD-Tau). Methods: Antemortem CSF samples were collected from 30 patients with FTLD in a single-center validation cohort, and CSF levels of 5 putative FTLD-TDP biomarkers as well as levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau 181 ) were measured using independent assays. Biomarkers most associated with FTLD-TDP were then tested in a separate 2-center validation cohort composed of subjects with FTLD-TDP, FTLD-Tau, Alzheimer disease (AD), and cognitively normal subjects. The sensitivity and specificity of FTLD-TDP biomarkers were determined. Results: In the first validation cohort, FTLD-TDP cases had decreased levels of p-Tau 181 and interleukin-23, and increased Fas. Reduced ratio of p-Tau 181 to t-Tau (p/t-Tau) was the strongest predictor of FTLD-TDP pathology. Analysis in the second validation cohort showed CSF p/t-Tau ratio Conclusion: A reduced CSF p/t-Tau ratio represents a reproducible, validated biomarker for FTLD-TDP with performance approaching well-established CSF AD biomarkers. Introducing this biomarker into research and the clinical arena can significantly increase the power of clinical trials targeting abnormal accumulations of TDP-43 or Tau, and select the appropriate patients for target-specific therapies. Classification of evidence: This study provides Class II evidence that the CSF p/t-Tau ratio distinguishes FTLD-TDP from FTLD-Tau.

The neuropathology of dementia

Abstract: 1. Definition, clinical features and neuroanatomical basis of dementia T. J. Grabowski, and A. R. Damasio 2. Practical approach to the pathological diagnosis of dementia: important anatomical landmarks in the brain in dementia M. M. Esiri, and J. H. Morris 3. Practical approach to pathological diagnosis M. M. Esiri, and J. H. Morris 4a. Alzheimer's disease M. M. Esiri, and J. H. Morris 4b. Neuropathological changes of Alzheimer's disease in persons with Down's syndrome D. Mann 5. Vascular dementia M. M. Esiri, and J. H. Morris 6. Parkinson's disease and dementia M. M. Esiri, and R. McShane 7. Amyotrophic lateral sclerosis/Parkinsonism-dementia complex of Guam D. P. Perl 8. Pick's disease J. H. Morris, and M. M. Esiri 9. Huntington disease J. P. G. von Sattel, P. Ge, and L. Kelley 10. Other neurodegenerative diseases causing dementia M. M. Esiri, and J. H. Morris 11. Familial cerebral amyloid angiopathies G. T. Plant, and M. M. Esiri 12. Human prion disease K. Hsiao 13. Alcoholism and dementia C. Harper, and D. Corbett 14. Dementia due to other metabolic diseases and toxins M. M. Esiri 15. Hydrocephalus and dementia M. M. Esiri 16. Head injury and dementia C. J. Bruton 17. Infectious diseases causing dementias F. Scaravilli, and M. J. G. Harrison 18. Schizophrenia and its dementia P. J. Harrison 19. Other diseases that cause dementia M. M. Esiri, and J. H. Morris Appendix 1. Morphometric methods and dementia J. M. Anderson Appendix 2. Addresses of dementia brain banks M. M. Esiri, and J. H. Morris Appendix 3. Safety precautions in laboratories involved in dementia diagnosis and research M. M. Esiri, and J. H. Morris.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

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。

The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease

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.

The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics

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.

Free Radicals in the Physiological Control of Cell Function

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...