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.

Lowering the risk of Alzheimer's disease: Evidence-based practices emerge from new research

Abstract: Background: The increasing prevalence of Alzheimer's disease (AD) and other aging-related dementias as the population ages will have a dramatic impact on both provision of health care and the economy if nothing is done to prevent or delay the onset of AD or to slow its progression. Methods: A comprehensive review of the literature in several promising areas of inquiry, other than those representing Food and Drug Administration (FDA)-approved AD- or dementia-specific pharmacologic therapies, that may impact the risk or progression of AD and related dementias was undertaken. Results: Results highlight a number of factors associated with AD and dementia. These include education and occupation, cognitive and leisure activities, exercise, cholesterol and statins, and head trauma. Conclusions: Factors associated with AD and dementia may have potential as strategies useful in preventing or delaying AD and dementia or slowing its progression. Further research is needed to determine the validity and strength of the associations and to ascertain causality. © 2005 The Alzheimer's Association. All rights reserved.

Expression of neurofilament and neuron-specific enolase in small cell tumors of skin using immunohistochemistry.

Abstract: Trabecular carcinoma of the skin (Merkel cell tumor), a neoplasm of putative neural origin, must be differentiated from other small cell tumors primary or metastatic to skin. In order to provide more objective diagnostic criteria, four were examined using monoclonal antibodies against neurofilament proteins (NF) and antiserum specific for neuron-specific enolase (NSE). Immunohistochemistry demonstrated immunoreactive NF in three and NSE in four cases. NF immunoreactivity was arranged in paranuclear balls, consistent with ultrastructural observations of aggregated intermediate filaments. A case of pulmonary oat cell carcinoma metastatic to the skin also contained immunoreactive NF and NSE. Although NF and NSE do not discriminate metastatic oat cell carcinoma from trabecular carcinoma of skin, they are useful antigens that provide objective criteria for recognizing tumors of neural histogenesis or neural differentiation. They should make it possible to exclude non-neural lesions from the differential diagnosis of small cell tumors of the skin.

APOE, thought disorder, and SPARE-AD predict cognitive decline in established Parkinson's disease

Abstract: BACKGROUND People with PD are at high risk of developing cognitive impairment and dementia. Cross-sectional studies have identified candidate biomarkers associated with cognitive decline. However, longitudinal studies on this topic are rarer, and few have investigated the use of biomarker panels encompassing multiple modalities. The objective of this study was to find baseline predictors of cognitive decline in longitudinally followed, nondemented Parkinson's disease patients. METHODS We performed a prospective cohort study of 100 PD patients with a median disease duration of 6.4 years. All participants were nondemented at baseline. We examined 16 baseline biomarkers from clinical, genetic, biochemical, and MRI-based imaging modalities for their association with longitudinal cognitive decline for up to 8 years. We investigated biomarkers individually, as well as in a multivariate linear mixed-effects model encompassing multimodal biomarkers, with change in the Mattis Dementia Rating Scale-2 over time as the primary outcome. Annual consensus process-derived cognitive diagnosis was used for Cox proportional hazards modeling of risk for cognitive decline. RESULTS In multivariate analysis, the presence of the APOE E4 allele, thought disorder, and an Alzheimer's disease pattern of brain atrophy (spatial pattern of abnormality for recognition of early Alzheimer's disease index) best predicted cognitive decline, with APOE E4 genotype exerting the greatest effect. The presence of the APOE E4 allele was associated with a 3.5 times higher risk of worsening cognitive diagnosis over time (HR, 3.53; 95% CI, 1.52-8.24; P < 0.05). The APOE genotype effect was not specific to any Mattis Dementia Rating Scale-2 domain. CONCLUSIONS Our results confirm the importance of Alzheimer's disease biomarkers as risk factors for cognitive decline in established Parkinson's disease. © 2017 International Parkinson and Movement Disorder Society.

Building a roadmap for developing combination therapies for Alzheimer's

Abstract: Combination therapy has proven to be an effective strategy for treating many of the world’s most intractable diseases. A growing number of investigators in academia, industry, regulatory agencies, foundations and advocacy organizations are interested in pursuing a combination approach to treating Alzheimer’s disease. A meeting co-hosted by the Accelerate Cure/Treatments for Alzheimer’s Disease Coalition, the Critical Path Institute and the Alzheimer’s Association addressed challenges in designing clinical trials to test multiple treatments in combination and outlined a roadmap for making such trials a reality.

Use of Alzheimer disease biomarkers: potentially yes for clinical trials but not yet for clinical practice.

Abstract: Research in Alzheimer disease (AD) is rapidly moving toward the point of the earliest identification of the underlying disease processes. These include the accumulation of AB plaques, tau tangles and neuron as well as synaptic loss, and it is likely that these do not all occur contemporaneously. Many investigators contend that, by the time the clinical symptoms appear, sufficient AD pathology and neurodegeneration have occurred, which if irreversible, may reduce the efficacy of disease modifying therapy for clinically manifest AD.1 As such, efforts are underway to try to identify the onset of these pathological processes that culminate in clinically manifest AD dementia. However, to accomplish this, the underlying pathology must be detected, possibly through the use of neuroimaging and chemical biomarker measures. In this issue of JAMA, Mattsson and colleagues2 report their evaluation of the utility of cerebrospinal fluid (CSF) markers for AD in a large multicenter study. The investigators from the Swedish Brainpower CSF Initiative enrolled individuals with mild cognitive impairment (MCI) from 12 centers in Europe as well as healthy individuals as controls and those with mild AD for comparison. They identified 750 individuals as having MCI and followed them for at least two years to determine whether the CSF profile at baseline of Aβ42, total tau (T-tau), and phosphorylated tau (P-tau) predicted the ultimate clinical course. They found that CSF Aβ42, T-tau, and P-tau could be used to predict outcomes and thus suggest that these markers may be useful in identifying patients for clinical trials and possibly screening tests in memory clinics. This group of investigators has been studying these issues for several years, and their study represents a tour de force of clinical and laboratory data collections. However, their study also represents several key challenges that need to be addressed before CSF markers are ready for broad clinical applications, although these markers already are being used in clinical trials of disease-modifying therapies for AD. Mild Cognitive Impairment is a heterogeneous condition, and based on the underlying conceptual nature of the condition, this is to be expected.3–4 International consensus meetings have characterized the construct by subtypes into amnestic and non amnestic MCI5–6 in an attempt to explain some of the heterogeneity. Amnestic MCI of a presumed degenerative etiology is generally considered to be the forerunner of clinical AD, and Mattsson et al2 have diagnosed MCI with that presumption. However, the investigators combined clinical data from 12 different memory disorders centers, using different instruments and likely different implementation of the criteria and consequently may have assembled a group of individuals with significant clinical variability. As such, while they present the Mini-Mental State Examination scores and demographic data, without the presentation of the other clinical data a precise comparison of the individuals from the different centers is difficult. The investigators describe that they enrolled a consecutive series of individuals presenting to memory centers with symptoms leading to the diagnoses of MCI or AD. Despite this variability, the investigators reported an annual rate of progression to AD of 11% which is typical for referral center cohorts.7 Similarly, there was likely considerable variability with respect to the CSF collection and assays, and the authors clearly acknowledge that their CSF assays require further standardization. The coefficients of a variation from other sites were discrepant from the primary site, and a formula was used to “correct” these data. This may have made the results comparable in a statistical sense from the various sites; however, it is also likely that the significant variability in the laboratory data could have compounded the problems with the clinical variability. The investigators in this report are accomplished in AD biomarker research and aware of the hurdles that need to be surmounted to bring an AD biomarker from the initial discovery stage to a validated test for AD diagnosis.8 Despite these potential sources of variability, the study documented the utility of CSF biomarkers to predict, with good accuracy, the outcome of individuals with MCI. Moreover, with further mining of their data, Mattsson et al may improve on their CSF biomarker algorithm. Shaw et al9 recently reported that APOE genotype contributed incrementally to test accuracy when combined with measures of CSF Aβ and tau. Thus, the study by Mattsson et al is an important contribution toward the goal of developing disease-modifying therapies based on the use of biomarkers and clinical measures. Despite the considerable clinical and laboratory variability, the results appear plausible and enticing. As the authors indicate, this multicenter study replicated the results of smaller single-center studies, with the caveat that some of the prior study samples were included in this study. The data likely reflect the underlying pathological processes of AD in some individuals with MCI; however, it is premature to recommend application of these techniques in clinical practice. The inherent clinical and laboratory variability precludes the adoption of these measures at this time. Significant refinement of the assay procedures is necessary before these techniques can be recommended for general clinical use along the lines described in previous publications.8–9 An effort in this direction is now underway in North America known as Alzheimer Disease Neuroimaging Initiative (ADNI)9–10 and is complemented by similar studies in Europe, Japan and Australia. This study represents 57 centers in the United States and Canada and was designed to evaluate the utility of neuroimaging and clinical biomarkers in characterizing the course of amnestic MCI with the intention of predicting clinical AD before the full criteria for dementia are met. A major focus of this study also involves reducing variability in the clinical, neuroimaging and laboratory procedures, including refining the clinical criteria for amnestic MCI (it is noteworthy that the clinical cohort recruited in ADNI has identical clinical features and rates of progression to AD as seen in an earlier clinical trial on amnestic MCI11); standardizing neuroimaging procedures for magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (PET), and PiB (Pittsburgh Compound B) PET; and centralizing the laboratory analysis of CSF biomarkers to ensure consistency and reliability. The biomarker data will be integrated with imaging and clinical data with the goal of identifying the optimal panel to use for predictive testing for AD, AD diagnosis, and clinical trial monitoring. Of critical importance, however, is what the clinician and patient will do with such results. The sensitivity and specificity of Aβ42, T-tau, and P-tau in the study by Mattsson et al were sufficient to be used for screening but not as a diagnostic test. Alzheimer disease has no treatment to prevent or alter the course of the disease, so making the diagnosis with good accuracy may aid in planning but also could be devastating news for some patients and families. Furthermore, false positives and false negatives occur as with any screening test. However, as biomarkers become more sophisticated, they are likely to take on an increasingly important role in the diagnosis and management of AD. The study by Mattsson et al2 represents a major step forward in suggesting that biomarkers may have sufficient accuracy to be used in the AD prodromal phase. The report highlights the challenges but also suggests solutions. Subsequent prospective investigations should clarify the true utility of these measures.

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...