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.

Persistence of immunoreactive neurofilament protein breakdown products in transected rat sciatic nerve

Abstract: Alterations occurring in nerve proteins of transected nerves were studied in rat sciatic nerves using polyclonal and monoclonal antibodies to identify and monitor neurofilament (NF) epitopes among nerve proteins following their electrophoresis and transfer to nitrocellulose paper. Immunoblot methods identified NF epitopes in NF triplet proteins (Mr 200,000, 150,000, and 68,000) and in NF nontriplet proteins (all other immunobands below Mr 200,000 and above Mr 40,000). NF triplet and nontriplet proteins were Triton-insoluble in both untransected and transected nerves. Extensive loss of NF triplet and most nontriplet proteins occurred during the 24-48-h period following nerve transection and was attributed to proteolytic degradation. Loss of protease-labile NF proteins led to a markedly reduced level of NF immunoreactivity in 2-day transected nerve. NF proteins which survived the 2-day posttransectional period were considered to represent protease-stable NF fragments. These fragments persisted in transected nerve for periods of at least 35 days. Most protease-stable NF fragments which retained immunoreactivity had Mr of 57,000-65,000. Low concentrations of the same immunobands were present in untransected nerves.

Quantitative assessment of finger tapping characteristics in mild cognitive impairment, Alzheimer’s disease, and Parkinson’s disease

Abstract: Fine motor impairments are common in neurodegenerative disorders, yet standardized, quantitative measurements of motor abilities are uncommonly used in neurological practice. Thus, understanding and comparing fine motor abilities across disorders have been limited. The current study compared differences in finger tapping, inter-tap interval, and variability in Alzheimer’s disease (AD), Parkinson’s disease (PD), mild cognitive impairment (MCI), and healthy older adults (HOA). Finger tapping was measured using a highly sensitive light-diode finger tapper. Total number of finger taps, inter-tap interval, and intra-individual variability (IIV) of finger tapping was measured and compared in AD (n = 131), PD (n = 63), MCI (n = 46), and HOA (n = 62), controlling for age and sex. All patient groups had fine motor impairments relative to HOA. AD and MCI groups produced fewer taps with longer inter-tap interval and higher IIV compared to HOA. The PD group, however, produced more taps with shorter inter-tap interval and higher IIV compared to HOA. Disease-specific changes in fine motor function occur in the most common neurodegenerative diseases. The findings suggest that alterations in finger tapping patterns are common in AD, MCI, and PD. In addition, the present results underscore the importance of motor dysfunction even in neurodegenerative disorders without primary motor symptoms.

Early marker for Alzheimer's disease: Hippocampus T1rho (T1ρ) estimation

Abstract: Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder in elderly and results in progressive memory loss and cognitive decline. The appearance of senile plaques and neurofibrillary tangles are the neuropathological hallmarks of AD (1). Autopsy studies have shown the hippocampus to be affected by AD pathology early in the disease process, with ≈20%–50% loss of neurons by the time individuals are moderately affected (2,3). As a result, imaging studies have focused on this region in order to detect the early changes during the disease progression. Currently the diagnosis of clinically probable AD can be confirmed only once the stage of dementia has been reached. Neuropsychological tests are necessary to recognize and monitor the subjects at risk. However, to date there is no accurate cognitive marker to identify AD in the early disease process. Moreover, cognitive performances depend not only on age and education but also on mood and attention at the time of testing, and thus lack wide generalizability. Quantitative analysis of tau protein and amyloid-Aβ in the cerebrospinal fluid (CSF) has shown some diagnostic value in probable AD (4,5), but the procedure is totally invasive and has thus received only little attention so far in diagnosing AD. An accurate diagnosis of AD in the early symptomatic stage is extremely challenging despite the development of useful clinical constructs like mild cognitive impairment (MCI), which enables the identification of individuals who may be in an early clinical phase of AD. MCI was previously defined as a transitional state that can precede dementia, but the condition and the rates of conversion remain controversial. Despite many consensus conferences, experts cannot agree on critical aspects of MCI, particularly with respect to its clinical utility. Based on neuropsychological studies, a hippocampal memory profile has been proposed for MCI as prodromal AD (6). In light of current drug development aimed at slowing AD progression, diagnosing AD at its prodromal stage is particularly important. Recently, research has begun to focus on developing new tools, such as neuroimaging and CSF biomarkers, that could increase the specificity of the prodromal AD diagnosis. The goal of research in this area is therefore to develop highly specific and sensitive methods capable of identifying the subjects in the early stage who progress to AD. Neuroimaging markers provide an alternative and objective assessment of progression of AD. Out of various imaging techniques MRI is the most widely accepted technique to diagnose the various pathological conditions, and to monitor the treatment response, based on the changes in T2 and T1 contrast relaxation properties. It has been shown that the T2 value was not significantly different between normal subjects and AD patients (7). In one recent study, Yuan et al (8) have shown that fluorodeoxyglucose positron emission tomography (FDG-PET) performs slightly better than single photon emission tomography (SPECT) and structural imaging in prediction of conversion to AD in patients with MCI. However, the wide clinical utility of the PET technique is hampered by its poor resolution and necessity of a cyclotron at the imaging center that can produce the radioactive tracers. Other MR techniques like diffusion tensor imaging (DTI) and proton spectroscopy (1HMRS) have also been used in detection of normal white matter changes in patients with AD (9, 10). Ukmar et al (9) have shown a significant difference in fractional anisotropy (FA) between control and AD, while the FA was not significantly different in AD compare to MCI. Similarly, in a 1HMRS study it has been shown that the hippocampal metabolite profile in MCI is similar to AD (10). An alternative contrast mechanism is T1rho (T1ρ), the spin lattice relaxation time constant in the rotating frame, which determines the decay of the transverse magnetization in the presence of a “spin-lock” radiofrequency field (11). In biological tissue, exchange between protons in different environments is expected to contribute T1ρ relaxation. The molecular process that occurs in the milliseconds range influences the T1ρ relaxation time constant. T1ρ MRI has been previously used to measure T1ρ relaxation time in normal human brain and showed the higher range of values compared to T2 (11). Earlier, T1ρ has been used to delineate brain tumors, characterize breast cancer tissue, and monitor the level of cartilage degeneration (12–14). The current study was performed with an aim to measure the baseline T1ρ in hippocampus in the brain of AD (n = 49), MCI (n = 48), and control (n = 31) cohorts and to determine whether the T1ρ value shows any significant difference between these cohorts.

Influence of genetic variation on plasma protein levels in older adults using a multi-analyte panel.

Abstract: Proteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease pathophysiology Effects of individual single nucleotide polymorphisms (SNPs) within a gene were analyzed for corresponding plasma protein levels using genome-wide association study (GWAS) genotype data and proteomic panel data with 132 quality-controlled analytes from 521 Caucasian participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort Linear regression analysis detected 112 significant (Bonferroni threshold p=244610 25 ) associations between 27 analytes and 112 SNPs 107 out of these 112 associations were tested in the Indiana Memory and Aging Study (IMAS) cohort for replication and 50 associations were replicated at uncorrected p,005 in the same direction of effect as those in the ADNI We identified multiple novel associations including the association of rs7517126 with plasma complement factor H-related protein 1 (CFHR1) level at p,146610 260 , accounting for 40 percent of total variation of the protein level We serendipitously found the association of rs6677604 with the same protein at p,929610 2112 Although these two SNPs were not in the strong linkage disequilibrium, 61 percent of total variation of CFHR1 was accounted for by rs6677604 without additional variation by rs7517126 when both SNPs were tested together 78 other SNP-protein associations in the ADNI sample exceeded genome-wide significance (5610 28 ) Our results confirmed previously identified gene-protein associations for interleukin-6 receptor, chemokine CC-4, angiotensin-converting enzyme, and angiotensinogen, although the direction of effect was reversed in some cases This study is among the first analyses of gene-protein product relationships integrating multiplex-panel proteomics and targeted genes extracted from a GWAS array With intensive searches taking place for proteomic biomarkers for many diseases, the role of genetic variation takes on new importance and should be considered in interpretation of proteomic results

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...