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.

T1rho (T1ρ) MR imaging in Alzheimer' disease and Parkinson's disease with and without dementia

Abstract: In the current study, we aim to measure T1rho (T (1ρ)) in the hippocampus in the brain of control, Alzheimer's disease (AD), Parkinson's disease (PD), and PD patients with dementia (PDD), and to determine efficacy of T (1ρ) in differentiating these cohorts. With informed consent, 53 AD patients, 62 PD patients, 11 PDD patients, and 46 age-matched controls underwent a standardized clinical assessment including mini-mental state examination (MMSE) and brain T (1ρ) MRI on a 1.5-T clinical-scanner. T(1ρ) maps were generated by fitting each pixel's intensity as a function of the spin-lock pulse duration. In control, AD, PD and PDD, mean ± SE T (1ρ) values in the right hippocampus (RH) were 92.15 ± 2.00, 99.65 ± 1.98, 85.68 ± 1.87, 102.47 ± 4.66 ms while in the left hippocampus (LH) these values were 90.16 ± 1.82, 99.53 ± 1.91, 84.33 ± 2.03, 95.33 ± 4.64 ms. Significant difference for both RH and LH T (1ρ) across the groups (p < 0.001) was observed. Both RH and LH T (1ρ) were significantly increased in AD compared to control (p = 0.034, p = 0.001) and PD (p < 0.001, p < 0.001). In control, both RH and LH T (1ρ) values were significantly increased compared to PD (p = 0.031, p = 0.027) while compared to PDD only the RH T (1ρ) value was significantly decreased (p = 0.043). Both RH and LH T (1ρ) values in PD were significantly lower than PDD (p = 0.004, p = 0.032). No significant correlation between the T (1ρ) and age as well as between T (1ρ) and MMSE scores was observed. The serial measurement of T(1ρ) in both AD and PD may provide the nature of disease progression and may contribute to their early diagnosis.

Sex differences in the genetic predictors of Alzheimer’s pathology

Abstract: Autopsy measures of Alzheimer’s disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer’s disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer’s disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer’s disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10−8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10−8) but not females (P = 0.85, sex-interaction P = 2.9 × 10−4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.

Amyotrophic lateral sclerosis-plus syndrome with TAR DNA-binding protein-43 pathology.

Abstract: Background Amyotrophic lateral sclerosis (ALS)–Plus syndromes meet clinical criteria for ALS but also include 1 or more additional features such as dementia, geographic clustering, extrapyramidal signs, objective sensory loss, autonomic dysfunction, cerebellar degeneration, or ocular motility disturbance. Methods We performed a whole-brain and spinal cord pathologic analysis in a patient with an ALS-Plus syndrome that included repetitive behaviors along with extrapyramidal and supranuclear ocular motility disturbances resembling the clinical phenotype of progressive supranuclear palsy. Results There was motoneuron cell loss and degeneration of the corticospinal tracts. Bunina bodies were present. TAR DNA-binding protein-43 pathology was diffuse. Significant tau pathology was absent. Conclusions TAR DNA-binding protein-43 disorders can produce a clinical spectrum of neurodegeneration that includes ALS, frontotemporal lobar degeneration, and ALS with frontotemporal lobar degeneration. The present case illustrates that isolated TAR DNA-binding protein-43 disorders can produce an ALS-Plus syndrome with extrapyramidal features and supranuclear gaze palsy resembling progressive supranuclear palsy.

Selective reduction of soluble Tau proteins in sporadic and familial frontotemporal dementias: an international follow-up study

Abstract: Recently, biochemical criteria were proposed to complement histological criteria for the diagnosis of dementia lacking distinctive histopathology (DLDH), the most common pathological variant of frontotemporal dementias (FTDs), based on evidence of a selective reduction of soluble tau proteins in brains from a large cohort of sporadic DLDH and hereditary FTD (HDDD2 family) patients. To ensure that these findings are not unique to the populations included in the initial report, we extended the previous work by analyzing 22 additional DLDH brains from the United States and international centers. Our biochemical analyses here confirmed the previous findings by demonstrating substantial reductions in soluble brain tau in gray and white matter of 14 cases and moderate reductions in 6 cases of DLDH. We also analyzed brain samples from an additional affected HDDD2 family member, and remarkably, unlike other previously studied members of this kindred, this patient's brain contained substantial amounts of pathological or insoluble tau. These findings confirm and extend the definition of DLDH as a sporadic or familial "tau-less" tauopathy with reduced levels of soluble brain tau and no insoluble tau or fibrillary tau inclusions, and the data also underline the phenotypic heterogeneity of HDDD2, which parallels the phenotypic heterogeneity of other hereditary neurodegenerative FTD tauopathies caused by tau gene mutations.

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...