John Q Trojanowski

William Penn University, Filadelfia, Pennsylvania, United States

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Publications (838)6961.7 Total impact

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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) is one of the leading causes of dementia after Alzheimer’s disease. A high-ranking candidate to become a diagnostic marker for a major pathological subtype of FTLD is the transactive response DNA binding protein of 43 kDa (TDP-43). The main objective is to elucidate which antibodies are specific for pathological TDP-43, with special interest in its modified isoforms. Indeed, TDP-43 has been shown to be hyperphosphorylated and truncated in disease. A secondary objective is to review existing immunoassays that quantify TDP-43 in biofluids. A systematic review of literature was performed by searching PubMed and Web of Science using predefined keywords. Of considered research papers the methods section was reviewed to select publications that enabled us to answer our learning objective. After quality assessment, antibody characteristics and related outcomes were extracted. We identified a series of well-characterized antibodies based on a scoring system that assessed the ability of each antibody to detect TDP-43 pathology. A selection of 29 unique antibodies was made comprising 10 high-ranking antibodies which were reported multiple times to detect TDP-43 pathology in both immunostaining and immunoblotting experiments and 19 additional antibodies which detected TDP-43 pathology but were only scored once. This systematic review provides an overview of antibodies that are reported to detect pathological TDP-43. These antibodies can be used in future studies of TDP-43 proteinopathies. Additionally, selected antibodies hold the potential to be used in the development of novel immunoassays for the quantification of TDP-43 in biofluids, as a possible biomarker for FTLD-TDP.
    12/2015; 3(15). DOI:10.1186/s40478-015-0195-1
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    ABSTRACT: Diagnosing behavioral variant frontotemporal dementia (bvFTD) in patients with prior history of stroke or with silent brain infarcts on neuroimaging studies can be challenging. Vascular changes in patients with bvFTD are not unusual, but bvFTD tends to be ruled out in the presence of cerebrovascular disease. We aimed to identify the clinical, cognitive, and risk factor profile of bvFTD with coexistent cerebrovascular disease (V-bvFTD). We compared demographic data, clinical diagnoses, vascular risk factors, functional status, and normalized neuropsychological z-scores between patients with V-bvFTD vs. bvFTD without concomitant cerebrovascular disease (NV-bvFTD) from the National Alzheimer's Coordinating Centre database. We included 391 neuropathologically diagnosed cases of frontotemporal lobe degeneration (FTLD). We excluded patients that were diagnosed with aphasic variants of frontotemporal dementia before death. Patients with V-bvFTD (n=62) were older at the time of onset of cognitive decline (71.6 vs. 62.5years, p<0.001) and death (78.7 vs. 69.6, p<0.001), more likely to be hypertensive (75.8 vs. 45.7%, p=0.002), and to have a history of stroke (21.2 vs. 6.1%, p=0.007) than those with NV-bvFTD (n=329). V-bvFTD was often underdiagnosed, affected elderly patients, and had a similar cognitive profile as NV-bvFTD despite the presence of brain infarcts. In the whole cohort, we observed enhanced cognitive performance with increasing age quintiles despite larger proportions of cerebrovascular disease pathology, likely meaning that FTLD-related primary neurodegeneration exerts a stronger impact on cognition than cerebrovascular disease. Coexisting cerebrovascular disease should not preclude the diagnosis of bvFTD.
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    ABSTRACT: We studied the biomarker signatures and prognoses of 3 different subtle cognitive impairment (SCI) groups (executive, memory, and multidomain) as well as the subjective memory complaints (SMC) group. We studied 522 healthy controls in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cutoffs for executive, memory, and multidomain SCI were defined using participants who remained cognitively normal (CN) for 7 years. CSF Alzheimer disease (AD) biomarkers, composite and region-of-interest (ROI) MRI, and fluorodeoxyglucose-PET measures were compared in these participants. Using a stringent cutoff (fifth percentile), 27.6% of the ADNI participants were classified as SCI. Most single ROI or global-based measures were not sensitive to detect differences between groups. Only MRI-SPARE-AD (Spatial Pattern of Abnormalities for Recognition of Early AD), a quantitative MRI pattern-based global index, showed differences between all groups, excluding the executive SCI group. Atrophy patterns differed in memory SCI and SMC. The CN and the SMC groups presented a similar distribution of preclinical dementia stages. Fifty percent of the participants with executive, memory, and multidomain SCI progressed to mild cognitive impairment or dementia at 7, 5, and 2 years, respectively. Our results indicate that (1) the different SCI categories have different clinical prognoses and biomarker signatures, (2) longitudinally followed CN subjects are needed to establish clinical cutoffs, (3) subjects with SMC show a frontal pattern of brain atrophy, and (4) pattern-based analyses outperform commonly used single ROI-based neuroimaging biomarkers and are needed to detect initial stages of cognitive impairment. © 2015 American Academy of Neurology.
    Neurology 06/2015; DOI:10.1212/WNL.0000000000001738 · 8.30 Impact Factor
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    ABSTRACT: Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 06/2015; 82. DOI:10.1016/j.nbd.2015.06.003 · 5.20 Impact Factor
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    ABSTRACT: Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein).
    Nature Communications 06/2015; 6. DOI:10.1038/ncomms8247 · 10.74 Impact Factor
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    ABSTRACT: Apathy is a common, troublesome symptom in Parkinson's disease (PD). However, little is known about its relationship with long-term cognition. We sought to determine if a caregiver-reported apathy measure predicts the development of PD dementia. Non-demented PD patients were recruited as part of a longitudinal study of cognition. Demographics, medications, Dementia Rating Scale-2, Unified Parkinson's Disease Rating Scale, Geriatric Depression Scale and the Neuropsychiatric Inventory-Questionnaire (NPI-Q) ratings were obtained. Apathy was defined as an NPI-Q apathy score ≥1. Participants were evaluated annually with cognitive and functional assessments until the end of the study period or a physician consensus diagnosis of dementia was assigned. Cox proportional hazard models were used to assess the effects of baseline apathy on dementia development while controlling for other clinical and demographic factors. Of 132 PD patients 12.1% (N = 16) scored in the apathetic range at baseline. A total of 19.6% (N = 26) individuals developed dementia over the course of the study, 8 of whom (30.8% of future dementia patients) had baseline apathy. In bivariate analyses baseline apathy, older age, and worse cognitive, motor, and depressive symptom scores predicted the development of dementia. In a multivariate analysis the predictive effects of baseline apathy were still significant (HR = 3.56; 95% CI = 1.09-11.62; p = 0.04). A simple, caregiver-reported measure of apathy is an independent predictor of progression to dementia in PD. This highlights the importance of apathy as a clinical characteristic of PD and could prove useful for the prediction of future dementia. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Parkinsonism & Related Disorders 06/2015; DOI:10.1016/j.parkreldis.2015.06.009 · 4.13 Impact Factor
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    ABSTRACT: Introduction Accumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer’s disease (AD) and other tauopathies. In most AD subjects, wild-type (WT) tau aggregates and accumulates in neurofibrillary tangles and dystrophic neurites in the brain; however, in some familial tauopathy disorders, mutations in the gene encoding tau cause disease. Results We generated a mouse model, Tau4RTg2652, that expresses high levels of normal human tau in neurons resulting in the early stages of tau pathology. In this model, over expression of WT human tau drives pre-tangle pathology in young mice resulting in behavioral deficits. These changes occur at a relatively young age and recapitulate early pre-tangle stages of tau pathology associated with AD and mild cognitive impairment. Several features distinguish the Tau4RTg2652 model of tauopathy from previously described tau transgenic mice. Unlike other mouse models where behavioral and neuropathologic changes are induced by transgenic tau harboring MAPT mutations pathogenic for frontotemporal lobar degeneration (FTLD), the mice described here express the normal tau sequence. Conclusions Features of Tau4RTg2652 mice distinguishing them from other established wild type tau overexpressing mice include very early phenotypic manifestations, non-progressive tau pathology, abundant pre-tangle and phosphorylated tau, sparse oligomeric tau species, undetectable fibrillar tau pathology, stability of tau transgene copy number/expression, and normal lifespan. These results suggest that Tau4RTg2652 animals may facilitate studies of tauopathy target engagement where WT tau is driving tauopathy phenotypes. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0210-6) contains supplementary material, which is available to authorized users.
    06/2015; 3(1). DOI:10.1186/s40478-015-0210-6
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    ABSTRACT: We investigated whether chromosome 9 open reading frame 72 hexanucleotide repeat expansion (C9orf72 expansion) size in peripheral DNA was associated with clinical differences in frontotemporal degeneration (FTD) and amyotrophic lateral sclerosis (ALS) linked to C9orf72 repeat expansion mutations. A novel quantification workflow was developed to measure C9orf72 expansion size by Southern blot densitometry in a cross-sectional cohort of C9orf72 expansion carriers with FTD (n = 39), ALS (n = 33), both (n = 35), or who are unaffected (n = 21). Multivariate linear regressions were performed to assess whether C9orf72 expansion size from peripheral DNA was associated with clinical phenotype, age of disease onset, disease duration and age at death. Mode values of C9orf72 expansion size were significantly shorter in FTD compared to ALS (p = 0.0001) but were not associated with age at onset in either FTD or ALS. A multivariate regression model correcting for patient's age at DNA collection and disease phenotype revealed that C9orf72 expansion size is significantly associated with shorter disease duration (p = 0.0107) for individuals with FTD, but not with ALS. Despite considerable somatic instability of the C9orf72 expansion, semi-automated expansion size measurements demonstrated an inverse relationship between C9orf72 expansion size and disease duration in patients with FTD. Our finding suggests that C9orf72 repeat size may be a molecular disease modifier in FTD linked to hexanucleotide repeat expansion.
    Acta Neuropathologica 05/2015; DOI:10.1007/s00401-015-1445-9 · 9.78 Impact Factor
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    ABSTRACT: This study assessed apolipoprotein E (APOE) ε4 carrier status effects on Alzheimer's disease imaging and cerebrospinal fluid (CSF) biomarkers in cognitively normal older adults with significant memory concerns (SMC). Cognitively normal, SMC, and early mild cognitive impairment participants from Alzheimer's Disease Neuroimaging Initiative were divided by APOE ε4 carrier status. Diagnostic and APOE effects were evaluated with emphasis on SMC. Additional analyses in SMC evaluated the effect of the interaction between APOE and [(18)F]Florbetapir amyloid positivity on CSF biomarkers. SMC ε4+ showed greater amyloid deposition than SMC ε4-, but no hypometabolism or medial temporal lobe (MTL) atrophy. SMC ε4+ showed lower amyloid beta 1-42 and higher tau/p-tau than ε4-, which was most abnormal in APOE ε4+ and cerebral amyloid positive SMC. SMC APOE ε4+ show abnormal changes in amyloid and tau biomarkers, but no hypometabolism or MTL neurodegeneration, reflecting the at-risk nature of the SMC group and the importance of APOE in mediating this risk. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
    Alzheimer's & dementia: the journal of the Alzheimer's Association 05/2015; DOI:10.1016/j.jalz.2015.03.003 · 17.47 Impact Factor
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    PLoS ONE 05/2015; 10(5):e0125614. DOI:10.1371/journal.pone.0125614 · 3.53 Impact Factor
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    ABSTRACT: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)). The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.
    04/2015; 2(4):417-26. DOI:10.1002/acn3.185
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    ABSTRACT: Cerebrospinal fluid (CSF) and positron emission tomographic (PET) amyloid biomarkers have been proposed for the detection of Alzheimer disease (AD) pathology in living patients and for the tracking of longitudinal changes, but the relation between biomarkers needs further study. To determine the association between CSF and PET amyloid biomarkers (cross-sectional and longitudinal measures) and compare the cutoffs for these measures. Longitudinal clinical cohort study from 2005 to 2014 including 820 participants with at least 1 florbetapir F-18 (hereafter referred to as simply florbetapir)-PET scan and at least 1 CSF β-amyloid 1-42 (Aβ1-42) sample obtained within 30 days of each other (501 participants had a second PET scan after 2 years, including 150 participants with CSF Aβ1-42 measurements). Data were obtained from the Alzheimer's Disease Neuroimaging Initiative database. Four different PET scans processing pipelines from 2 different laboratories were compared. The PET cutoff values were established using a mixture-modeling approach, and different mathematical models were applied to define the association between CSF and PET amyloid measures. The values of the CSF Aβ1-42 samples and florbetapir-PET scans showed a nonlinear association (R2 = 0.48-0.66), with the strongest association for values in the middle range. The presence of a larger dynamic range of florbetapir-PET scan values in the higher range compared with the CSF Aβ1-42 plateau explained the differences in correlation with cognition (R2 = 0.36 and R2 = 0.25, respectively). The APOE genotype significantly modified the association between both biomarkers. The PET cutoff values derived from an unsupervised classifier converged with previous PET cutoff values and the established CSF Aβ1-42 cutoff levels. There was no association between longitudinal Aβ1-42 levels and standardized uptake value ratios during follow-up. The association between both biomarkers is limited to a middle range of values, is modified by the APOE genotype, and is absent for longitudinal changes; 4 different approaches in 2 different platforms converge on similar pathological Aβ cutoff levels; and different pipelines to process PET scans showed correlated but not identical results. Our findings suggest that both biomarkers measure different aspects of AD Aβ pathology.
    03/2015; 72(5). DOI:10.1001/jamaneurol.2014.4829
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    ABSTRACT: The relationship between primary age-related tauopathy (PART) and Alzheimer’s disease (AD) is currently a matter of discussion. Recently the term PART was referred to cases characterized by mainly allocortical neurofibrillary (NF) pathology (Braak stages 0-IV) with only few or no amyloid (Aβ) deposits (Thal Aβ phases 0-2) [49]. In addition, no elevated soluble Aβ was detected in this disorder [9, 46]. PART cases that lack any Aβ do not meet formal criteria for sporadic AD according to the NIA-AA guidelines [35]. These neurofibrillary tangle (NFT)+/Aβ-brains are commonly observed in extreme old age [9, 15, 19]. When associated with a high density of NFTs in the same distribution and some cognitive deficits, the disorder has been referred to as tangle-predominant senile dementia (TPSD) [27] or “tangle-only dementia” [55].The new neuropathologic criteria recommend subdividing PART cases into “definite” (Braak stage ≤IV, Thal Aβ phase 0) and “possible” (Braak stage ≤IV, Thal Aβ phase 1-2) ...
    Acta Neuropathologica 03/2015; DOI:10.1007/s00401-015-1407-2 · 9.78 Impact Factor
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    ABSTRACT: Previous studies revealed that examples of the non-naturally occurring microtubule (MT)-stabilizing triazolopyrimidines are both brain penetrant and orally bioavailable, indicating that this class of compounds may be potentially attractive in the development of MT-stabilizing therapies for the central nervous system (CNS). We now report on the pharmacokinetics (PK), pharmacodynamics (PD), and metabolism of a selected triazolopyrimidine congener, (S)-3-(4-(5-chloro-7-((1,1,1-trifluoropropan-2-yl)amino)-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy)-propan-1-ol (4). These studies revealed that 4 exhibits longer brain than plasma half-life that may be exploited to achieve a selective accumulation of the compound within the CNS. Furthermore, compound metabolism studies suggest that in plasma 4 is rapidly oxidized at the terminal hydroxyl group to form a comparatively inactive carboxylic acid metabolite. Peripheral administration of relatively low doses of 4 to normal mice was found to produce a significant elevation in acetylated α-tubulin, a marker of stable MTs, in the brain. Collectively, these results indicate that 4 may effectively target brain MTs at doses that produce minimal peripheral exposure. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Bioorganic & medicinal chemistry letters 03/2015; DOI:10.1016/j.bmcl.2015.03.002 · 2.33 Impact Factor
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    ABSTRACT: Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are 2 neurodegenerative disorders that share clinical, genetic, and neuropathologic features. The presence of abnormal expansions of GGGGCC repeats (G4C2 repeats) in a noncoding region of the Chromosome 9 open reading frame 72 (C9orf72) gene is the major genetic cause of both FTLD and ALS. Transcribed G4C2 repeats can form nuclear RNA foci and recruit RNA-binding proteins, thereby inhibiting their normal function. Moreover, through a repeat-associated non-ATG translation mechanism, G4C2 repeats translation leads to dipeptide-repeat protein aggregation in the cytoplasm of neurons. Here, we identify Drosha protein as a new component of these dipeptide-repeat aggregates. In C9orf72 mutation cases of FTLD-TDP (c9FTLD-TDP) and ALS (c9ALS), but not in FTLD or ALS cases without C9orf72 mutation, Drosha is mislocalized to form neuronal cytoplasmic inclusions in the hippocampus, frontal cortex, and cerebellum. Further characterization of Drosha-positive neuronal cytoplasmic inclusions in the hippocampus, frontal cortex, and cerebellum revealed colocalization with p62 and ubiquilin-2, 2 pathognomonic signatures of c9FTLD-TDP and c9ALS cases; however, Drosha inclusions rarely colocalized with TDP-43 pathology. We conclude that Drosha may play a unique pathogenic role in the onset or progression of FTLD-TDP/ALS in patients with the C9orf72 mutation.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    Journal of Neuropathology and Experimental Neurology 03/2015; 74(4). DOI:10.1097/NEN.0000000000000182 · 4.37 Impact Factor
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    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.
    Expert Review of Neurotherapeutics 03/2015; 15(3):327-33. DOI:10.1586/14737175.2015.996551 · 2.83 Impact Factor
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    ABSTRACT: In the current study, we have evaluated the performance of magnetic resonance (MR) T1rho (T1ρ) imaging and CSF biomarkers (T-tau, P-tau and Aβ-42) in characterization of Alzheimer's disease (AD) patients from mild cognitive impairment (MCI) and control subjects. With informed consent, AD (n = 27), MCI (n = 17) and control (n = 17) subjects underwent a standardized clinical assessment and brain MRI on a 1.5-T clinical-scanner. T1ρ images were obtained at four different spin-lock pulse duration (10, 20, 30 and 40 ms). T1ρ maps were generated by pixel-wise fitting of signal intensity as a function of the spin-lock pulse duration. T1ρ values from gray matter (GM) and white matter (WM) of medial temporal lobe were calculated. The binary logistic regression using T1ρ and CSF biomarkers as variables was performed to classify each group. T1ρ was able to predict 77.3% controls and 40.0% MCI while CSF biomarkers predicted 81.8% controls and 46.7% MCI. T1ρ and CSF biomarkers in combination predicted 86.4% controls and 66.7% MCI. When comparing controls with AD, T1ρ predicted 68.2% controls and 73.9% AD, while CSF biomarkers predicted 77.3% controls and 78.3% for AD. Combination of T1ρ and CSF biomarkers improved the prediction rate to 81.8% for controls and 82.6% for AD. Similarly, on comparing MCI with AD, T1ρ predicted 35.3% MCI and 81.9% AD, whereas CSF biomarkers predicted 53.3% MCI and 83.0% AD. Collectively CSF biomarkers and T1ρ were able to predict 59.3% MCI and 84.6% AD. On receiver operating characteristic analysis T1ρ showed higher sensitivity while CSF biomarkers showed greater specificity in delineating MCI and AD from controls. No significant correlation between T1ρ and CSF biomarkers, between T1ρ and age, and between CSF biomarkers and age was observed. The combined use of T1ρ and CSF biomarkers have promise to improve the early and specific diagnosis of AD. Furthermore, disease progression form MCI to AD might be easily tracked using these two parameters in combination.
    02/2015; 58. DOI:10.1016/j.nicl.2015.02.016
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. Here we report the results of a moderate-scale sequencing study aimed at identifying new genes contributing to predisposition for ALS. We performed whole exome sequencing of 2,874 ALS patients and compared them to 6,405 controls. Several known ALS genes were found to be associated, and the non-canonical IκB kinase family TANK-Binding Kinase 1 (TBK1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention. Copyright © 2015, American Association for the Advancement of Science.
    Science 02/2015; 347(6229). DOI:10.1126/science.aaa3650 · 31.48 Impact Factor
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    ABSTRACT: To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls. Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis. A small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10(-8)). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1. We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD. © 2015 American Academy of Neurology.
    Neurology 02/2015; 84(10). DOI:10.1212/WNL.0000000000001332 · 8.30 Impact Factor
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    ABSTRACT: To determine the independent association of the TMEM106B variants with transactive response DNA binding protein 43 (TDP-43) pathology in older persons without frontotemporal lobar degeneration (FTLD) and to explore functional pathways that link the risk variants to the pathology, including a GRN mRNA pathway. Data came from 544 autopsied participants without FTLD in 2 community-based studies of aging. Participants underwent uniform neuropathologic evaluations, including TDP-43 cytoplasmic inclusions. We examined the association of TMEM106B variants with a semiquantitative measure of TDP-43 pathology in a series of regression analysis. We explored potential pathways by leveraging genetic, brain DNA methylation, miRNA, and transcriptomic data collected from this same group of participants. TDP-43 pathology was identified in 51.7% of the participants. The index single-nucleotide polymorphism (SNP), rs1990622(A), was associated with more advanced TDP-43 pathology. Top hits from fine mapping of the locus were in linkage disequilibrium of the index SNP. The association remained significant after adjustment for other neuropathologies including Alzheimer disease and hippocampal sclerosis (odds ratio = 1.351, 95% confidence interval = 1.068-1.709, p = 0.012). GRN expression was upregulated in rs1990622(AA/AG) carriers, and was associated with more advanced TDP-43 pathology. The TMEM106B variants were associated with lower level of DNA methylation in an active enhancer in GRN. Common variants in TMEM106B serve as a distinct risk factor for TDP-43 pathology in older persons without FTLD. The role of GRN expression and epigenetic mechanisms associating TMEM106B in the accumulation of TDP-43 in older persons require further study. © 2015 American Academy of Neurology.
    Neurology 02/2015; 84(9). DOI:10.1212/WNL.0000000000001313 · 8.30 Impact Factor

Publication Stats

56k Citations
6,961.70 Total Impact Points


  • 1992–2015
    • William Penn University
      • Biology
      Filadelfia, Pennsylvania, United States
  • 1985–2015
    • University of Pennsylvania
      • • Department of Pathology and Laboratory Medicine
      • • Center for Neurodegenerative Disease Research
      • • Department of Neurology
      • • Department of Pathology
      • • Department of Neurosurgery
      • • Department of Psychiatry
      Filadelfia, Pennsylvania, United States
    • Duke University
      Durham, North Carolina, United States
  • 2014
    • University of Tuebingen
      • Department of Psychiatry and Psychotherapy
      Tübingen, Baden-Württemberg, Germany
  • 2012
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2010–2012
    • University of Washington Seattle
      • • Department of Pathology
      • • Department of Medicine
      Seattle, WA, United States
    • Mayo Clinic - Rochester
      • Department of Radiology
      Рочестер, Minnesota, United States
  • 2011
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States
    • University of Gothenburg
      • Department of Psychiatry and Neurochemistry
      Göteborg, Vaestra Goetaland, Sweden
  • 2009
    • Monell Chemical Senses Center
      Philadelphia, Pennsylvania, United States
  • 2007–2009
    • University of California, San Francisco
      San Francisco, California, United States
    • University of Oklahoma Health Sciences Center
      Oklahoma City, Oklahoma, United States
    • Carl von Ossietzky Universität Oldenburg
      Oldenburg, Lower Saxony, Germany
    • Treatment Research Institute, Philadelphia PA
      Philadelphia, Pennsylvania, United States
    • Ludwig-Maximilian-University of Munich
      • Center for Neuropathology and Prion Research
      München, Bavaria, Germany
  • 2008
    • Robarts Research Institute
      London, Ontario, Canada
  • 2005–2006
    • National Institute on Aging
      Baltimore, Maryland, United States
    • In Silico Biosciences, Inc.
      Lexington, Massachusetts, United States
  • 1990–2006
    • The Children's Hospital of Philadelphia
      • Department of Pathology and Laboratory Medicine
      Philadelphia, PA, United States
  • 2004
    • University of North Carolina at Chapel Hill
      North Carolina, United States
    • Drexel University
      Filadelfia, Pennsylvania, United States
  • 2003
    • Johns Hopkins University
      Baltimore, Maryland, United States
  • 2002
    • Goethe-Universität Frankfurt am Main
      Frankfurt, Hesse, Germany
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2001
    • Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
      • Neurorianimazione
      Milano, Lombardy, Italy
  • 1998
    • McGill University
      • Department of Neurology and Neurosurgery
      Montréal, Quebec, Canada
    • American University of Health Sciences
      United States
  • 1997
    • Washington University in St. Louis
      • Department of Neurology
      San Luis, Missouri, United States
  • 1996
    • Hospital of the University of Pennsylvania
      • Department of Pathology and Laboratory Medicine
      Philadelphia, Pennsylvania, United States
  • 1995
    • University of Groningen
      Groningen, Groningen, Netherlands
  • 1994
    • The Philadelphia Center
      Philadelphia, Pennsylvania, United States
  • 1991
    • Duke University Medical Center
      • Department of Pathology
      Durham, NC, United States