John Q Trojanowski

Publications (444)3090.88 Total impact

• Source

  Available from: J. Paul Taylor

  Dataset: Cell Leading Edge on PrLD mutations

  Hong Joo Kim, Nam Chul Kim, Yong-Dong Wang, Emily A. Scarborough, Jennifer Moore, Zamia Diaz, Kyle S. MacLea, Brian Freibaum, Songqing Li, Amandine Molliex, [......], Yun R. Li, Alice Flynn Ford, Aaron D. Gitler, Michael Benatar, Oliver D. King, Virginia E. Kimonis, Eric D. Ross, Conrad C. Weihl, James Shorter, J. Paul Taylor
• Source

  Available from: Stephan Klebe

  Article: A Multicenter Study of Glucocerebrosidase Mutations in Dementia With Lewy Bodies.

  Michael A Nalls, Raquel Duran, Grisel Lopez, Marzena Kurzawa-Akanbi, Ian G McKeith, Patrick F Chinnery, Christopher M Morris, Jessie Theuns, David Crosiers, Patrick Cras, [......], Benoit I Giasson, John Q Trojanowski, Howard I Hurtig, Nahid Tayebi, Claudia Landazabal, Melanie A Knight, Margaux Keller, Andrew B Singleton, Tyra G Wolfsberg, Ellen Sidransky
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  ABSTRACT: IMPORTANCE While mutations in glucocerebrosidase (GBA1) are associated with an increased risk for Parkinson disease (PD), it is important to establish whether such mutations are also a common risk factor for other Lewy body disorders. OBJECTIVE To establish whether GBA1 mutations are a risk factor for dementia with Lewy bodies (DLB). DESIGN We compared genotype data on patients and controls from 11 centers. Data concerning demographics, age at onset, disease duration, and clinical and pathological features were collected when available. We conducted pooled analyses using logistic regression to investigate GBA1 mutation carrier status as predicting DLB or PD with dementia status, using common control subjects as a reference group. Random-effects meta-analyses were conducted to account for additional heterogeneity. SETTING Eleven centers from sites around the world performing genotyping. PARTICIPANTS Seven hundred twenty-one cases met diagnostic criteria for DLB and 151 had PD with dementia. We compared these cases with 1962 controls from the same centers matched for age, sex, and ethnicity. MAIN OUTCOME MEASURES Frequency of GBA1 mutations in cases and controls. RESULTS We found a significant association between GBA1 mutation carrier status and DLB, with an odds ratio of 8.28 (95% CI, 4.78-14.88). The odds ratio for PD with dementia was 6.48 (95% CI, 2.53-15.37). The mean age at diagnosis of DLB was earlier in GBA1 mutation carriers than in noncarriers (63.5 vs 68.9 years; P < .001), with higher disease severity scores. CONCLUSIONS AND RELEVANCE Mutations in GBA1 are a significant risk factor for DLB. GBA1 mutations likely play an even larger role in the genetic etiology of DLB than in PD, providing insight into the role of glucocerebrosidase in Lewy body disease.
  JAMA neurology. 04/2013;
• Article: GWAS of Cerebrospinal Fluid Tau Levels Identifies Risk Variants for Alzheimer's Disease.

  Carlos Cruchaga, John S K Kauwe, Oscar Harari, Sheng Chih Jin, Yefei Cai, Celeste M Karch, Bruno A Benitez, Amanda T Jeng, Tara Skorupa, David Carrell, [......], Richard Mayeux, Margaret A Pericak-Vance, Lindsay A Farrer, Gerard D Schellenberg, Elaine R Peskind, Douglas Galasko, Anne M Fagan, David M Holtzman, John C Morris, Alison M Goate
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  ABSTRACT: Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ42 are established biomarkers for Alzheimer's disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10(-9) for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10(-8) and p = 3.22 × 10(-9) for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10(-8) for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10(-4), 0.039, 4.86 × 10(-5), respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
  Neuron 04/2013; · 14.74 Impact Factor
• Source

  Available from: J. Paul Taylor

  Dataset: nature11922-s1

  Hong Joo Kim, Nam Chul Kim, Yong-Dong Wang, Emily A. Scarborough, Jennifer Moore, Zamia Diaz, Kyle S. MacLea, Brian Freibaum, Songqing Li, Amandine Molliex, [......], Yun R. Li, Alice Flynn Ford, Aaron D. Gitler, Michael Benatar, Oliver D. King, Virginia E. Kimonis, Eric D. Ross, Conrad C. Weihl, James Shorter, J. Paul Taylor
• Article: Comparing PET imaging and CSF measurements of Aß

  Susan M Landau, Ming Lu, Abhinay D Joshi, Michael Pontecorvo, Mark A Mintun, John Q Trojanowski, Leslie M Shaw, William J Jagust
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  ABSTRACT: Objective: We examined agreement and disagreement between two biomarkers of Aß deposition (amyloid PET and CSF Aß1-42 ) in normal aging and dementia in a large multicenter study. Methods: Concurrently acquired florbetapir-PET and CSF Aß were measured in cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease (AD) participants (N=374) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We also compared Aß measurements in a separate group with serial CSF measurements over 3.1 +/- 0.8 yrs that preceded a single florbetapir session. Additional biomarker and cognitive data allowed us to further examine profiles of discordant cases. Results: Florbetapir and CSF Aß were inversely correlated across all diagnostic groups, and dichotomous measurements were in agreement in 86% of subjects. Among subjects showing the most disagreement, the two discordant groups had different profiles: the florbetapir+/CSF Aß- group was larger (N=13) and was made up of only normal and early MCI subjects; while the florbetapir-/CSF Aß+ group was smaller (N=7), had poorer cognitive function and higher CSF tau, but no ApoE4 carriers. In the longitudinal sample, we observed both stable longitudinal CSF Aß trajectories and those actively transitioning from normal to abnormal, but the final CSF Aß measurements were in good agreement with florbetapir cortical retention. Interpretation: CSF and amyloid-PET measurements of Aß were consistent in the majority of subjects in the cross-sectional and longitudinal populations. Based on our analysis of discordant subjects, the available evidence did not show that CSF Aß regularly becomes abnormal prior to fibrillar Aß accumulation early in the course of disease. ANN NEUROL 2013. © 2013 American Neurological Association.
  Annals of Neurology 03/2013; · 11.09 Impact Factor
• Article: Association of plasma and cortical amyloid beta is modulated by APOE ε4 status.

  Shanker Swaminathan, Shannon L Risacher, Karmen K Yoder, John D West, Li Shen, Sungeun Kim, Mark Inlow, Tatiana Foroud, William J Jagust, Robert A Koeppe, Chester A Mathis, Leslie M Shaw, John Q Trojanowski, Holly Soares, Paul S Aisen, Ronald C Petersen, Michael W Weiner, Andrew J Saykin
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  ABSTRACT: BACKGROUND: Apolipoprotein E (APOE) ε4 allele's role as a modulator of the relationship between soluble plasma amyloid beta (Aβ) and fibrillar brain Aβ measured by Pittsburgh compound B positron emission tomography ([(11)C]PiB PET) has not been assessed. METHODS: Ninety-six Alzheimer's Disease Neuroimaging Initiative participants with [(11)C]PiB scans and plasma Aβ1-40 and Aβ1-42 measurements at the time of PET scanning were included. Regional and voxelwise analyses of [(11)C]PiB data were used to determine the influence of APOE ε4 allele on association of plasma Aβ1-40, Aβ1-42, and Aβ1-40/Aβ1-42 with [(11)C]PiB uptake. RESULTS: In APOE ε4- but not ε4+ participants, positive relationships between plasma Aβ1-40/Aβ1-42 and [(11)C]PiB uptake were observed. Modeling the interaction of APOE and plasma Aβ1-40/Aβ1-42 improved the explained variance in [(11)C]PiB binding compared with using APOE and plasma Aβ1-40/Aβ1-42 as separate terms. CONCLUSIONS: The results suggest that plasma Aβ is a potential Alzheimer's disease biomarker and highlight the importance of genetic variation in interpretation of plasma Aβ levels.
  Alzheimer's & dementia: the journal of the Alzheimer's Association 03/2013; · 5.90 Impact Factor
• Article: Clinical Utility and Analytical Challenges in Measurement of Cerebrospinal Fluid Amyloid-β1-42 and τ Proteins as Alzheimer Disease Biomarkers.

  Ju-Hee Kang, Magdalena Korecka, Jon B Toledo, John Q Trojanowski, Leslie M Shaw
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  ABSTRACT: BACKGROUND: Over the past 2 decades, clinical studies have provided evidence that cerebrospinal fluid (CSF) amyloid β1-42 (Aβ1-42), total τ (t-τ), and τ phosphorylated at Thr181 (p-τ181) are reliable biochemical markers of Alzheimer disease (AD) neuropathology.Content:In this review, we summarize the clinical performance and describe the major challenges for the analytical performance of the most widely used immunoassay platforms [based on ELISA or microbead-based multianalyte profiling (xMAP) technology] for the measurement of CSF AD biomarkers (Aβ1-42, t-τ, and p-τ181). With foundational immunoassay data providing the diagnostic and prognostic values of CSF AD biomarkers, the newly revised criteria for the diagnosis of AD include CSF AD biomarkers for use in research settings. In addition, it has been suggested that the selection of AD patients at the predementia stage by use of CSF AD biomarkers can improve the statistical power of clinical trial design. Owing to the lack of a replenishable and commutable human CSF-based standardized reference material (SRM) and significant differences across different immunoassay platforms, the diagnostic-prognostic cutpoints of CSF AD biomarker concentrations are not universal at this time. These challenges can be effectively met in the future, however, through collaborative ongoing standardization efforts to minimize the sources of analytical variability and to develop reference methods and SRMs.Summary:Measurements of CSF Aβ1-42, t-τ, and p-τ181 with analytically qualified immunoassays reliably reflect the neuropathologic hallmarks of AD in patients at the early predementia stage of the disease and even in presymptomatic patients. Thus these CSF biomarker tests are useful for early diagnosis of AD, prediction of disease progression, and efficient design of drug intervention clinical trials.
  Clinical Chemistry 03/2013; · 7.91 Impact Factor
• Article: White matter imaging helps dissociate tau from TDP-43 in frontotemporal lobar degeneration.

  Corey T McMillan, David J Irwin, Brian B Avants, John Powers, Philip A Cook, Jon B Toledo, Elisabeth McCarty Wood, Vivianna M Van Deerlin, Virginia M-Y Lee, John Q Trojanowski, Murray Grossman
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  ABSTRACT: BACKGROUND: Frontotemporal lobar degeneration (FTLD) is most commonly associated with TAR-DNA binding protein (TDP-43) or tau pathology at autopsy, but there are no in vivo biomarkers reliably discriminating between sporadic cases. As disease-modifying treatments emerge, it is critical to accurately identify underlying pathology in living patients so that they can be entered into appropriate etiology-directed clinical trials. Patients with tau inclusions (FTLD-TAU) appear to have relatively greater white matter (WM) disease at autopsy than those patients with TDP-43 (FTLD-TDP). In this paper, we investigate the ability of white matter (WM) imaging to help discriminate between FTLD-TAU and FTLD-TDP during life using diffusion tensor imaging (DTI). METHODS: Patients with autopsy-confirmed disease or a genetic mutation consistent with FTLD-TDP or FTLD-TAU underwent multimodal T1 volumetric MRI and diffusion weighted imaging scans. We quantified cortical thickness in GM and fractional anisotropy (FA) in WM. We performed Eigenanatomy, a statistically robust dimensionality reduction algorithm, and used leave-one-out cross-validation to predict underlying pathology. Neuropathological assessment of GM and WM disease burden was performed in the autopsy-cases to confirm our findings of an ante-mortem GM and WM dissociation in the neuroimaging cohort. RESULTS: ROC curve analyses evaluated classification accuracy in individual patients and revealed 96% sensitivity and 100% specificity for WM analyses. FTLD-TAU had significantly more WM degeneration and inclusion severity at autopsy relative to FTLD-TDP. CONCLUSIONS: These neuroimaging and neuropathological investigations provide converging evidence for greater WM burden associated with FTLD-TAU, and emphasise the role of WM neuroimaging for in vivo discrimination between FTLD-TAU and FTLD-TDP.
  Journal of neurology, neurosurgery, and psychiatry 03/2013; · 4.87 Impact Factor
• Article: Plasma amyloid beta measurements - a desired but elusive Alzheimer's disease biomarker.

  Jon B Toledo, Leslie M Shaw, John Q Trojanowski
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  ABSTRACT: Cerebrospinal fluid and positron emission tomography biomarkers accurately predict an underlying Alzheimer's disease (AD) pathology; however, they represent either invasive or expensive diagnostic tools. Therefore, a blood-based biomarker like plasma amyloid beta (Aβ) that could correlate with the underlying AD pathology and serve as a prognostic biomarker or an AD screening strategy is urgently needed as a cost-effective and non-invasive diagnostic tool. In this paper we review the demographic, biologic, genetic and technical aspects that affect plasma Aβ levels. Findings of cross-sectional and longitudinal studies of plasma Aβ, including autosomal dominant AD cases, sporadic AD cases, Down syndrome cases and population studies, are also discussed. Finally, we review the association between cerebrovascular disease and Aβ plasma levels and the responses observed in clinical trials. Based on our review of the current literature on plasma Aβ, we conclude that further clinical research and assay development are needed before measures of plasma Aβ can be interpreted so they can be applied as trait, risk or state biomarkers for AD.
  Alzheimer's Research and Therapy 03/2013; 5(2):8.
• Article: Neocortical β-amyloid area is associated with dementia and APOE in the oldest-old.

  Daniel J Berlau, María M Corrada, John L Robinson, Felix Geser, Steven E Arnold, Virginia M-Y Lee, Claudia H Kawas, John Q Trojanowski
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  ABSTRACT: OBJECTIVE: Apolipoprotein E (APOE) ε2 carriers may be protected from dementia because of reduced levels of cortical β-amyloid. In the oldest-old, however, APOE ε2 carriers have high β-amyloid plaque scores and preserved cognition. We compared different measures of β-amyloid pathology across APOE genotypes in the oldest-old, and their relationship with dementia. METHODS: The study included 96 participants from The 90+ Study. Using all information, dementia diagnoses were made. Neuropathological examination included staging for amyloid plaques and β-amyloid cortical percent area stained by NAB228 antibody. RESULTS: Both APOE ε2 and APOE ε4 carriers had high Consortium to Establish a Registry for Alzheimer's Disease plaque scores. However, APOE ε2 carriers had low cortical β-amyloid percent areas. β-amyloid percent area was associated with dementia across APOE genotypes. CONCLUSIONS: Lower levels of percent area in APOE ε2 carriers may reflect lower total β-amyloid and may contribute to APOE ε2 carriers' decreased risk of dementia, despite high β-amyloid plaque scores. The relationship between β-amyloid plaques and dementia in the oldest-old may vary by APOE genotype.
  Alzheimer's & dementia: the journal of the Alzheimer's Association 03/2013; · 5.90 Impact Factor
• Source

  Available from: J. Paul Taylor

  Article: Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS

  Hong Joo Kim, Nam Chul Kim, Yong-Dong Wang, Emily A. Scarborough, Jennifer Moore, Zamia Diaz, Kyle S. MacLea, Brian Freibaum, Songqing Li, Amandine Molliex, [......], Yun R. Li, Alice Flynn Ford, Aaron D. Gitler, Michael Benatar, Oliver D. King, Virginia E. Kimonis, Eric D. Ross, Conrad C. Weihl, James Shorter, J. Paul Taylor
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  ABSTRACT: Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a ‘steric zipper’ motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.
  Nature 03/2013; · 36.28 Impact Factor
• Article: Plasma apolipoprotein A1 as a biomarker for parkinson's disease.

  Judy K Qiang, Yvette C Wong, Andrew Siderowf, Howard I Hurtig, Sharon X Xie, Virginia M-Y Lee, John Q Trojanowski, Dora Yearout, James Leverenz, Thomas J Montine, Matt Stern, Susan Mendick, Danna Jennings, Cyrus Zabetian, Ken Marek, Alice S Chen-Plotkin
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  ABSTRACT: OBJECTIVE: To identify plasma-based biomarkers for Parkinson's Disease (PD) risk. METHODS: In a discovery cohort of 152 PD patients, plasma levels of 96 proteins were measured by multiplex immunoassay; proteins associated with age at PD onset were identified by linear regression. Findings from discovery screening were then assessed in a second cohort of 187 PD patients, using a different technique. Finally, in a third cohort of at-risk, asymptomatic individuals enrolled in the Parkinson's Associated Risk Study (PARS, n=134), plasma levels of the top candidate biomarker were measured, and dopamine transporter (DAT) imaging performed, to evaluate the association of plasma protein levels with dopaminergic system integrity. RESULTS: One of the best candidate protein biomarkers to emerge from discovery screening was apolipoprotein A1 (ApoA1, p=0.001). Low levels of ApoA1 correlated with earlier PD onset, with a 26% decrease in risk of developing PD associated with each tertile increase in ApoA1 (Cox proportional hazards p<0.001, hazard ratio=0.742). The association between plasma ApoA1 levels and age at PD onset replicated in an independent cohort of PD patients (p<0.001). Finally, in the PARS cohort of high-risk, asymptomatic subjects, lower plasma levels of ApoA1 were associated with greater putaminal DAT deficit (p=0.037). INTERPRETATION: Lower ApoA1 levels correlate with dopaminergic system vulnerability in symptomatic PD patients and in asymptomatic individuals with physiological reductions in dopamine transporter density consistent with prodromal PD. Plasma ApoA1 may be a new biomarker for PD risk. ANN NEUROL 2010.
  Annals of Neurology 02/2013; · 11.09 Impact Factor
• Article: Aminothienopyridazines and Methylene Blue affect Tau Fibrillization via Cysteine Oxidation.

  Alex Crowe, Michael J James, Virginia M-Y Lee, Amos B Smith, John Q Trojanowski, Carlo Ballatore, Kurt R Brunden
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  ABSTRACT: Alzheimers disease (AD)and several other neurodegenerative disorders are characterized by the accumulation of intraneuronal fibrils comprised of the protein tau. Tau is normally a soluble protein that stabilizes microtubules, with splice isoforms that contain either three (3-R) or four (4-R) microtubule-binding repeats. The formation of tau fibrils is thought to result in neuronal damage, and inhibitors of tau fibrillization may hold promise as therapeutic agents. The process of tau fibrillization can be replicated in vitro and a number of small molecules have been identified which inhibit tau fibril formation. However, little is known about how these molecules affect tau fibrillization. Here, we examined the mechanism by which the previously described aminothienopyridazine (ATPZ) series of compounds inhibit tau fibrillization. Active ATPZs were found to promote the oxidation of the two cysteine residues within 4-R tau by a redox cycling mechanism, resulting in the formation of a disulfide-containing compact monomer that was refractory to fibrillization. Moreover, the ATPZs facilitated intermolecular disulfide formation between 3-R tau monomers, leading to dimers that were capable of fibrillization. The ATPZs also caused cysteine oxidation in molecules unrelated to tau. Interestingly, methylene blue (MB), an inhibitor of tau fibrillization under evaluation in AD clinical trials, causes a similar oxidation of cysteines in tau and other molecules. These findings reveal that the ATPZs and MB act by a mechanism that may affect their viability as potential therapeutic agents.
  Journal of Biological Chemistry 02/2013; · 4.77 Impact Factor
• Source

  Available from: Konrad Talbot

  Dataset: Talbot-Wang - Brain Insulin Resistance in AD Suppl Data 4-2-12

  Konrad Talbot, Hoau-Yan Wang, Hala Kazi, Li-Ying Han, Kalindi P Bakshi, Andres Stucky, Robert L Fuino, Krista R Kawaguchi, Andrew J Samoyedny, Robert S Wilson, Zoe Arvanitakis, Julie A Schneider, Bryan A Wolf, David A Bennett, John Q Trojanowski, Steven E Arnold
• Source

  Available from: Konrad Talbot

  Dataset: Talbot-Wang - Brain Insulin Resistance in AD Suppl Data 4-2-12

  Konrad Talbot, Hoau-Yan Wang, Hala Kazi, Li-Ying Han, Kalindi P Bakshi, Andres Stucky, Robert L Fuino, Krista R Kawaguchi, Andrew J Samoyedny, Robert S Wilson, Zoe Arvanitakis, Julie A Schneider, Bryan A Wolf, David A Bennett, John Q Trojanowski, Steven E Arnold
• Article: Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers.

  Clifford R Jack, David S Knopman, William J Jagust, Ronald C Petersen, Michael W Weiner, Paul S Aisen, Leslie M Shaw, Prashanthi Vemuri, Heather J Wiste, Stephen D Weigand, Timothy G Lesnick, Vernon S Pankratz, Michael C Donohue, John Q Trojanowski
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  ABSTRACT: In 2010, we put forward a hypothetical model of the major biomarkers of Alzheimer's disease (AD). The model was received with interest because we described the temporal evolution of AD biomarkers in relation to each other and to the onset and progression of clinical symptoms. Since then, evidence has accumulated that supports the major assumptions of this model. Evidence has also appeared that challenges some of our assumptions, which has allowed us to modify our original model. Refinements to our model include indexing of individuals by time rather than clinical symptom severity; incorporation of interindividual variability in cognitive impairment associated with progression of AD pathophysiology; modifications of the specific temporal ordering of some biomarkers; and recognition that the two major proteinopathies underlying AD biomarker changes, amyloid β (Aβ) and tau, might be initiated independently in sporadic AD, in which we hypothesise that an incident Aβ pathophysiology can accelerate antecedent limbic and brainstem tauopathy.
  The Lancet Neurology 02/2013; 12(2):207-216. · 23.46 Impact Factor
• Article: APOE ϵ4 Increases Risk for Dementia in Pure Synucleinopathies.

  Debby Tsuang, James B Leverenz, Oscar L Lopez, Ronald L Hamilton, David A Bennett, Julie A Schneider, Aron S Buchman, Eric B Larson, Paul K Crane, Jeffrey A Kaye, [......], Doug Galasko, Eliezer Masliah, Joseph F Quinn, Kathryn A Chung, Dora Yearout, Ignacio F Mata, Jia Y Wan, Karen L Edwards, Thomas J Montine, Cyrus P Zabetian
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  ABSTRACT: OBJECTIVE To test for an association between the apolipoprotein E (APOE) ϵ4 allele and dementias with synucleinopathy. DESIGN Genetic case-control association study. SETTING Academic research. PATIENTS Autopsied subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD group; n = 244), dementia with LBDNCs and high-level ADNCs (LBD-AD group; n = 224), dementia with LBDNCs and no or low levels of ADNCs (pure DLB [pDLB] group; n = 91), Parkinson disease dementia (PDD) with no or low levels of ADNCs (n = 81), and control group (n = 269). MAIN OUTCOME MEASURE The APOE allele frequencies. RESULTS The APOE ϵ4 allele frequency was significantly higher in the AD (38.1%), LBD-AD (40.6%), pDLB (31.9%), and PDD (19.1%) groups compared with the control group (7.2%; overall χ24 = 185.25; P = 5.56 × 10-39), and it was higher in the pDLB group than the PDD group (P = .01). In an age-adjusted and sex-adjusted dominant model, ϵ4 was strongly associated with AD (odds ratio, 9.9; 95% CI, 6.4-15.3), LBD-AD (odds ratio, 12.6; 95% CI, 8.1-19.8), pDLB (odds ratio, 6.1; 95% CI, 3.5-10.5), and PDD (odds ratio, 3.1; 95% CI, 1.7-5.6). CONCLUSIONS The APOE ϵ4 allele is a strong risk factor across the LBD spectrum and occurs at an increased frequency in pDLB relative to PDD. This suggests that ϵ4 increases the likelihood of presenting with dementia in the context of a pure synucleinopathy. The elevated ϵ4 frequency in the pDLB and PDD groups, in which the overall brain neuritic plaque burden was low, indicates that apoE might contribute to neurodegeneration through mechanisms unrelated to amyloid processing.
  JAMA neurology. 02/2013; 70(2):223-8.
• Article: Synthetic Tau Fibrils Mediate Transmission of Neurofibrillary Tangles in a Transgenic Mouse Model of Alzheimer's-Like Tauopathy.

  Michiyo Iba, Jing L Guo, Jennifer D McBride, Bin Zhang, John Q Trojanowski, Virginia M-Y Lee
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  ABSTRACT: Tauopathies, including Alzheimer's disease (AD) and frontotemporal lobar degeneration with tau pathologies, are neurodegenerative diseases characterized by neurofibrillary tangles (NFTs) comprising filamentous tau protein. Although emerging evidence suggests that tau pathology may be transmitted, we demonstrate here that synthetic tau fibrils are sufficient to transmit tau inclusions in a mouse model. Specifically, intracerebral inoculation of young PS19 mice overexpressing mutant human tau (P301S) with synthetic preformed fibrils (pffs) assembled from recombinant full-length tau or truncated tau containing four microtubule binding repeats resulted in rapid induction of NFT-like inclusions that propagated from injected sites to connected brain regions in a time-dependent manner. Interestingly, injection of tau pffs into either hippocampus or striatum together with overlaying cortex gave rise to distinct pattern of spreading. Moreover, unlike tau pathology that spontaneously develops in old PS19 mice, the pff-induced tau inclusions more closely resembled AD NFTs because they were Thioflavin S positive, acetylated, and more resistant to proteinase K digestion. Together, our study demonstrates that synthetic tau pffs alone are capable of inducing authentic NFT-like tau aggregates and initiating spreading of tau pathology in a tauopathy mouse model.
  Journal of Neuroscience 01/2013; 33(3):1024-37. · 7.11 Impact Factor
• Article: Relationship between Plasma Analytes and SPARE-AD Defined Brain Atrophy Patterns in ADNI.

  Jon B Toledo, Xiao Da, Priyanka Bhatt, David A Wolk, Steven E Arnold, Leslie M Shaw, John Q Trojanowski, Christos Davatzikos
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  ABSTRACT: Different inflammatory and metabolic pathways have been associated with Alzheimeŕs disease (AD). However, only recently multi-analyte panels to study a large number of molecules in well characterized cohorts have been made available. These panels could help identify molecules that point to the affected pathways. We studied the relationship between a panel of plasma biomarkers (Human DiscoveryMAP®) and presence of AD-like brain atrophy patterns defined by a previously published index (SPARE-AD) at baseline in subjects of the ADNI cohort. 818 subjects had MRI-derived SPARE-AD scores, of these subjects 69% had plasma biomarkers and 51% had CSF tau and Aβ measurements. Significant analyte-SPARE-AD and analytes correlations were studied in adjusted models. Plasma cortisol and chromogranin A showed a significant association that did not remain significant in the CSF signature adjusted model. Plasma macrophage inhibitory protein-1α and insulin-like growth factor binding protein 2 showed a significant association with brain atrophy in the adjusted model. Cortisol levels showed an inverse association with tests measuring processing speed. Our results indicate that stress and insulin responses and cytokines associated with recruitment of inflammatory cells in MCI-AD are associated with its characteristic AD-like brain atrophy pattern and correlate with clinical changes or CSF biomarkers.
  PLoS ONE 01/2013; 8(2):e55531. · 4.09 Impact Factor
• Article: Inflammation and white matter degeneration persist for years after a single traumatic brain injury.

  Victoria E Johnson, Janice E Stewart, Finn D Begbie, John Q Trojanowski, Douglas H Smith, William Stewart
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  ABSTRACT: A single traumatic brain injury is associated with an increased risk of dementia and, in a proportion of patients surviving a year or more from injury, the development of hallmark Alzheimer's disease-like pathologies. However, the pathological processes linking traumatic brain injury and neurodegenerative disease remain poorly understood. Growing evidence supports a role for neuroinflammation in the development of Alzheimer's disease. In contrast, little is known about the neuroinflammatory response to brain injury and, in particular, its temporal dynamics and any potential role in neurodegeneration. Cases of traumatic brain injury with survivals ranging from 10 h to 47 years post injury (n = 52) and age-matched, uninjured control subjects (n = 44) were selected from the Glasgow Traumatic Brain Injury archive. From these, sections of the corpus callosum and adjacent parasaggital cortex were examined for microglial density and morphology, and for indices of white matter pathology and integrity. With survival of ≥3 months from injury, cases with traumatic brain injury frequently displayed extensive, densely packed, reactive microglia (CR3/43- and/or CD68-immunoreactive), a pathology not seen in control subjects or acutely injured cases. Of particular note, these reactive microglia were present in 28% of cases with survival of >1 year and up to 18 years post-trauma. In cases displaying this inflammatory pathology, evidence of ongoing white matter degradation could also be observed. Moreover, there was a 25% reduction in the corpus callosum thickness with survival >1 year post-injury. These data present striking evidence of persistent inflammation and ongoing white matter degeneration for many years after just a single traumatic brain injury in humans. Future studies to determine whether inflammation occurs in response to or, conversely, promotes white matter degeneration will be important. These findings may provide parallels for studying neurodegenerative disease, with traumatic brain injury patients serving as a model for longitudinal investigations, in particular with a view to identifying potential therapeutic interventions.
  Brain 01/2013; 136(Pt 1):28-42. · 9.46 Impact Factor