Rare coding variants in PLCG2, ABI3, ad TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
July 2017 | Rebecca Sims, Sven J van der Lee, Adam C Naj, Céline Bellenguez, Nandini Badarinarayan, Johanna Jakobsdottir, Brian W Kunkle, Anne Boland, Rachel Raybould, Joshua C Bis, Eden R Martin, Benjamin Grenier-Boley, Stefanie Heilmann-Heimbach, Vincent Chouraki, Amanda B Kuzma, Kristel Sleegers, Maria Vronskaya, Agustin Ruiz, Robert R Graham, Robert Olaso, Per Hoffmann, Megan L Grove, Badri N Vardarajan, Mikko Hiltunen, Markus M Nöthen, et al.
ABSTRACT: We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
Unique pathological tau conformers from Alzheimer's brains transmit tau pathology in nontransgenic mice
October 2016 | Jing L. Guo, Sneha Narasimhan, Lakshmi Changolkar, Zhuohao He, Anna Stieber, Bin Zhang, Ronald J. Gathagan, Michiyo Iba, Jennifer D. McBride, John Q. Trojanowski, Virginia M.Y. Lee
ABSTRACT: Filamentous tau aggregates are hallmark lesions in numerous neurodegenerative diseases, including Alzheimer’s disease (AD). Cell culture and animal studies showed that tau fibrils can undergo cell-to-cell transmission and seed aggregation of soluble tau, but this phenomenon was only robustly demonstrated in models overexpressing tau. In this study, we found that intracerebral inoculation of tau fibrils purified from AD brains (AD-tau), but not synthetic tau fibrils, resulted in the formation of abundant tau inclusions in anatomically connected brain regions in nontransgenic mice. Recombinant human tau seeded by AD-tau revealed unique conformational features that are distinct from synthetic tau fibrils, which could underlie the differential potency in seeding physiological levels of tau to aggregate. Therefore, our study establishes a mouse model of sporadic tauopathies and points to important differences between tau fibrils that are generated artificially and authentic ones that develop in AD brains.
Association of Antipsychotic Use With Mortality Risk in Patients With Parkinson Disease
March 2016 | Daniel Weintraub, MD; Claire Chiang, PhD; Hyungjin Myra Kim, ScD; Jayne Wilkinson, MD, MSCE; Connie Marras, MD, PhD; Barbara Stanislawski, MPH, MSW; Eugenia Mamikonyan, MS; Helen C. Kales, MD
AbstractImportance: As many as 60% of patients with Parkinson disease (PD) experience psychosis, 80% develop dementia, and the use of antipsychotics (APs) in the population with PD is common. The use of APs by patients with dementia in the general population is associated with increased mortality, but whether this risk extends to patients with PD remains unknown.
Objective: To determine whether AP use in patients with PD is associated with increased mortality.
Design, Setting, and Participants: This retrospective matched-cohort study used data from a Veterans Health Administration database from fiscal years 1999 to 2010 to examine the risk associated with AP use in a cohort of patients with idiopathic PD and recent stable physical health. The rates of 180-day mortality were compared in 7877 patients initiating AP therapy and 7877 patients who did not initiate AP therapy (matched for age ±2.5 years, sex, race, index year, presence and duration of dementia, PD duration, delirium, hospitalization, Charlson Comorbidity Index, and new nonpsychiatric medications). Data were analyzed from October 19, 2012, to September 21, 2015.
Main Outcomes and Measures: Mortality rates at 180 days in those patients who initiated AP therapy compared with matched patients who did not use APs. Cox proportional hazards regression models were used with intent-to-treat (ITT) and exposure-only analyses.
Results: The study population included 7877 matched pairs of patients with PD (65 women [0.8%] and 7812 men [99.2%] in each cohort; mean [SD] age, 76.3 [7.7] years for those who initiated AP therapy and 76.4 [7.6] years for those who did not). Antipsychotic use was associated with more than twice the hazard ratio (HR) of death compared with nonuse (ITT HR, 2.35; 95% CI, 2.08-2.66; P < .001). The HR was significantly higher for patients who used typical vs atypical APs (ITT HR, 1.54; 95% CI, 1.24-1.91; P < .001). Among the atypical APs used, HRs relative to nonuse of APs in descending order were 2.79 (95% CI, 1.97-3.96) for olanzapine, 2.46 (95% CI, 1.94-3.12) for risperidone, and 2.16 (95% CI, 1.88-2.48) for quetiapine fumarate.
Conclusions and Relevance: Use of APs is associated with a significantly increased mortality risk in patients with PD, after adjusting for measurable confounders. This finding highlights the need for cautious use of APs in patients with PD. Future studies should examine the role of nonpharmacologic strategies in managing psychosis in PD. In addition, new pharmacologic treatments that do not increase mortality in patients with neurodegenerative diseases need to be developed.
Penn Medicine Researchers Pinpoint Potential New Drug Target for Protection against Certain Neurodegenerative Diseases
March 2015 | Corey T. McMillan, Jenny Russ, Elisabeth M. Wood, David J. Irwin, Murray Grossman, Leo McCluskey, Lauren Elman, Vivianna Van Deerlin, Edward B. Lee
Penn Medicine researchers have discovered that hypermethylation - the epigenetic ability to turn down or turn off a bad gene implicated in 10 to 30 percent of patients with Amyotrophic lateral sclerosis (ALS) and Frontotemporal Degeneration (FTD) - serves as a protective barrier inhibiting the development of these diseases. Their work, published this month in Neurology, may suggest a neuroprotective target for drug discovery efforts.
"This is the first epigenetic modification of a gene that seems to be protective against neuronal disease," says lead author Corey McMillan, PhD, research assistant professor of Neurology in the Frontotemporal Degeneration Center in the Perelman School of Medicine at the University of Pennsylvania.
Expansions in the offending gene, c9orf72, have been linked with TAR DNA binding protein (TDP-43) which is the pathological source that causes ALS and FTD. "Understanding the role of C9orf72 has the possibility to be truly translational and improve the lives of patients suffering from these devastating diseases," says senior author, Edward Lee, PhD, assistant professor of Neuropathology in Pathology and Laboratory Medicine at Penn.
McMillan and team evaluated 20 patients recruited from both the FTD Center and the ALS Center at the University of Pennsylvania who screen positive for a mutation in the C9orf72 gene and were clinically diagnosed with FTD or ALS. All patients completed a neuroimaging study, a blood test to evaluate C9orf72 methylation levels, and a brief neuropsychological screening assessment. The study also included 25 health controls with no history of neurological or psychiatric disease.
MRI revealed recuded grey matter in several regions that were affected in patients compared to controls. Grey matter is needed for the proper function of the brain in regions involved with muscle control, memory, emotions, speech and decision-making. Critically, patients with hypermethylation of C9orf72 showed more dense grey matter in the hippocampus, frontal cortex, and thalamus, regions of the brain important for the above described tasks and affected in ALS and FTD, suggesting that hypermethylation is neuroprotective in these regions.
To validate these findings, the Penn team also looked at autopsies of 35 patients with C9orf72 expansions and found that their pathology also suggested that increased methylation was associated with reduced neuronal loss in both the frontal cortex and hippocampus.
Longitudinal analysis was performed in 11 of the study patients to evaluate the neuroprotective effects of hypermethylation in individuals over their disease course. This showed reduced changes in grey matter of the hippocampus, thalamus, and frontal cortex, associated with hypermethylation suggesting that disease progresses more slowly over time in individuals with C9orf72 hypermethylation. Longitudinal neuropsychological assessments also showed a correlation between protected memory decline and hypermethylation.
These findings are consistent with a growing number of studies which have suggested the neuroprotective effects of the hypermethylation of C9orf72. "We believe that this work provides additional data supporting the notion that C9orf72 methylation is neuroprotective and therefore opens up the exciting possibility of a new avenue for precision medicine treatments and targets for drug development in neurodegenerative disease," says McMillan.
This research was funded by the National Institutes of Health (AG043503, AG017586, AG039510, AG10124, AG032953) and the Wyncote Foundation. Dr. Lee is supported by the Doris Duke Charitable Foundation Clinical Scientist Development Award.
More CNDR & Neurodegenerative Disease-related Publications
Ann Neurol. 2017 Jul 18; Authors: Irwin DJ, Lleó A, Xie SX, McMillan CT, Wolk D, Lee EB, Van Deerlin VM, Shaw LM, Trojanowski JQ, Grossman M
Clinically silent Alzheimer's and vascular pathologies influence brain networks supporting executive function in healthy older adults.
Neurobiol Aging. 2017 Jun 24; Authors: Gold BT, Brown CA, Hakun JG, Shaw LM, Trojanowski JQ, Smith CD
Phosphorylated neurofilament heavy chain: A biomarker of survival for C9ORF72-associated amyotrophic lateral sclerosis.
Ann Neurol. 2017 Jun 19; Authors: Gendron TF, Daughrity LM, Heckman MG, Diehl NN, Wuu J, Miller TM, Pastor P, Trojanowski JQ, Grossman M, Berry JD, Hu WT, Ratti A, Benatar M, Silani V, Glass JD, Floeter MK, Jeromin A, Boylan KB, Petrucelli L, C9ORF72 Neurofilament Study Group
Regional brain amyloid-β accumulation associates with domain-specific cognitive performance in Parkinson disease without dementia.
PLoS One. 2017 May 25; Authors: Akhtar RS, Xie SX, Chen YJ, Rick J, Gross RG, Nasrallah IM, Van Deerlin VM, Trojanowski JQ, Chen-Plotkin AS, Hurtig HI, Siderowf AD, Dubroff JG, Weintraub D
Neurology. 2017 May 17; Authors: Giannini LAA, Irwin DJ, McMillan CT, Ash S, Rascovsky K, Wolk DA, Van Deerlin VM, Lee EB, Trojanowski JQ, Grossman M
Novel conformation-selective alpha-synuclein antibodies raised against different in vitro fibril forms show distinct patterns of Lewy pathology in Parkinson's disease.
Neuropathol Appl Neurobiol. 2017 Apr 07; Authors: Covell DJ, Robinson JL, Akhtar RS, Grossman M, Weintraub D, Bucklin HM, Pitkin RM, Riddle D, Yousef A, Trojanowski JQ, Lee VM
Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis.
Sci Transl Med. 2017 Mar 29;9(383): Authors: Gendron TF, Chew J, Stankowski JN, Hayes LR, Zhang YJ, Prudencio M, Carlomagno Y, Daughrity LM, Jansen-West K, Perkerson EA, O'Raw A, Cook C, Pregent L, Belzil V, van Blitterswijk M, Tabassian LJ, Lee CW, Yue M, Tong J, Song Y, Castanedes-Casey M, Rousseau L, Phillips V, Dickson DW, Rademakers R, Fryer JD, Rush BK, Pedraza O, Caputo AM, Desaro P, Palmucci C, Robertson A, Heckman MG, Diehl NN, Wiggs E, Tierney M, Braun L, Farren J, Lacomis D, Ladha S, Fournier CN, McCluskey LF, Elman LB, Toledo JB, McBride JD, Tiloca C, Morelli C, Poletti B, Solca F, Prelle A, Wuu J, Jockel-Balsarotti J, Rigo F, Ambrose C, Datta A, Yang W, Raitcheva D, Antognetti G, McCampbell A, Van Swieten JC, Miller BL, Boxer AL, Brown RH, Bowser R, Miller TM, Trojanowski JQ, Grossman M, Berry JD, Hu WT, Ratti A, Traynor BJ, Disney MD, Benatar M, Silani V, Glass JD, Floeter MK, Rothstein JD, Boylan KB, Petrucelli L
Evaluating the Patterns of Aging-Related Tau Astrogliopathy Unravels Novel Insights Into Brain Aging and Neurodegenerative Diseases.
J Neuropathol Exp Neurol. 2017 Mar 14; Authors: Kovacs GG, Robinson JL, Xie SX, Lee EB, Grossman M, Wolk DA, Irwin DJ, Weintraub D, Kim CF, Schuck T, Yousef A, Wagner ST, Suh E, Van Deerlin VM, Lee VM, Trojanowski JQ
Alzheimers Dement. 2017 Feb 04; Authors: Sposato LA, Ruíz Vargas E, Riccio PM, Toledo JB, Trojanowski JQ, Kukull WA, Cipriano LE, Nucera A, Whitehead SN, Hachinski V
Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration.
Acta Neuropathol. 2017 Jan 27; Authors: Lee EB, Porta S, Michael Baer G, Xu Y, Suh E, Kwong LK, Elman L, Grossman M, Lee VM, Irwin DJ, Van Deerlin VM, Trojanowski JQ
Non-Naturally Occurring Small Molecule Microtubule-Stabilizing Agents: A Potential Tactic for CNS-Directed Therapies.
ACS Chem Neurosci. 2017 Jan 18; Authors: Ballatore C, Brunden KR, Trojanowski JQ, Lee VM, Smith AB
Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis.
Lancet Neurol. 2017 Jan; Authors: Irwin DJ, Grossman M, Weintraub D, Hurtig HI, Duda JE, Xie SX, Lee EB, Van Deerlin VM, Lopez OL, Kofler JK, Nelson PT, Jicha GA, Woltjer R, Quinn JF, Kaye J, Leverenz JB, Tsuang D, Longfellow K, Yearout D, Kukull W, Keene CD, Montine TJ, Zabetian CP, Trojanowski JQ
Tauopathy with hippocampal 4-repeat tau immunoreactive spherical inclusions: a report of three cases.
Brain Pathol. 2016 Dec 26; Authors: Kovacs GG, Kwong LK, Grossman M, Irwin DJ, Lee EB, Robinson JL, Suh E, Van Deerlin VM, Lee VM, Trojanowski JQ
Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs.
Neurobiol Dis. 2016 Dec 21; Authors: Brunden KR, Lee VM, Smith AB, Trojanowski JQ, Ballatore C
Longitudinal imaging reveals sub-hippocampal dynamics in glutamate levels associated with histopathologic events in a mouse model of tauopathy and healthy mice.
Hippocampus. 2016 Dec 20; Authors: Crescenzi R, DeBrosse C, Nanga RP, Byrne MD, Krishnamoorthy G, D'Aquilla K, Nath H, Morales KH, Iba M, Hariharan H, Lee VM, Detre JA, Reddy R
Mov Disord. 2016 Dec; Authors: Willis AW, Thibault DP, Schmidt PN, Dorsey ER, Weintraub D
Development, validation and application of a new fornix template for studies of aging and preclinical Alzheimer's disease.
Neuroimage Clin. 2016 Nov 26; Authors: Brown CA, Johnson NF, Anderson-Mooney AJ, Jicha GA, Shaw LM, Trojanowski JQ, Van Eldik LJ, Schmitt FA, Smith CD, Gold BT
Unique pathological tau conformers from Alzheimer's brains transmit tau pathology in nontransgenic mice.
J Exp Med. 2016 Oct 17; Authors: Guo JL, Narasimhan S, Changolkar L, He Z, Stieber A, Zhang B, Gathagan RJ, Iba M, McBride JD, Trojanowski JQ, Lee VM
Sci Rep. 2016 Oct 10; Authors: Imamura K, Sahara N, Kanaan NM, Tsukita K, Kondo T, Kutoku Y, Ohsawa Y, Sunada Y, Kawakami K, Hotta A, Yawata S, Watanabe D, Hasegawa M, Trojanowski JQ, Lee VM, Suhara T, Higuchi M, Inoue H
Alzheimers Dement. 2016 Oct; Authors: Khanna MR, Kovalevich J, Lee VM, Trojanowski JQ, Brunden KR
Evaluation of the brain-penetrant microtubule-stabilizing agent, dictyostatin, in the PS19 tau transgenic mouse model of tauopathy.
Acta Neuropathol Commun. 2016; Authors: Makani V, Zhang B, Han H, Yao Y, Lassalas P, Lou K, Paterson I, Lee VM, Trojanowski JQ, Ballatore C, Smith AB, Brunden KR
Progression of motor neuron disease is accelerated and the ability to recover is compromised with advanced age in rNLS8 mice.
Acta Neuropathol Commun. 2016; Authors: Spiller KJ, Restrepo CR, Khan T, Stieber AM, Kwong LK, Trojanowski JQ, Lee VM
Neurology. 2016 Sep 28; Authors: Placek K, Massimo L, Olm C, Ternes K, Firn K, Van Deerlin V, Lee EB, Trojanowski JQ, Lee VM, Irwin D, Grossman M, McMillan CT
Cereb Cortex. 2016 Sep 24; Authors: Wisse LE, Adler DH, Ittyerah R, Pluta JB, Robinson JL, Schuck T, Trojanowski JQ, Grossman M, Detre JA, Elliott MA, Toledo JB, Liu W, Pickup S, Das SR, Wolk DA, Yushkevich PA
Neuropathol Appl Neurobiol. 2016 Sep 22; Authors: Brettschneider J, Irwin DJ, Boluda S, Byrne MD, Fang L, Lee EB, Robinson JL, Suh E, Van Deerlin VM, Toledo JB, Grossman M, Hurtig H, Dengler R, Petri S, Lee VM, Trojanowski JQ
Neurobiol Aging. 2016 Sep 2; Authors: Kun-Rodrigues C, Ross OA, Orme T, Shepherd C, Parkkinen L, Darwent L, Hernandez D, Ansorge O, Clark LN, Honig LS, Marder K, Lemstra A, Scheltens P, van der Flier W, Louwersheimer E, Holstege H, Rogaeva E, St George-Hyslop P, Londos E, Zetterberg H, Barber I, Braae A, Brown K, Morgan K, Maetzler W, Berg D, Troakes C, Al-Sarraj S, Lashley T, Holton J, Compta Y, Van Deerlin V, Trojanowski JQ, Serrano GE, Beach TG, Clarimon J, Lleó A, Morenas-Rodríguez E, Lesage S, Galasko D, Masliah E, Santana I, Diez M, Pastor P, Tienari PJ, Myllykangas L, Oinas M, Revesz T, Lees A, Boeve BF, Petersen RC, Ferman TJ, Escott-Price V, Graff-Radford N, Cairns NJ, Morris JC, Stone DJ, Pickering-Brown S, Mann D, Dickson DW, Halliday GM, Singleton A, Guerreiro R, Bras J
Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson's disease.
J Exp Med. 2016 Aug 8; Authors: Rey NL, Steiner JA, Maroof N, Luk KC, Madaj Z, Trojanowski JQ, Lee VM, Brundin P
Amyloid-Beta Positron Emission Tomography Imaging of Alzheimer's Pathology in Parkinson's Disease Dementia.
Mov Disord Clin Pract. 2016 Jul-Aug; Authors: Akhtar RS, Xie SX, Brennan L, Pontecorvo MJ, Hurtig HI, Trojanowski JQ, Weintraub D, Siderowf AD
Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.
Nat Genet. 2016 Jul 25; Authors: van Rheenen W, Shatunov A, Dekker AM, McLaughlin RL, Diekstra FP, Pulit SL, van der Spek RA, Võsa U, de Jong S, Robinson MR, Yang J, Fogh I, van Doormaal PT, Tazelaar GH, Koppers M, Blokhuis AM, Sproviero W, Jones AR, Kenna KP, van Eijk KR, Harschnitz O, Schellevis RD, Brands WJ, Medic J, et al.
Selective Motor Neuron Resistance and Recovery in a New Inducible Mouse Model of TDP-43 Proteinopathy.
J Neurosci. 2016 Jul 20; Authors: Spiller KJ, Cheung CJ, Restrepo CR, Kwong LK, Stieber AM, Trojanowski JQ, Lee VM
Neuron. 2016 Jun 15; Authors: Lee S, Shang Y, Redmond SA, Urisman A, Tang AA, Li KH, Burlingame AL, Pak RA, Jovičić A, Gitler AD, Wang J, Gray NS, Seeley WW, Siddique T, Bigio EH, Lee VM, Trojanowski JQ, Chan JR, Huang EJ
Correction: Comparison of strategies for non-perturbing labeling of α-synuclein to study amyloidogenesis.
Org Biomol Chem. 2016 May 12; Authors: Haney CM, Wissner RF, Warner JB, Wang YJ, Ferrie JJ, Covell DJ, Karpowicz RJ, Lee VM, Petersson EJ
Relationship between APOE Genotype and Structural MRI Measures throughout Adulthood in the Study of Health in Pomerania Population-Based Cohort.
AJNR Am J Neuroradiol. 2016 May 12; Authors: Habes M, Toledo JB, Resnick SM, Doshi J, Van der Auwera S, Erus G, Janowitz D, Hegenscheid K, Homuth G, Völzke H, Hoffmann W, Grabe HJ, Davatzikos C
Features of Patients With Nonfluent/Agrammatic Primary Progressive Aphasia With Underlying Progressive Supranuclear Palsy Pathology or Corticobasal Degeneration.
JAMA Neurol. 2016 Apr 25; Authors: Santos-Santos MA, Mandelli ML, Binney RJ, Ogar J, Wilson SM, Henry ML, Hubbard HI, Meese M, Attygalle S, Rosenberg L, Pakvasa M, Trojanowski JQ, Grinberg LT, Rosen H, Boxer AL, Miller BL, Seeley WW, Gorno-Tempini ML
Defining and validating a short form Montreal Cognitive Assessment (s-MoCA) for use in neurodegenerative disease.
J Neurol Neurosurg Psychiatry. 2016 Apr 12; Authors: Roalf DR, Moore TM, Wolk DA, Arnold SE, Mechanic-Hamilton D, Rick J, Kabadi S, Ruparel K, Chen-Plotkin AS, Chahine LM, Dahodwala NA, Duda JE, Weintraub DA, Moberg PJ
Advanced brain aging: relationship with epidemiologic and genetic risk factors, and overlap with Alzheimer disease atrophy patterns.
Transl Psychiatry. 2016 April 5; Authors: Habes M, Janowitz D, Erus G, Toledo JB, Resnick SM, Doshi J, Van der Auwera S, Wittfeld K, Hegenscheid K, Hosten N, Biffar R, Homuth G, Völzke H, Grabe HJ, Hoffmann W, Davatzikos C
CSF biomarkers associated with disease heterogeneity in early Parkinson's disease: the Parkinson's Progression Markers Initiative study.
Acta Neuropathol. 2016 Mar 28; Authors: Kang JH, Mollenhauer B, Coffey CS, Toledo JB, Weintraub D, Galasko DR, Irwin DJ, Van Deerlin V, Chen-Plotkin AS, Caspell-Garcia C, Waligórska T, Taylor P, Shah N, Pan S, Zero P, Frasier M, Marek K, Kieburtz K, Jennings D, Tanner CM, Simuni T, Singleton A, Toga AW, Chowdhury S, Trojanowski JQ, Shaw LM, Parkinson’s Progression Marker Initiative
Characterization of brain-penetrant pyrimidine-containing molecules with differential microtubule-stabilizing activities developed as potential therapeutic agents for Alzheimer's disease and related tauopathies.
J Pharmacol Exp Ther. 2016 Mar 15; Authors: Kovalevich J, Cornec AS, Yao Y, James M, Crowe A, Lee VM, Trojanowski JQ, Smith AB, Ballatore C, Brunden KR
Brain. 2016 Feb 24; Authors: Habes M, Erus G, Toledo JB, Zhang T, Bryan N, Launer LJ, Rosseel Y, Janowitz D, Doshi J, Van der Auwera S, von Sarnowski B, Hegenscheid K, Hosten N, Homuth G, Völzke H, Schminke U, Hoffmann W, Grabe HJ, Davatzikos C
J Alzheimers Dis. 2016 Feb 6; Authors: White MT, Shaw LM, Xie SX
An Alzheimer's Disease-Derived Biomarker Signature Identifies Parkinson's Disease Patients with Dementia.
PLoS One. 2016 Jan 26; Authors: Berlyand Y, Weintraub D, Xie SX, Mellis IA, Doshi J, Rick J, McBride J, Davatzikos C, Shaw LM, Hurtig H, Trojanowski JQ, Chen-Plotkin AS
Org Biomol Chem. 2015 Dec 22; Authors: Haney CM, Wissner RF, Warner JB, Wang YJ, Ferrie JJ, J Covell D, Karpowicz RJ, Lee VM, James Petersson E
Inflammatory Eicosanoids Increase Amyloid Precursor Protein Expression via Activation of Multiple Neuronal Receptors.
Sci Rep. 2015 Dec 17; Authors: Herbst-Robinson KJ, Liu L, James M, Yao Y, Xie SX, Brunden KR
Acta Neuropathol. 2015 Dec 10; Authors: Kovacs GG, Ferrer I, Grinberg LT, Alafuzoff I, Attems J, Budka H, Cairns NJ, Crary JF, Duyckaerts C, Ghetti B, Halliday GM, Ironside JW, Love S, Mackenzie IR, Munoz DG, Murray ME, Nelson PT, Takahashi H, Trojanowski JQ, Ansorge O, Arzberger T, Baborie A, Beach TG, Bieniek KF, Bigio EH, Bodi I, Dugger BN, Feany M, Gelpi E, Gentleman SM, Giaccone G, Hatanpaa KJ, Heale R, Hof PR, Hofer M, Hortobágyi T, Jellinger K, Jicha GA, Ince P, Kofler J, Kövari E, Kril JJ, Mann DM, Matej R, McKee AC, McLean C, Milenkovic I, Montine TJ, Murayama S, Lee EB, Rahimi J, Rodriguez RD, Rozemüller A, Schneider JA, Schultz C, Seeley W, Seilhean D, Smith C, Tagliavini F, Takao M, Thal DR, Toledo JB, Tolnay M, Troncoso JC, Vinters HV, Weis S, Wharton SB, White CL, Wisniewski T, Woulfe JM, Yamada M, Dickson DW
Ann Neurol. 2015 Nov 19; Authors: Irwin DJ, Brettschneider J, McMillan CT, Cooper F, Olm C, Arnold SE, Van Deerlin VM, Seeley WW, Miller BL, Lee EB, Lee VM, Grossman M, Trojanowski JQ
Eye Movement Deficits Are Consistent with a Staging Model of pTDP-43 Pathology in Amyotrophic Lateral Sclerosis.
PLoS One. 2015 Nov 11; Authors: Gorges M, Müller HP, Lulé D, Del Tredici K, Brettschneider J, Keller J, Pfandl K, Ludolph AC, Kassubek J, Pinkhardt EH
Association of Cerebrospinal Fluid Neurofilament Light Concentration With Alzheimer Disease Progression.
JAMA Neurol. 2015 Nov 2; Authors: Zetterberg H, Skillbäck T, Mattsson N, Trojanowski JQ, Portelius E, Shaw LM, Weiner MW, Blennow K, Alzheimer’s Disease Neuroimaging Initiative
An insoluble frontotemporal lobar degeneration-associated TDP-43 C-terminal fragment causes neurodegeneration and hippocampus pathology in transgenic mice.
Hum Mol Genet. 2015 Oct 16; Authors: Walker AK, Tripathy K, Restrepo CR, Ge G, Xu Y, Kwong LK, Trojanowski JQ, Lee VM
Identifying amyloid pathology-related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study.
Alzheimers Dement (Amst). 2015 Sep 1; Authors: Leung YY, Toledo JB, Nefedov A, Polikar R, Raghavan N, Xie SX, Farnum M, Schultz T, Baek Y, Deerlin VV, Hu WT, Holtzman DM, Fagan AM, Perrin RJ, Grossman M, Soares HD, Kling MA, Mailman M, Arnold SE, Narayan VA, Lee VM, Shaw LM, Baker D, Wittenberg GM, Trojanowski JQ, Wang LS
Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer's disease.
Brain. 2015 Sep 15; Authors: Portelius E, Zetterberg H, Skillbäck T, Törnqvist U, Andreasson U, Trojanowski JQ, Weiner MW, Shaw LM, Mattsson N, Blennow K, Alzheimer’s Disease Neuroimaging Initiative
Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration.
Acta Neuropathol. 2015 Sep; Authors: Suh E, Lee EB, Neal D, Wood EM, Toledo JB, Rennert L, Irwin DJ, McMillan CT, Krock B, Elman LB, McCluskey LF, Grossman M, Xie SX, Trojanowski JQ, Van Deerlin VM
Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease.
Alzheimers Dement. 2015 Aug 29; Authors: Montine TJ, Monsell SE, Beach TG, Bigio EH, Bu Y, Cairns NJ, Frosch M, Henriksen J, Kofler J, Kukull WA, Lee EB, Nelson PT, Schantz AM, Schneider JA, Sonnen JA, Trojanowski JQ, Vinters HV, Zhou XH, Hyman BT
Diagnosis of Parkinson's disease on the basis of clinical and genetic classification: a population-based modelling study.
Lancet Neurol. 2015 Aug 10; Authors: Nalls MA, McLean CY, Rick J, Eberly S, Hutten SJ, Gwinn K, Sutherland M, Martinez M, Heutink P, Williams NM, Hardy J, Gasser T, Brice A, Price TR, Nicolas A, Keller MF, Molony C, Gibbs JR, Chen-Plotkin A, Suh E, Letson C, Fiandaca MS, Mapstone M, Federoff HJ, Noyce AJ, Morris H, Van Deerlin VM, Weintraub D, Zabetian C, Hernandez DG, Lesage S, Mullins M, Conley ED, Northover CA, Frasier M, Marek K, Day-Williams AG, Stone DJ, Ioannidis JP, Singleton AB, Parkinson's Disease Biomarkers Program and Parkinson's Progression Marker Initiative investigators*
Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43.
Acta Neuropathol. 2015 Jul 22; Authors: Walker AK, Spiller KJ, Ge G, Zheng A, Xu Y, Zhou M, Tripathy K, Kwong LK, Trojanowski JQ, Lee VM
Neurology. 2015 Jul 14; Authors: Toledo JB, Bjerke M, Chen K, Rozycki M, Jack CR, Weiner MW, Arnold SE, Reiman EM, Davatzikos C, Shaw LM, Trojanowski JQ, Alzheimer's Disease Neuroimaging Initiative
Common neuropathological features underlie distinct clinical presentations in three siblings with hereditary diffuse leukoencephalopathy with spheroids caused by CSF1R p.Arg782His.
Acta Neuropathol Commun. 2015 Jul 4; Authors: Robinson JL, Suh E, Wood EM, Lee EB, Coslett HB, Raible K, Lee VM, Trojanowski JQ, Van Deerlin VM
Role of brain infarcts in behavioral variant frontotemporal dementia: Clinicopathological characterization in the National Alzheimer's Coordinating Center database.
Neurobiol Aging. 2015 Oct, Epub 2015 Jul 3; Authors: Torralva T, Sposato LA, Riccio PM, Gleichgerrcht E, Roca M, Toledo JB, Trojanowski JQ, Kukull WA, Manes F, Hachinski V
Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration.
Neurobiol Dis. 2015 Jun 17; Authors: Paumier KL, Luk KC, Manfredsson FP, Kanaan NM, Lipton JW, Collier TJ, Steece-Collier K, Kemp CJ, Celano S, Schulz E, Sandoval IM, Fleming S, Dirr E, Polinski NK, Trojanowski JQ, Lee VM, Sortwell CE
Erratum to: Sequential distribution of pTDP-43 pathology in behavioral variant frontotemporal dementia (bvFTD).
Acta Neuropathol. 2015 Jun; Authors: Brettschneider J, Del Tredici K, Irwin DJ, Grossman M, Robinson JL, Toledo JB, Lee EB, Fang L, Van Deerlin VM, Ludolph AC, Lee VM, Braak H, Trojanowski JQ
Clinicopathological Study of Patients With C9ORF72-Associated Frontotemporal Dementia Presenting With Delusions.
J Geriatr Psychiatry Neurol. 2015 Jun; Authors: Shinagawa S, Naasan G, Karydas AM, Coppola G, Pribadi M, Seeley WW, Trojanowski JQ, Miller BL, Grinberg LT
Nonlinear Association Between Cerebrospinal Fluid and Florbetapir F-18 β-Amyloid Measures Across the Spectrum of Alzheimer Disease.
JAMA Neurol. 2015 May; Authors: Toledo JB, Bjerke M, Da X, Landau SM, Foster NL, Jagust W, Jack C, Weiner M, Davatzikos C, Shaw LM, Trojanowski JQ, Alzheimer’s Disease Neuroimaging Initiative Investigators
Neurology. 2015 Apr 21; Authors: McMillan CT, Russ J, Wood EM, Irwin DJ, Grossman M, McCluskey L, Elman L, Van Deerlin V, Lee EB
Acta Neuropathol. 2015 Apr; Authors: Irwin DJ, Cairns NJ, Grossman M, McMillan CT, Lee EB, Van Deerlin VM, Lee VM, Trojanowski JQ
Neurology. 2015 Mar 10; Authors: Beecham GW, Dickson DW, Scott WK, Martin ER, Schellenberg G, Nuytemans K, Larson EB, Buxbaum JD, Trojanowski JQ, Van Deerlin VM, Hurtig HI, Mash DC, Beach TG, Troncoso JC, Pletnikova O, Frosch MP, Ghetti B, Foroud TM, Honig LS, Marder K, Vonsattel JP, Goldman SM, Vinters HV, Ross OA, Wszolek ZK, Wang L, Dykxhoorn DM, Pericak-Vance MA, Montine TJ, Leverenz JB, Dawson TM, Vance JM
Neurology. 2015 Mar 3; Authors: Yu L, De Jager PL, Yang J, Trojanowski JQ, Bennett DA, Schneider JA
Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer's disease or corticobasal degeneration brains.
Acta Neuropathol. 2015 Feb; Authors: Boluda S, Iba M, Zhang B, Raible KM, Lee VM, Trojanowski JQ
Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice.
Neurobiol Dis. 2015 Jan; Authors: Peeraer E, Bottelbergs A, Van Kolen K, Stancu IC, Vasconcelos B, Mahieu M, Duytschaever H, Ver Donck L, Torremans A, Sluydts E, Van Acker N, Kemp JA, Mercken M, Brunden KR, Trojanowski JQ, Dewachter I, Lee VM, Moechars D
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