1. Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.

    Cell 165(4):921 (2016) PMID 27114033 PMCID PMC4860138

    Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progre...
  2. Distinct Lysosomal Network Protein Profiles in Parkinsonian Syndrome Cerebrospinal Fluid.

    Journal of Parkinson's Disease 6(2):307 (2016) PMID 27061067 PMCID PMC4927933

    Clinical diagnosis of parkinsonian syndromes like Parkinson's disease (PD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is hampered by overlapping symptomatology and lack of diagnostic biomarkers, and definitive diagnosis is only possible post-mortem. Since impaired ...
  3. Plasma neurofilament light chain predicts progression in progressive supranuclear palsy.

    Annals of clinical and translational neurology 3(3):216 (2016) PMID 27042681 PMCID PMC4774256

    Blood-based biomarkers for neurodegenerative conditions could improve diagnosis and treatment development. Neurofilament light chain (NfL), a marker of axonal injury, is elevated in cerebrospinal fluid (CSF) of patients with progressive supranuclear palsy (PSP). The goal of this study was to det...
  4. Amyloid in dementia associated with familial FTLD: not an innocent bystander.

    Neurocase 22(1):76 (2016) PMID 26040468 PMCID PMC4662906

    Patients with frontotemporal lobar degeneration (FTLD) can show superimposed amyloid pathology, though the impact of amyloid on the clinical presentation of FTLD is not well characterized. This cross-sectional case-control study compared clinical features, fluorodeoxyglucose-positron emission to...
  5. Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain.

    Molecular Neurodegeneration 11(1):31 (2016) PMID 27112350 PMCID PMC4845325

    Biological pathways that significantly contribute to sporadic Alzheimer's disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted...
  6. Prosaposin is a regulator of progranulin levels and oligomerization.

    Nature Communications 7:11992 (2016) PMID 27356620 PMCID PMC4931318

    Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports also indicated PGRN-mediated neuroprotection in models of Alzheimer's and Parkinson's disease; thus, increasing PGRN levels is a ...
  7. Divergent CSF τ alterations in two common tauopathies: Alzheimer's disease and progressive supranuclear palsy.

    Journal of Neurology, Neurosurgery & Psychiatry 86(3):244 (2015) PMID 24899730 PMCID PMC4256124

    Elevated CSF τ is considered a biomarker of neuronal injury in newly developed Alzheimer's disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of τ species in other primary tauopathies. We assessed CSF τ protein abnormalities in ...
  8. Rarity of the Alzheimer disease-protective APP A673T variant in the United States.
    Li-San Wang, Adam C Naj, Robert Graham, Paul K Crane, Brian W Kunkle, Carlos Cruchaga, Josue D Gonzalez Murcia, Lisa Cannon-Albright, Clinton T Baldwin, Henrik Zetterberg, Kaj Blennow, Walter A Kukull, Kelley M Faber, Nicole Schupf, Maria C Norton, JoAnn Tschanz, Ronald G Munger, Christopher D Corcoran, Ekaterina Rogaeva, Chiao-Feng Lin, Beth A Dombroski, Laura B Cantwell, Amanda Partch, Otto Valladares, Hakon Hakonarson, Peter St George-Hyslop, Robert C Green, Alison M Goate, Tatiana M Foroud, Regina M Carney, Eric B Larson, Timothy W Behrens, John S Kauwe, Jonathan L Haines, Lindsay A Farrer, Margaret A Pericak-Vance, Richard Mayeux, Gerard D Schellenberg, Marilyn S Albert, Roger L Albin, Liana G Apostolova, Steven E Arnold, Robert Barber, Michael Barmada, Lisa Barnes, Thomas G Beach, James T Becker, Gary W Beecham, Duane Beekly, David A Bennett, Eileen H Bigio, Thomas D Bird, Deborah Blacker, Bradley F Boeve, James D Bowen, Adam Boxer, James R Burke, Joseph D Buxbaum, Nigel J Cairns, Chuanhai Cao, Chris S Carlson, Steven L Carroll, Helena Chui, David G Clark, David H Cribbs, Elizabeth A Crocco, Charles DeCarli, Steven T DeKosky, F Yesim Demirci, Malcolm Dick, Dennis W Dickson, Ranjan Duara, Nilufer Ertekin-Taner, Kenneth B Fallon, Martin R Farlow, Steven Ferris, Matthew P Frosch, Douglas R Galasko, Mary Ganguli, Marla Gearing, Daniel H Geschwind, Bernardino Ghetti, John R Gilbert, Jonathan D Glass, Neill R Graff-Radford, John H Growdon, Ronald L Hamilton, Kara L Hamilton-Nelson, Lindy E Harrell, Elizabeth Head, Lawrence S Honig, Christine M Hulette, Bradley T Hyman, Gail P Jarvik, Gregory A Jicha, Lee-Way Jin, Gyungah Jun, Gyungah Jun, M Ilyas Kamboh, Anna Karydas, Jeffrey A Kaye, Ronald Kim, Edward H Koo, Neil W Kowall, Joel H Kramer, Frank M LaFerla, James Lah, James B Leverenz, Allan I Levey, Gei Li, Andrew P Lieberman, Oscar Lopez, Kathryn Lunetta, Constantine G Lyketsos, Wendy J Mack, Daniel C Marson, Eden R Martin, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Wayne C McCormick, Susan McCurry, Andrew N McDavid, Ann C McKee, W Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, Thomas J Montine, John C Morris, Jill R Murrell, John M Olichney, Joseph E Parisi, William Perry, Elaine Peskind, Ronald C Petersen, Aimee Pierce, Wayne Poon, Huntington Potter, Joseph F Quinn, Ashok Raj, Murray Raskind, Eric M Reiman, Barry Reisberg, Christiane Reitz, John M Ringman, Erik D Roberson, Howard J Rosen, Roger N Rosenberg, Mary Sano, Andrew J Saykin, Julie A Schneider, Lon Schneider, William Seeley, Amanda G Smith, Joshua A Sonnen, Salvatore Spina, Robert A Stern, Rudolph E Tanzi, Tricia A Thornton-Wells, John Q Trojanowski, Juan C Troncoso, Debby W Tsuang, Vivianna M Van Deerlin, Linda J Van Eldik, Badri N Vardarajan, Harry Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A Welsh-Bohmer, Jennifer Williamson, Sarah Wishnek, Randall L Woltjer, Clinton B Wright, Steven G Younkin, Chang-En Yu, and Lei Yu

    JAMA Neurology 72(2):209 (2015) PMID 25531812 PMCID PMC4324097

    Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this varia...
  9. Apolipoprotein ε4 is associated with lower brain volume in cognitively normal Chinese but not white older adults.

    PLoS ONE 10(3):e0118338 (2015) PMID 25738563 PMCID PMC4349764

    Studying ethnically diverse groups is important for furthering our understanding of biological mechanisms of disease that may vary across human populations. The ε4 allele of apolipoprotein E (APOE ε4) is a well-established risk factor for Alzheimer's disease (AD), and may confer anatomic and fun...
  10. A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques.

    Acta neuropathologica communications 3(1):19 (2015) PMID 25853458 PMCID PMC4382926

    Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease. We describe a pedigre...
  11. Decision tree analysis of genetic risk for clinically heterogeneous Alzheimer's disease.

    BMC Neurology 15(1):47 (2015) PMID 25880661 PMCID PMC4459447

    Heritability of Alzheimer's disease (AD) is estimated at 74% and genetic contributors have been widely sought. The ε4 allele of apolipoprotein E (APOE) remains the strongest common risk factor for AD, with numerous other common variants contributing only modest risk for disease. Variability in c...
  12. The 5-HTTLPR variant in the serotonin transporter gene modifies degeneration of brain regions important for emotion in behavioral variant frontotemporal dementia.

    NeuroImage: Clinical 9:283 (2015) PMID 26509115 PMCID PMC4576414

    The serotonin transporter length polymorphism (5-HTTLPR) short allele (5-HTTLPR-s) has been associated with differential susceptibility for anxiety and depression in multiple psychiatric disorders. 5-HTTLPR-s modifies the serotonergic systems that support emotion and behavioral regulation by red...
  13. Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.
    Adam C Naj, Gyungah Jun, Christiane Reitz, Brian W Kunkle, William Perry, Yo Son Park, Gary W Beecham, Ruchita A Rajbhandary, Kara L Hamilton-Nelson, Li-San Wang, John S Kauwe, Matthew J Huentelman, Amanda J Myers, Thomas D Bird, Bradley F Boeve, Clinton T Baldwin, Gail P Jarvik, Paul K Crane, Ekaterina Rogaeva, Michael Barmada, F Yesim Demirci, Carlos Cruchaga, Patricia L Kramer, Nilufer Ertekin-Taner, John Hardy, Neill R Graff-Radford, Robert C Green, Eric B Larson, Peter H St George-Hyslop, Joseph D Buxbaum, Denis A Evans, Julie A Schneider, Kathryn Lunetta, M Ilyas Kamboh, Andrew J Saykin, Eric M Reiman, Philip L De Jager, David A Bennett, John C Morris, Thomas J Montine, Alison M Goate, Deborah Blacker, Debby W Tsuang, Hakon Hakonarson, Walter A Kukull, Tatiana M Foroud, Eden R Martin, Jonathan L Haines, Richard P Mayeux, Lindsay A Farrer, Gerard D Schellenberg, Margaret A Pericak-Vance, Marilyn S Albert, Roger L Albin, Liana G Apostolova, Steven E Arnold, Robert Barber, Lisa Barnes, Thomas G Beach, James T Becker, Duane Beekly, Eileen H Bigio, James D Bowen, Adam Boxer, James R Burke, Nigel J Cairns, Laura B Cantwell, Chuanhai Cao, Chris S Carlson, Regina M Carney, Minerva Carrasquillo, Steven L Carroll, Helena Chui, David G Clark, Jason Corneveaux, David H Cribbs, Elizabeth A Crocco, Charles DeCarli, Steven T DeKosky, Malcolm Dick, Dennis W Dickson, Ranjan Duara, Kelley M Faber, Kenneth B Fallon, Martin R Farlow, Steven Ferris, Matthew P Frosch, Douglas R Galasko, Mary Ganguli, Marla Gearing, Daniel H Geschwind, Bernardino Ghetti, John R Gilbert, Jonathan D Glass, John H Growdon, Ronald L Hamilton, Lindy E Harrell, Elizabeth Head, Lawrence S Honig, Christine M Hulette, Bradley T Hyman, Gregory A Jicha, Lee-Way Jin, Anna Karydas, Jeffrey A Kaye, Ronald Kim, Edward H Koo, Neil W Kowall, Joel H Kramer, Frank M LaFerla, James Lah, James B Leverenz, Allan I Levey, Ge Li, Andrew P Lieberman, Chiao-Feng Lin, Oscar Lopez, Constantine G Lyketsos, Wendy J Mack, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Wayne C McCormick, Susan McCurry, Andrew N McDavid, Ann C McKee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, Jill R Murrell, John M Olichney, Vernon S Pankratz, Joseph E Parisi, Henry L Paulson, Elaine Peskind, Ronald C Petersen, Aimee Pierce, Wayne Poon, Huntington Potter, Joseph F Quinn, Ashok Raj, Murray Raskind, Barry Reisberg, John M Ringman, Erik D Roberson, Howard J Rosen, Roger N Rosenberg, Mary Sano, Lon Schneider, William Seeley, Amanda G Smith, Joshua A Sonnen, Salvatore Spina, Robert A Stern, Rudolph E Tanzi, Tricia A Thornton-Wells, John Q Trojanowski, Juan C Troncoso, Otto Valladares, Vivianna M Van Deerlin, Linda J Van Eldik, Badri N Vardarajan, Harry Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A Welsh-Bohmer, Jennifer Williamson, Sarah Wishnek, Randall L Woltjer, Clinton B Wright, Steven G Younkin, Chang-En Yu, and Lei Yu

    JAMA Neurology 71(11):1394 (2014) PMID 25199842 PMCID PMC4314944

    Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. To investigate the effects of known Alzheimer disease risk lo...
  14. AMYLOID IN DEMENTIA ASSOCIATED WITH FAMILIAL FTLD: NOT AN INNOCENT BYSTANDER

    Alzheimer's & Dementia 10(4):P249 (2014)

  15. Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients.

    Journal of Neurology, Neurosurgery & Psychiatry 85(3):266 (2014) PMID 23965289 PMCID PMC3946299

    Apolipoprotein E ε4 (ApoE4) has been associated with an increased risk of Alzheimer's disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and ...
  16. An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy.

    PLoS Genetics 10(3):e1004211 (2014) PMID 24603599 PMCID PMC3945475

    Little is known about how changes in DNA methylation mediate risk for human diseases including dementia. Analysis of genome-wide methylation patterns in patients with two forms of tau-related dementia--progressive supranuclear palsy (PSP) and frontotemporal dementia (FTD)--revealed significant d...
  17. Satiety-related hormonal dysregulation in behavioral variant frontotemporal dementia.

    Neurology 82(6):512 (2014) PMID 24415571 PMCID PMC3937860

    To investigate whether patients with behavioral variant frontotemporal dementia (bvFTD) have dysregulation in satiety-related hormonal signaling using a laboratory-based case-control study. Fifty-four participants (19 patients with bvFTD, 17 patients with Alzheimer disease dementia, and 18 healt...
  18. Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration.

    Annals of Neurology 75(1):116 (2014) PMID 24242746 PMCID PMC4020786

    Cerebrospinal fluid (CSF) neurofilament light chain (NfL) concentration is elevated in neurological disorders, including frontotemporal degeneration (FTD). We investigated the clinical correlates of elevated CSF NfL levels in FTD. CSF NfL, amyloid-β1-42 (Aβ42), tau, and phosphorylated tau concen...
  19. C9ORF72 repeat expansions in cases with previously identified pathogenic mutations.

    Neurology 81(15):1332 (2013) PMID 24027057 PMCID PMC3806926

    To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 (C9ORF72), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutation...
  20. TDP-43 frontotemporal lobar degeneration and autoimmune disease.

    Journal of Neurology, Neurosurgery & Psychiatry 84(9):956 (2013) PMID 23543794 PMCID PMC3840954

    The aetiology and pathogenesis of non-genetic forms of frontotemporal dementia (FTD) is unknown and even with the genetic forms of FTD, pathogenesis remains elusive. Given the association between systemic inflammation and other neurodegenerative processes, links between autoimmunity and FTD need...