Acta Neuropathologica

, Volume 137, Issue 1, pp 47–69 | Cite as

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

  • Mukesh Gautam
  • Javier H. Jara
  • Nuran Kocak
  • Lauren E. Rylaarsdam
  • Ki Dong Kim
  • Eileen H. Bigio
  • P. Hande ÖzdinlerEmail author
Original Paper


Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as “TDP-43 pathology” in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. In an effort to define the underlying causes of corticospinal motor neuron (CSMN) degeneration, we generated and characterized a novel CSMN reporter line with TDP-43 pathology, the prp-TDP-43A315T-UeGFP mice. We find that TDP-43 pathology related intracellular problems emerge very early in the disease. The Betz cells in humans and CSMN in mice both have impaired mitochondria, and display nuclear membrane and ER defects with respect to TDP-43 pathology.


ALS CSMN Betz cells Selective vulnerability 



This work was supported by NIH (R21NS085750, R01 NS085161) and Les Turner ALS Foundation. We thank Dr. Marco Martina and Gabriella Sekerkova for help with EM analysis, and Megan Schultz for immunohistochemistry experiments. We thank Jayson Wilson for excellent help with preparing sections of postmortem human samples.

Author contributions

MG, JHJ, EHB, PHO designed the experiments. MG, JHJ, LER, NK, KDK conducted the experiments. MG, JHJ, EHB and PHO analyzed the data and wrote the manuscript.

Supplementary material

401_2018_1934_MOESM1_ESM.tif (1.4 mb)
Supplementary Fig. 1 A representative electron micrographic image taken in layer 5 of the motor cortex. Betz cells are distinguished by their pyramidal cell body, the large size of their nucleus and soma (black arrowhead). Non-Betz cells are much smaller in size (black arrow). Scale bar = 5 μm
401_2018_1934_MOESM2_ESM.tif (4.5 mb)
Supplementary Fig. 2 Betz cells of ALS patients with TDP-43 pathology that lack nucleocytoplasmic inclusions (NCIs) also display key ultrastructural defects. a, b Representative images of Betz cells (green) display low levels of TDP-43 (red, arrow) expression in the nucleus, without any accumulations in the cytoplasm or in the nucleus. Electron micrograph of a representative Betz cell with numerous autophagolysosomes in the cytoplasm (c). A close look reveal nuclear membrane defects (d, white arrow), presence autophagolysosomes (e, white arrows), swollen ER (f, white arrows), and disintegrating mitochondria (g, white arrow). Scale bar: a, b = 20 μm; c = 1 μm; d, e, f = 500 nm; g = 200 nm


  1. 1.
    Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R et al (2007) TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61:435–445. CrossRefGoogle Scholar
  2. 2.
    Arnold ES, Ling SC, Huelga SC, Lagier-Tourenne C, Polymenidou M, Ditsworth D et al (2013) ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc Natl Acad Sci U S A 110:E736–E745. CrossRefGoogle Scholar
  3. 3.
    Atkin JD, Farg MA, Walker AK, McLean C, Tomas D, Horne MK (2008) Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. Neurobiol Dis 30:400–407. CrossRefGoogle Scholar
  4. 4.
    Ayala YM, Zago P, D’Ambrogio A, Xu YF, Petrucelli L, Buratti E et al (2008) Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci 121:3778–3785. CrossRefGoogle Scholar
  5. 5.
    Bennett CL, Dastidar SG, Ling SC, Malik B, Ashe T, Wadhwa M et al (2018) Senataxin mutations elicit motor neuron degeneration phenotypes and yield TDP-43 mislocalization in ALS4 mice and human patients. Acta Neuropathol. Google Scholar
  6. 6.
    Bose JK, Huang CC, Shen CK (2011) Regulation of autophagy by neuropathological protein TDP-43. J Biol Chem 286:44441–44448. CrossRefGoogle Scholar
  7. 7.
    Braak H, Ludolph AC, Neumann M, Ravits J, Del Tredici K (2017) Pathological TDP-43 changes in Betz cells differ from those in bulbar and spinal alpha-motoneurons in sporadic amyotrophic lateral sclerosis. Acta Neuropathol 133:79–90. CrossRefGoogle Scholar
  8. 8.
    Buratti E (2015) Functional significance of TDP-43 mutations in disease. Adv Genet 91:1–53. CrossRefGoogle Scholar
  9. 9.
    Buratti E, Baralle FE (2001) Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J Biol Chem 276:36337–36343. CrossRefGoogle Scholar
  10. 10.
    Buratti E, Baralle FE (2008) Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Front Biosci 13:867–878CrossRefGoogle Scholar
  11. 11.
    Cannon A, Yang B, Knight J, Farnham IM, Zhang Y, Wuertzer CA et al (2012) Neuronal sensitivity to TDP-43 overexpression is dependent on timing of induction. Acta Neuropathol 123:807–823. CrossRefGoogle Scholar
  12. 12.
    Chaudhury A, Chander P, Howe PH (2010) Heterogeneous nuclear ribonucleoproteins (hnRNPs) in cellular processes: focus on hnRNP E1’s multifunctional regulatory roles. RNA 16:1449–1462. CrossRefGoogle Scholar
  13. 13.
    Chou CC, Zhang Y, Umoh ME, Vaughan SW, Lorenzini I, Liu F et al (2018) TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci 21:228–239. CrossRefGoogle Scholar
  14. 14.
    Cykowski MD, Powell SZ, Peterson LE, Appel JW, Rivera AL, Takei H et al (2017) Clinical significance of TDP-43 neuropathology in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 76:402–413. CrossRefGoogle Scholar
  15. 15.
    Darshi M, Mendiola VL, Mackey MR, Murphy AN, Koller A, Perkins GA et al (2011) ChChd3, an inner mitochondrial membrane protein, is essential for maintaining crista integrity and mitochondrial function. J Biol Chem 286:2918–2932. CrossRefGoogle Scholar
  16. 16.
    Eisen A, Pant B, Stewart H (1993) Cortical excitability in amyotrophic lateral sclerosis: a clue to pathogenesis. Can J Neurol Sci 20:11–16CrossRefGoogle Scholar
  17. 17.
    Eymard-Pierre E, Lesca G, Dollet S, Santorelli FM, di Capua M, Bertini E et al (2002) Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am J Hum Genet 71:518–527. CrossRefGoogle Scholar
  18. 18.
    Fil D, DeLoach A, Yadav S, Alkam D, MacNicol M, Singh A et al (2017) Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease. Hum Mol Genet 26:686–701. Google Scholar
  19. 19.
    Filosto M, Scarpelli M, Cotelli MS, Vielmi V, Todeschini A, Gregorelli V et al (2011) The role of mitochondria in neurodegenerative diseases. J Neurol 258:1763–1774. CrossRefGoogle Scholar
  20. 20.
    Fink JK (2002) Hereditary spastic paraplegia. Neurol Clin 20:711–726CrossRefGoogle Scholar
  21. 21.
    Gautam M, Jara JH, Sekerkova G, Yasvoina MV, Martina M, Ozdinler PH (2016) Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms. Hum Mol Genet 25:1074–1087. CrossRefGoogle Scholar
  22. 22.
    Geevasinga N, Menon P, Nicholson GA, Ng K, Howells J, Kril JJ et al (2015) Cortical function in asymptomatic carriers and patients with C9orf72 amyotrophic lateral sclerosis. JAMA Neurol 72:1268–1274. CrossRefGoogle Scholar
  23. 23.
    Geevasinga N, Menon P, Ozdinler PH, Kiernan MC, Vucic S (2016) Pathophysiological and diagnostic implications of cortical dysfunction in ALS. Nat Rev Neurol 12:651–661. CrossRefGoogle Scholar
  24. 24.
    Goossens J, Vanmechelen E, Trojanowski JQ, Lee VM, Van Broeckhoven C, van der Zee J et al (2015) TDP-43 as a possible biomarker for frontotemporal lobar degeneration: a systematic review of existing antibodies. Acta Neuropathol Commun 3:15. CrossRefGoogle Scholar
  25. 25.
    Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775CrossRefGoogle Scholar
  26. 26.
    Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N et al (2013) Autophagosomes form at ER-mitochondria contact sites. Nature 495:389–393. CrossRefGoogle Scholar
  27. 27.
    Helle SC, Kanfer G, Kolar K, Lang A, Michel AH, Kornmann B (2013) Organization and function of membrane contact sites. Biochim Biophys Acta 1833:2526–2541. CrossRefGoogle Scholar
  28. 28.
    Hetz C, Saxena S (2017) ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol 13:477–491. CrossRefGoogle Scholar
  29. 29.
    Huynh W, Simon NG, Grosskreutz J, Turner MR, Vucic S, Kiernan MC (2016) Assessment of the upper motor neuron in amyotrophic lateral sclerosis. Clin Neurophysiol 127:2643–2660. CrossRefGoogle Scholar
  30. 30.
    Igaz LM, Kwong LK, Lee EB, Chen-Plotkin A, Swanson E, Unger T et al (2011) Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest 121:726–738. CrossRefGoogle Scholar
  31. 31.
    Izumikawa K, Nobe Y, Yoshikawa H, Ishikawa H, Miura Y, Nakayama H et al (2017) TDP-43 stabilises the processing intermediates of mitochondrial transcripts. Sci Rep 7:7709. CrossRefGoogle Scholar
  32. 32.
    Janssens J, Wils H, Kleinberger G, Joris G, Cuijt I, Ceuterick-de Groote C et al (2013) Overexpression of ALS-associated p. M337 V human TDP-43 in mice worsens disease features compared to wild-type human TDP-43 mice. Mol Neurobiol 48:22–35. CrossRefGoogle Scholar
  33. 33.
    Jara JH, Genc B, Cox GA, Bohn MC, Roos RP, Macklis JD et al (2015) Corticospinal motor neurons are susceptible to increased ER stress and display profound degeneration in the absence of UCHL1 function. Cereb Cortex 25:4259–4272. CrossRefGoogle Scholar
  34. 34.
    Jara JH, Genc B, Klessner JL, Ozdinler PH (2014) Retrograde labeling, transduction, and genetic targeting allow cellular analysis of corticospinal motor neurons: implications in health and disease. Front Neuroanat 8:16. CrossRefGoogle Scholar
  35. 35.
    Kim HJ, Taylor JP (2017) Lost in transportation: nucleocytoplasmic transport defects in ALS and other neurodegenerative diseases. Neuron 96:285–297. CrossRefGoogle Scholar
  36. 36.
    Kinoshita Y, Ito H, Hirano A, Fujita K, Wate R, Nakamura M et al (2009) Nuclear contour irregularity and abnormal transporter protein distribution in anterior horn cells in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 68:1184–1192. CrossRefGoogle Scholar
  37. 37.
    Korobova F, Ramabhadran V, Higgs HN (2013) An actin-dependent step in mitochondrial fission mediated by the ER-associated formin INF2. Science 339:464–467. CrossRefGoogle Scholar
  38. 38.
    Ling SC, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438. CrossRefGoogle Scholar
  39. 39.
    Ludolph AC, Bendotti C, Blaugrund E, Chio A, Greensmith L, Loeffler JP et al (2010) Guidelines for preclinical animal research in ALS/MND: a consensus meeting. Amyotroph Lateral Scler 11:38–45. CrossRefGoogle Scholar
  40. 40.
    Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ et al (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434. CrossRefGoogle Scholar
  41. 41.
    Magrane J, Cortez C, Gan WB, Manfredi G (2014) Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum Mol Genet 23:1413–1424. CrossRefGoogle Scholar
  42. 42.
    Muller-Taubenberger A, Lupas AN, Li H, Ecke M, Simmeth E, Gerisch G (2001) Calreticulin and calnexin in the endoplasmic reticulum are important for phagocytosis. EMBO J 20:6772–6782. CrossRefGoogle Scholar
  43. 43.
    Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE et al (2007) Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114:221–229. CrossRefGoogle Scholar
  44. 44.
    Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133. CrossRefGoogle Scholar
  45. 45.
    Nishimura AL, Zupunski V, Troakes C, Kathe C, Fratta P, Howell M et al (2010) Nuclear import impairment causes cytoplasmic trans-activation response DNA-binding protein accumulation and is associated with frontotemporal lobar degeneration. Brain 133:1763–1771. CrossRefGoogle Scholar
  46. 46.
    Oyanagi K, Yamazaki M, Takahashi H, Watabe K, Wada M, Komori T et al (2008) Spinal anterior horn cells in sporadic amyotrophic lateral sclerosis show ribosomal detachment from, and cisternal distention of the rough endoplasmic reticulum. Neuropathol Appl Neurobiol 34:650–658. CrossRefGoogle Scholar
  47. 47.
    Ozdinler PH, Benn S, Yamamoto TH, Guzel M, Brown RH Jr, Macklis JD (2011) Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G(9)(3)A transgenic ALS mice. J Neurosci 31:4166–4177. CrossRefGoogle Scholar
  48. 48.
    Paillusson S, Stoica R, Gomez-Suaga P, Lau DHW, Mueller S, Miller T et al (2016) There’s something wrong with my MAM; the ER-mitochondria axis and neurodegenerative diseases. Trends Neurosci 39:146–157. CrossRefGoogle Scholar
  49. 49.
    Pemberton LF, Paschal BM (2005) Mechanisms of receptor-mediated nuclear import and nuclear export. Traffic 6:187–198. CrossRefGoogle Scholar
  50. 50.
    Picher-Martel V, Valdmanis PN, Gould PV, Julien JP, Dupre N (2016) From animal models to human disease: a genetic approach for personalized medicine in ALS. Acta Neuropathol Commun 4:70. CrossRefGoogle Scholar
  51. 51.
    Pinarbasi ES, Cagatay T, Fung HYJ, Li YC, Chook YM, Thomas PJ (2018) Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization. Sci Rep 8:7083. CrossRefGoogle Scholar
  52. 52.
    Rowland AA, Voeltz GK (2012) Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat Rev Mol Cell Biol 13:607–625. CrossRefGoogle Scholar
  53. 53.
    Ruffoli R, Bartalucci A, Frati A, Fornai F (2015) Ultrastructural studies of ALS mitochondria connect altered function and permeability with defects of mitophagy and mitochondriogenesis. Front Cell Neurosci 9:341. CrossRefGoogle Scholar
  54. 54.
    Saberi S, Stauffer JE, Jiang J, Garcia SD, Taylor AE, Schulte D et al (2018) Sense-encoded poly-GR dipeptide repeat proteins correlate to neurodegeneration and uniquely co-localize with TDP-43 in dendrites of repeat-expanded C9orf72 amyotrophic lateral sclerosis. Acta Neuropathol 135:459–474. CrossRefGoogle Scholar
  55. 55.
    Sasaki S (2010) Endoplasmic reticulum stress in motor neurons of the spinal cord in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 69:346–355. CrossRefGoogle Scholar
  56. 56.
    Sasaki S, Iwata M (1999) Ultrastructural change of synapses of Betz cells in patients with amyotrophic lateral sclerosis. Neurosci Lett 268:29–32CrossRefGoogle Scholar
  57. 57.
    Saxena S, Cabuy E, Caroni P (2009) A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat Neurosci 12:627–636. CrossRefGoogle Scholar
  58. 58.
    Saxton WM, Hollenbeck PJ (2012) The axonal transport of mitochondria. J Cell Sci 125:2095–2104. CrossRefGoogle Scholar
  59. 59.
    Schroder M, Kaufman RJ (2005) ER stress and the unfolded protein response. Mutat Res 569:29–63. CrossRefGoogle Scholar
  60. 60.
    Scotter EL, Chen HJ, Shaw CE (2015) TDP-43 proteinopathy and ALS: insights into disease mechanisms and therapeutic targets. Neurotherapeutics 12:352–363. CrossRefGoogle Scholar
  61. 61.
    Shan X, Chiang PM, Price DL, Wong PC (2010) Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice. Proc Natl Acad Sci U S A 107:16325–16330. CrossRefGoogle Scholar
  62. 62.
    Smith EF, Shaw PJ, De Vos KJ (2017) The role of mitochondria in amyotrophic lateral sclerosis. Neurosci Lett. Google Scholar
  63. 63.
    Stalekar M, Yin X, Rebolj K, Darovic S, Troakes C, Mayr M et al (2015) Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport. Neuroscience 293:157–170. CrossRefGoogle Scholar
  64. 64.
    Stallings NR, Puttaparthi K, Luther CM, Burns DK, Elliott JL (2010) Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol Dis 40:404–414. CrossRefGoogle Scholar
  65. 65.
    Stoica R, De Vos KJ, Paillusson S, Mueller S, Sancho RM, Lau KF et al (2014) ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat Commun 5:3996. CrossRefGoogle Scholar
  66. 66.
    Swarup V, Phaneuf D, Bareil C, Robertson J, Rouleau GA, Kriz J et al (2011) Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments. Brain 134:2610–2626. CrossRefGoogle Scholar
  67. 67.
    Torres P, Ramirez-Nunez O, Romero-Guevara R, Bares G, Granado-Serrano AB, Ayala V et al (2018) Cryptic exon splicing function of tardbp interacts with autophagy in nervous tissue. Autophagy. Google Scholar
  68. 68.
    Vijayalakshmi K, Alladi PA, Ghosh S, Prasanna VK, Sagar BC, Nalini A et al (2011) Evidence of endoplasmic reticular stress in the spinal motor neurons exposed to CSF from sporadic amyotrophic lateral sclerosis patients. Neurobiol Dis 41:695–705. CrossRefGoogle Scholar
  69. 69.
    Vucic S, Kiernan MC (2006) Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. Brain 129:2436–2446. CrossRefGoogle Scholar
  70. 70.
    Wang W, Li L, Lin WL, Dickson DW, Petrucelli L, Zhang T et al (2013) The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. Hum Mol Genet 22:4706–4719. CrossRefGoogle Scholar
  71. 71.
    Ward ME, Taubes A, Chen R, Miller BL, Sephton CF, Gelfand JM et al (2014) Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD. J Exp Med 211:1937–1945. CrossRefGoogle Scholar
  72. 72.
    Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH (2009) TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 106:18809–18814. CrossRefGoogle Scholar
  73. 73.
    Wils H, Kleinberger G, Janssens J, Pereson S, Joris G, Cuijt I et al (2010) TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 107:3858–3863. CrossRefGoogle Scholar
  74. 74.
    Xu YF, Gendron TF, Zhang YJ, Lin WL, D’Alton S, Sheng H et al (2010) Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J Neurosci 30:10851–10859. CrossRefGoogle Scholar
  75. 75.
    Xu YF, Zhang YJ, Lin WL, Cao X, Stetler C, Dickson DW et al (2011) Expression of mutant TDP-43 induces neuronal dysfunction in transgenic mice. Mol Neurodegener 6:73. CrossRefGoogle Scholar
  76. 76.
    Yasvoina MV, Genc B, Jara JH, Sheets PL, Quinlan KA, Milosevic A et al (2013) eGFP expression under UCHL1 promoter genetically labels corticospinal motor neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model. J Neurosci 33:7890–7904. CrossRefGoogle Scholar
  77. 77.
    Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P et al (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525:56–61. CrossRefGoogle Scholar
  78. 78.
    Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469:221–225. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Davee Department of Neurology and Clinical Neurological SciencesNorthwestern University Feinberg School of MedicineChicagoUSA
  2. 2.Les Turner ALS Research and Patient CenterChicagoUSA
  3. 3.Department of PathologyNorthwestern UniversityChicagoUSA
  4. 4.Cognitive Neurology and Alzheimer’s Disease CenterNorthwestern University Feinberg School of MedicineChicagoUSA
  5. 5.Robert H. Lurie Comprehensive Cancer CenterNorthwestern UniversityChicagoUSA

Personalised recommendations