Neurodegenerative Disorders as Proteinopathies: Phenotypic Relationships

  • Jeffrey L. Cummings
Conference paper
Part of the Research and Perspectives in Alzheimer's Disease book series (ALZHEIMER)


The phenotype of neurodegenerative diseases is defined by the distribution of cellular changes, which in turn depends on vulnerability to specific abnormalities of protein metabolism. Distinctive features have been identified that assist in the recognition of specific diseases or specific types of abnormalities of protein metabolism that are shared by several neurodegenerative disorders. Identification of the earliest manifestations of the phenotype will facilitate early implementation of therapy and improve understanding of protein metabolism abnormalities and their secondary consequences. This will assist in drug development and effective therapeutics for neurodegenerative disorders.


Amyotrophic Lateral Sclerosis Multiple System Atrophy Frontotemporal Dementia Progressive Supranuclear Palsy Corticobasal Degeneration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Ames D, Cummings JL, Wirshing WC, Quinn B, Mahler M (1994) Repetitive and compulsive behavior in frontal lobe degenerations. J Neuropsychiat Clin Neurosci 6:100–113.Google Scholar
  2. Ballard C, O'Brien J, Gray A, Cormack F, Ayre G, Rowan E, Thompson P, Bucks R, Mckeith I, Walker M, Tovee M (2001) Attention and fluctuating attention in patients with dementia with Lewy bodies and Alzheimer disease. Arch Neurol 58:977–982.CrossRefPubMedGoogle Scholar
  3. Ballard CG, Aarsland D, McKeith I, O'Brien J, Gray A, Cormack F, Burn D, Cassidy T, Starfeldt R, Larsen JP, Brown R, Tovee M. (2002) Fluctuations in attention: PD dementia vs DLB with parkinsonism. Neurology 59:1714–1720.PubMedGoogle Scholar
  4. Barnes J, David AS (2001) Visual hallucinations in Parkinson's disease: a review and phenomenological survey. J Neurol Neurosurg Psychiat 70:727–733.CrossRefPubMedGoogle Scholar
  5. Barnham KJ, Masters CL, Bush AI (2004) Neurodegenerative diseases and oxidative stress. Nature Rev Drug Discov 3:205–214.CrossRefGoogle Scholar
  6. Bird TD (1999) Clinical genetics of familial Alzheimer disease. In: Terry RD, Katzman R, Bick KL (eds) Alzheimer disease. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, pp. 57–66.Google Scholar
  7. Blacker D, Tanzi R (2000) Genetic testing in the early diagnosis of Alzheimer's disease. In: Scinto LMF, Daffner KR (eds) Early diagnosis of Alzheimer's disease. Totowa, NJ: Humana Press, Inc., pp. 105–125.Google Scholar
  8. Bossy-Wetzel E, Schwarzenbacher R, Lipton SA (2004) Molecular pathways to neurodegeneration. Nature Med 5:2–9.CrossRefGoogle Scholar
  9. Braak H, De Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24:197–211.CrossRefPubMedGoogle Scholar
  10. Caldwell GA, Cao S, Sexton EG, Gelwix CC, Bevel JP, Caldwell KA (2003) Suppression of polyglutamine-induced protein aggregation in Caenorhabditis elegans by torsin proteins. Human Mol Genet 12:307–319.CrossRefGoogle Scholar
  11. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, Bian J, Guo L, Farrell LA, Hersch SM, Hobbs W, Vonsattel JP, Cha JH, Friedlander RM (2000) Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nature Med 6:797–801.CrossRefPubMedGoogle Scholar
  12. Cohen H (2003) Disorders of speech and language in Parkinson's disease. In: Bedard M-A (ed) Mental and behavioral dysfunction in movement disorders. Totowa, NJ: Humana Press, Inc., pp. 125–134.Google Scholar
  13. Comella C, Nardine TM, Diedrich NJ, Stebbins GT (1998) Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson's disease. Neurology 51:526–529.PubMedGoogle Scholar
  14. Cummings JL (1993) Frontal-subcortical circuits and human behavior. Arch Neurol 50:873–880.PubMedGoogle Scholar
  15. Cummings JL (2000) Cognitive and behavioral heterogeneity in Alzheimer's disease: seeking the neurological basis. Response to commentaries. Neurobiol Aging 21:845–861.CrossRefPubMedGoogle Scholar
  16. Cummings JL (2003a) Towards a molecular neuropsychiatry of neurodegenerative diseases. Ann Neurol 54:147–154.CrossRefPubMedGoogle Scholar
  17. Cummings JL (2003b) The Neuropsychiatry of Alzheimer's Disease and Related Dementia's. London: Martin Dunitz.Google Scholar
  18. Cummings JL, Litvan I (2000) Neuropsychiatric aspects of corticobasal degeneration. Adv Neurol 82:147–152.PubMedGoogle Scholar
  19. Dickson DW, Liu WK, Ksiezak-Reding H, Yen SH (2000) Neuropathologic and molecular considerations. In: Litvan I, Goetz CG, Lang AE (eds) Corticobasal degeneration. Advances in neurology. Philadelphia: Lippincott & Williams, pp. 9–27.Google Scholar
  20. Fantini ML, Gagnon JF, Petit D, Rompre S, Decary A, Carrier J, Montplaisir J (2003) Slowing of electroencephalogram in rapid eye movement sleep behavior disorder. Ann Neurol 53:774–780.CrossRefPubMedGoogle Scholar
  21. Fenelon G, Mahieux F, Huon R, Ziegler M (2000) Hallucinations in Parkinson's disease. Prevalence, phenomenology and risk factors. Brain 123:733–745.CrossRefPubMedGoogle Scholar
  22. Ferini-Strambi L, Di Gioia MR, Castronovo V, Oldani A, Zucconi M, Cappa SF (2004) Neuropsychological assessment in idiopathic REM sleep behavior disorder (RBD). Does the idiopathic form of RBD really exist? Neurology 62:41–45.PubMedGoogle Scholar
  23. Ferman TJ, Boeve BF, Smith GE, Silber MH, Kokmen E, Petersen RC, Ivnik RJ (1999) REM sleep behavior disorder and dementia: cognitive differences when compared with AD. Neurology 52:951–957.PubMedGoogle Scholar
  24. Gagnon J-F, Bedard M-A, Fantini ML, Petit D, Panisset M, Rompre S, Carrier J, Montplaisir J (2002) REM sleep behavior disorder and REM sleep without atonia in Parkinson's disease. Neurology 59:585–589.PubMedGoogle Scholar
  25. Gagnon JF, Fantini ML, Bedard MA, Petit D, Carrier J, Rompre S, Decary A, Panisset M, Montplaisir J (2004) Association between waking EEG slowing and REM sleep behavior disorder in PD without dementia. Neurology 62:401–406.PubMedGoogle Scholar
  26. Hardy J, Gwinn-Hardy K (1998) Genetic classification of primary neurodegenerative disease. Science 282:1075–1079.CrossRefPubMedGoogle Scholar
  27. Hauw JJ, Daniel SE, Dickson D, Horoupian DS, Jellinger K, Lantos PL, McKee A, Tabaton M, Litvan I (1994) Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology 44:2015–2019.PubMedGoogle Scholar
  28. Hodges JR, Garrard P, Partterson K. Semantic dementia. (1998) In: Kertesz A, Munoz DG (eds) Pick's disease and Pick complex. New York: Wiley-Liss, Inc., pp. 83–104.Google Scholar
  29. Holroyd S, Currie L, Wooten GF (2001) Prospective study of hallucinations and delusions in Parkinson's disease. J Neurol Neurosurg Psychiat 70:734–738.CrossRefPubMedGoogle Scholar
  30. Johnson JK, Head E, Kim R, Starr A, Cotman CW (1999) Clinical and pathological evidence for a frontal variant of Alzheimer's disease. Arch Neurol 56:1233–1239.CrossRefPubMedGoogle Scholar
  31. Kermer P, Liman J, Weishaupt JH, Bähr M (2004) Neuronal apoptosis in neurodegenerative diseases: from basic research to clinical application. Neurodegen Dis 1:9–19.CrossRefGoogle Scholar
  32. Kertesz A (1998) Primary progressive aphasia. In: Kertesz A, Munoz DG (eds) Pick's disease and Pick complex. New York: Wiley-Liss, Inc., pp. 69–81.Google Scholar
  33. Levy ML, Miller BL, Cummings JL, Fairbanks LA, Craig A (1996) Alzheimer disease and frontotemporal dementias: behavioral distinctions. Arch Neurol 53:687–690.PubMedGoogle Scholar
  34. Levy ML, Cummings JL, Fairbanks LA, Masterman D, Miller BL, Craig AH, Paulsen JS, Litvan I (1998) Apathy is not depression. J Neuropsychiat Clin Neurosci 10:314–319.Google Scholar
  35. Litvan I, Mega MS, Cummings JL, Fairbanks L (1996) Neuropsychiatric aspects of progressive supranuclear palsy. Neurology 47:1184–1189.PubMedGoogle Scholar
  36. Litvan I, Paulsen JS, Mega MS, Cummings JL (1998) Neuropsychiatric assessment of patients with hyperkinetic and hypokinetic Mov Disord Arch Neurol 55:1313–1319.Google Scholar
  37. Litvan I, Cummings JL, Mega M (1998) Neuropsychiatric features of corticobasal degeneration. J Neurol Neurosurg Psychiat 65:717–721.PubMedGoogle Scholar
  38. Lovestone S, McLoughlin DM (2002) Protein aggregates and dementia: is there a common toxicity? J Neurol Neurosurg Psychiat 72:152–161.CrossRefPubMedGoogle Scholar
  39. Masliah E, Alford M, DeTeresa R, Mallory M, Hansen L (1996) Deficient glutamate transport is associated with neurodegeneration in Alzheimer's disease. Ann Neurol 40:759–766.CrossRefPubMedGoogle Scholar
  40. McLean PJ, Kawamata H, Shariff S, Hewett J, Sharma N, Ueda K, Breakefield XO, Hyman BT (2002) TorsinA and heat shock proteins act as molecular chaperones: suppression of alphasynuclein aggregation. J Neurochem 83:846–854.CrossRefPubMedGoogle Scholar
  41. Mega MS, Cummings JL, Fiorello T, Gornbein J (1996) The spectrum of behavioral changes in Alzheimer's disease. Neurology 46:130–135.PubMedGoogle Scholar
  42. Miller B, Boone K, Mishkin F, Swartz JR, Koras N, Kushii J (1998) Clinical and neuropsychological features of frontotemporal dementia. In: Kertesz A, Munoz DG (eds) Pick's disease and Pick complex. New York: Wiley-Liss, Inc., pp. 23–32.Google Scholar
  43. Munoz DG (1998) The pathology of Pick complex. In: Kertesz A, Munoz DG (eds) Clinical and neuropsychological features of frontotemporal dementia. New York, Wiley-Liss, Inc., pp. 211–241.Google Scholar
  44. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ; Memantine Study Group (2003) Memantine in moderate-to-severe Alzheimer's disease. New Engl J Med 348:1333–1341.CrossRefPubMedGoogle Scholar
  45. Ritchie K, Lovestone S (2002) The dementias. Lancet 360:1759–1766.CrossRefPubMedGoogle Scholar
  46. Ross CA, Poirier MA (2004) Protein aggregation and neurodegenerative disease. Nature Med 5:10–17.CrossRefGoogle Scholar
  47. Sanchez-Ramos J, Ortoll R, Paulson G (1996) Visual hallucinations associated with Parkinson disease. Arch Neurol 53:1265–1268.PubMedGoogle Scholar
  48. Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ (1997) A controlled trial of selegiline, alphatocopherol, or both as treatment for Alzheimer's disease. New Engl J Med 336:1216–1222.CrossRefPubMedGoogle Scholar
  49. Scheff SW, Price DA (2003) Synaptic pathology in Alzheimer's disease: a review of ultrastructural studies. Neurobiol Aging 24:1029–1046.CrossRefPubMedGoogle Scholar
  50. Selkoe DJ (2002) Alzheimer's disease is a synaptic failure. Science 298:789–791.CrossRefPubMedGoogle Scholar
  51. Shoulson I (1998) Experimental therapeutics of neurodegenerative disorders: unmet needs. Science 282:1072–1074.CrossRefPubMedGoogle Scholar
  52. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M; Parkinson Study Group (2002) Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 59:1541–1550.CrossRefPubMedGoogle Scholar
  53. Soto C (2003) Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 4:49–60.CrossRefPubMedGoogle Scholar
  54. Stout JC, Paulsen JS (2003) Assessing cognition in movement disorders. In: Bedard M-A (ed) Mental and behavioral dysfunction in movement disorders. Totowa, NJ: Humana Press, Inc., pp. 85–99.Google Scholar
  55. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I, Memantine Study Group (2004) Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 291:317–324.CrossRefPubMedGoogle Scholar
  56. Taylor JP, Hardy J, Fischbeck KH (2002) Toxic proteins in neurodegenerative disease. Science 296:1991–1995.CrossRefPubMedGoogle Scholar
  57. Tekin S, Mega MS, Masterman DL, Chow T, Garakian J, Vinters HV, Cummings JL (2001) Orbitofrontal and anterior cingulate cortex: neurofibrillary tangle burden is associated with agitation in Alzheimer's disease. Ann Neurol 49:355–361.CrossRefPubMedGoogle Scholar
  58. Trojanowski JQ (2004) Protein mis-folding emerges as a “drugable” target for discovery of novel therapies for neuropsychiatric diseases of aging. Am J Geriatr Psychiat 12:134–135.CrossRefGoogle Scholar
  59. Turner RS (2002) Idiopathic rapid eye movement sleep behavior disorder is a harbinger of dementia with Lewy bodies. J Geriatr Psychiat Neurol 15:195–199.Google Scholar
  60. Trojanowski JQ, Lee VM (2000) “Fatal attractions” of proteins. A comprehensive hypothetical mechanism underlying Alzheimer's disease and other neurodegenerative disorders. Ann NY Acad Sci 924:62–67.PubMedGoogle Scholar
  61. Walker MP, Ayre GA, Cummings JL, Wesnes K, McKeith IG, O'Brien JT, Ballard CG (2000) Quantifying fluctuation in dementia with Lewy bodies, Alzheimer's disease, and vascular dementia. Neurology 54:1616–1624.PubMedGoogle Scholar
  62. Walker MP, Ayre GA, Cummings J, Wesnes K, McKeith IG, O'Brien JT, Ballard CG (2000) The clinician assessment of fluctuation and the one day fluctuation assessment scale. Two methods to assess fluctuating confusion in dementia. Brit J Psychiat 177:252–256.CrossRefPubMedGoogle Scholar
  63. Zhu S, Stavrovskaya IG, Drozda M, Kim BYS, Ona V, Mingwei Li, Satinder Sarang, Liu AS, Hartley DM, Wu DC, Gullans S, Ferrante RJ, Przedborski S, Kristal BS, Friedlander RM (2002) Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417:74–78.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • Jeffrey L. Cummings
    • 1
  1. 1.Departments of Neurology and Psychiatry and Biobehavioral SciencesDavid Geffen School of Medicine at UCLALos AngelesUSA

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