Skip to main content

Neurobildgebung genetischer Aspekte der Parkinson-Krankheit

Imaging of genetic aspects of Parkinson’s disease

Der Nervenarzt volume 81, pages 1196–1203 (2010)Cite this article

Zusammenfassung

Die Pathogenese der idiopathischen Parkinson-Krankheit (PK) ist bisher weitgehend unbekannt. Genetische Faktoren scheinen wesentlich an der Krankheitsentstehung beteiligt zu sein. In besonderer Weise gilt dies für monogene Formen, bei denen Veränderungen in einem einzigen Gen zu einem Parkinson-Syndrom führen können. Wenngleich relativ selten, eröffnen die monogen verursachten Formen der PK einzigartige Möglichkeiten, die pathophysiologischen Mechanismen der PK aufzuklären. Dieser Übersichtsartikel beleuchtet, wie Neurobildgebung und Neurogenetik miteinander kombiniert werden können, um pathophysiologische Aspekte der PK zu ergründen. Hierbei wird besonders auf den Einsatz der Neurobildgebung bei nicht erkrankten Mutationsträgern eingegangen, um präklinische Stadien der PK zu erforschen. Dieser Ansatz kann wesentlich zur Klärung der Frage beitragen, wie das motorische System eine latente nigrostriatale dopaminerge Dysfunktion kompensieren und somit die klinische Manifestation der PK hinauszögern kann.

Summary

Although the mechanisms which cause Parkinson’s disease (PD) are still poorly understood, research on monogenic forms of PD have demonstrated a significant genetic contribution to its etiology. Monogenic forms of PD only account for a minority of cases but offer a unique avenue of research into the pathogenesis of PD. In this article the potential of structural and functional neuroimaging in monogenic forms to provide general insights into the pathophysiology of PD, including the more common idiopathic disease is reviewed. The review has a particular focus on neuroimaging of non-manifesting mutation carriers to study functional and structural changes in the brain at the asymptomatic stage of PD. This line of research has started to provide valuable insights into how the brain can cope with a latent nigrostriatal dopaminergic deficit and thereby delay the clinical onset of PD.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Abb. 1
Abb. 2

Literatur

  1. Adams JR, Netten H van, Schulzer M et al (2005) PET in LRRK2 mutations: comparison to sporadic Parkinson’s disease and evidence for presymptomatic compensation. Brain 128:2777–2785

    Article  PubMed  Google Scholar 

  2. Ahn TB, Kim SY, Kim JY et al (2008) alpha-Synuclein gene duplication is present in sporadic Parkinson disease. Neurology 70:43–49

    Article  PubMed  Google Scholar 

  3. Albanese A, Valente EM, Romito LM et al (2005) The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. Neurology 64:1958–1960

    Article  PubMed  Google Scholar 

  4. Ashburner J, Friston KJ (2000) Voxel-based morphometry – the methods. Neuroimage 11:805–821

    Article  PubMed  Google Scholar 

  5. Berg D, Godau J, Walter U (2008) Transcranial sonography in movement disorders. Lancet Neurol 7:1044–1055

    Article  PubMed  Google Scholar 

  6. Berg D, Roggendorf W, Schroder U et al (2002) Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol 59:999–1005

    Article  PubMed  Google Scholar 

  7. Binkofski F, Reetz K, Gaser C et al (2007) Morphometric fingerprint of asymptomatic Parkin and PINK1 mutation carriers in the basal ganglia. Neurology 69:842–850

    Article  PubMed  Google Scholar 

  8. Bonifati V, Rizzu P, Baren MJ van et al (2003) Mutations in the DJ-1 gene associated with autosomal-recessive early-onset parkinsonism. Science 299:256–259

    Article  PubMed  Google Scholar 

  9. Brooks DJ (2004) Neuroimaging in Parkinson’s disease. NeuroRx 1:243–254

    Article  PubMed  Google Scholar 

  10. Brueggemann N, Odin P, Gruenewald A et al (2008) Re: Alpha-synuclein gene duplication is present in sporadic Parkinson disease. Neurology 71:1294 (author reply 1294)

    Article  PubMed  Google Scholar 

  11. Buhmann C, Binkofski F, Klein C et al (2005) Motor reorganization in asymptomatic carriers of a single mutant Parkin allele: a human model for presymptomatic parkinsonism. Brain 128:2281–2290

    Article  PubMed  Google Scholar 

  12. Lau LM de, Breteler MM (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535

    Article  PubMed  Google Scholar 

  13. Rijk MC de, Launer LJ, Berger K et al (2000) Prevalence of Parkinson’s disease in Europe: A collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54:S21–S23

    PubMed  Google Scholar 

  14. Dekker MC, Eshuis SA, Maguire RP et al (2004) PET neuroimaging and mutations in the DJ-1 gene. J Neural Transm 111:1575–1581

    Article  PubMed  Google Scholar 

  15. Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160:636–645

    Article  PubMed  Google Scholar 

  16. Hagenah JM, Becker B, Bruggemann N et al (2008) Transcranial sonography findings in a large family with homozygous and heterozygous PINK1 mutations. J Neurol Neurosurg Psychiatry 79:1071–1074

    Article  PubMed  Google Scholar 

  17. Hagenah JM, Konig IR, Becker B et al (2007) Substantia nigra hyperechogenicity correlates with clinical status and number of Parkin mutated alleles. J Neurol 254:1407–1413

    Article  PubMed  Google Scholar 

  18. Hedrich K, Hagenah J, Djarmati A et al (2006) Clinical spectrum of homozygous and heterozygous PINK1 mutations in a large German family with Parkinson disease: role of a single hit? Arch Neurol 63:833–838

    Article  PubMed  Google Scholar 

  19. Hering R, Strauss KM, Tao X et al (2004) Novel homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7). Hum Mutat 24:321–329

    Article  PubMed  Google Scholar 

  20. Hilker R, Klein C, Ghaemi M et al (2001) Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 49:367–376

    Article  PubMed  Google Scholar 

  21. Hu MT, Scherfler C, Khan NL et al (2006) Nigral degeneration and striatal dopaminergic dysfunction in idiopathic and Parkin-linked Parkinson’s disease. Mov Disord 21:299–305

    Article  PubMed  Google Scholar 

  22. Isaias IU, Benti R, Goldwurm S et al (2006) Striatal dopamine transporter binding in Parkinson’s disease associated with the LRRK2 Gly2019Ser mutation. Mov Disord 21:1144–1147

    Article  PubMed  Google Scholar 

  23. Kessler KR, Hamscho N, Morales B et al (2005) Dopaminergic function in a family with the PARK6 form of autosomal-recessive Parkinson’s syndrome. J Neural Transm 112:1345–1353

    Article  PubMed  Google Scholar 

  24. Khan NL, Brooks DJ, Pavese N et al (2002) Progression of nigrostriatal dysfunction in a parkin kindred: an [18F]dopa PET and clinical study. Brain 125:2248–2256

    Article  PubMed  Google Scholar 

  25. Khan NL, Jain S, Lynch JM et al (2005) Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson’s disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 128:2786–2796

    Article  PubMed  Google Scholar 

  26. Khan NL, Valente EM, Bentivoglio AR et al (2002) Clinical and subclinical dopaminergic dysfunction in PARK6-linked parkinsonism: an 18F-dopa PET study. Ann Neurol 52:849–853

    Article  PubMed  Google Scholar 

  27. Kitada T, Asakawa S, Hattori N et al (1998) Mutations in the parkin gene cause autosomal-recessive juvenile parkinsonism. Nature 392:605–608

    Article  PubMed  Google Scholar 

  28. Kruger R, Kuhn W, Leenders KL et al (2001) Familial parkinsonism with synuclein pathology: clinical and PET studies of A30P mutation carriers. Neurology 56:1355–1362

    PubMed  Google Scholar 

  29. Lang AE, Obeso JA (2004) Challenges in Parkinson’s disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol 3:309–316

    Article  PubMed  Google Scholar 

  30. Lee CS, Samii A, Sossi V et al (2000) In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 47:493–503

    Article  PubMed  Google Scholar 

  31. Logothetis NK (2008) What we can do and what we cannot do with fMRI. Nature 453:869–878

    Article  PubMed  Google Scholar 

  32. Nandhagopal R, McKeown MJ, Stoessl AJ (2008) Functional imaging in Parkinson disease. Neurology 70:1478–1488

    Article  PubMed  Google Scholar 

  33. Paisan-Ruiz C, Jain S, Evans EW et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron 44:595–600

    Article  PubMed  Google Scholar 

  34. Pellecchia MT, Varrone A, Annesi G et al (2007) Parkinsonism and essential tremor in a family with pseudo-dominant inheritance of PARK2: an FP-CIT SPECT study. Mov Disord 22:559–563

    Article  PubMed  Google Scholar 

  35. Piccini P (2004) Neurodegenerative movement disorders: the contribution of functional imaging. Curr Opin Neurol 17:459–466

    Article  PubMed  Google Scholar 

  36. Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    Article  PubMed  Google Scholar 

  37. Reetz K, Gaser C, Klein C et al (2009) Structural findings in the basal ganglia in genetically determined and idiopathic Parkinson’s disease. Mov Disord 24:99–103

    Article  PubMed  Google Scholar 

  38. Reetz K, Lencer R, Steinlechner S et al (2008) Limbic and frontal cortical degeneration is associated with psychiatric symptoms in PINK1 mutation carriers. Biol Psychiatry 64:241–247

    Article  PubMed  Google Scholar 

  39. Reetz K, Siebner HR, Gaser C et al (2008) Premotor Gray Matter Volume is Associated with Clinical Findings in Idiopathic and Genetically Determined Parkinson’s Disease. Open Neuroimag J 2:102–105

    Article  PubMed  Google Scholar 

  40. Reetz K, Tadic V, Kasten M et al (2010) Structural imaging in the presymptomatic stage of genetically determined parkinsonism. Neurobiol Dis 39:402–408

    Article  PubMed  Google Scholar 

  41. Samii A, Markopoulou K, Wszolek ZK et al (1999) PET studies of parkinsonism associated with mutation in the alpha-synuclein gene. Neurology 53:2097–2102

    PubMed  Google Scholar 

  42. Scherfler C, Khan NL, Pavese N et al (2004) Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism. Brain 127:1332–1342

    Article  PubMed  Google Scholar 

  43. Scherfler C, Khan NL, Pavese N et al (2006) Upregulation of dopamine D2 receptors in dopaminergic drug-naive patients with Parkin gene mutations. Mov Disord 21:783–788

    Article  PubMed  Google Scholar 

  44. Shih MC, Amaro E Jr, Ferraz HB et al (2006) Neuroimaging of the dopamine transporter in Parkinsons disease: first study using [99mTc]-TRODAT-1 and SPECT in Brazil. Arq Neuropsiquiatr 64:628–634

    PubMed  Google Scholar 

  45. Siebner HR, Callicott JH, Sommer T, Mattay VS (2009) From the genome to the phenome and back: linking genes with human brain function and structure using genetically informed neuroimaging. Neuroscience 164:1–6

    Article  PubMed  Google Scholar 

  46. Steinlechner S, Stahlberg J, Voelkel B et al (2007) Co-occurrence of affective and schizophrenia spectrum disorders with PINK1 mutations. J Neurol Neurosurg Psychiatry 78:532–535

    Article  PubMed  Google Scholar 

  47. Valente EM, Abou-Sleiman PM, Caputo V et al (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–1160

    Article  PubMed  Google Scholar 

  48. Vegt JP van der, Nuenen BF van, Bloem BR et al (2009) Imaging the impact of genes on Parkinson’s disease. Neuroscience 164:191–204

    Article  PubMed  Google Scholar 

  49. Eimeren T van, Binkofski F, Buhmann C et al (2010) Imaging movement-related activity in medicated Parkin-associated and sporadic Parkinson’s disease. Parkinsonism Relat Disord 16:384–387

    Article  PubMed  Google Scholar 

  50. Eimeren T van, Siebner HR (2006) An update on functional neuroimaging of parkinsonism and dystonia. Curr Opin Neurol 19:412–419

    Article  PubMed  Google Scholar 

  51. Nuenen BF van, Weiss MM, Bloem BR et al (2009) Heterozygous carriers of a Parkin or PINK1 mutation share a common functional endophenotype. Neurology 72:1041–1047

    Article  PubMed  Google Scholar 

  52. Varrone A, Pellecchia MT, Amboni M et al (2004) Imaging of dopaminergic dysfunction with [123I]FP-CIT SPECT in early-onset parkin disease. Neurology 63:2097–2103

    PubMed  Google Scholar 

  53. Verstappen CC, Bloem BR, Haaxma CA et al (2007) Diagnostic value of asymmetric striatal D2 receptor upregulation in Parkinson’s disease: an [123I]IBZM and [123I]FP-CIT SPECT study. Eur J Nucl Med Mol Imaging 34:502–507

    Article  PubMed  Google Scholar 

  54. Zimprich A, Biskup S, Leitner P et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607

    Article  PubMed  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

Author information

Affiliations

  1. Sektion für Klinische und Molekulare Neurogenetik an der Klinik für Neurologie, Universität zu Lübeck, Lübeck, Deutschland

    N. Brüggemann & C. Klein

  2. Danish Research Centre for Magnetic Resonance, Universitätsklinikum Hvidovre der Universität zu Kopenhagen, Hvidovre Kettegaard Allé 30, 2650, Hvidovre, Dänemark

    N. Brüggemann, J. Vegt &  H.R. Siebner

  3. Abteilung für Neurologie, Radboud-Universität Nijmegen, Nijmegen, Niederlande

    J. Vegt

Authors
  1. N. Brüggemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Vegt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H.R. Siebner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to H.R. Siebner.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Brüggemann, N., Vegt, J., Klein, C. et al. Neurobildgebung genetischer Aspekte der Parkinson-Krankheit. Nervenarzt 81, 1196–1203 (2010). https://doi.org/10.1007/s00115-010-3024-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00115-010-3024-6

Schlüsselwörter

  • Parkinson-Krankheit
  • Neurogenetik
  • Magnetresonanztomographie
  • Positronenemissionstomographie
  • Voxelbasierte Morphometrie

Keywords

  • Parkinson disease
  • Neurogenetics
  • Magnetic resonance imaging
  • Positron emission tomography
  • Voxel-based morphometry