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Substantia nigra hyperechogenicity is a risk marker of Parkinson’s disease: yes

  • Movement Disorders - CONy Pro/Con debate
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Abstract

As there is increasing evidence that the neurodegenerative process in Parkinson’s disease (PD) starts years to decades before clinical symptoms allow diagnosis, markers for the identification of subjects at risk are eagerly sought after in order to allow an earlier, disease modulating or even neuroprotective therapy. In recent years, transcranial sonography (TCS) has evolved as a useful instrument in the differential diagnosis and also very early diagnosis of PD. The typical hallmark for PD, hyperechogenicity at the anatomical site of the substantia nigra (SN), can also be found in about 10% of healthy subjects. There is accumulating evidence that SN hyperechogenicity discloses a vulnerability of the nigrostriatal system in at least some of these persons. Moreover, an association of the ultrasound sign with a number of risk and premotor markers has been shown. However, the most striking argument for a relevance of SN hyperechogenicity in healthy subjects can be derived from the observation that some initially healthy subjects with SN hyperechogenicity developed PD in the long run, an observation which has led to longitudinal studies on the predictive value of the ultrasound sign for the development of PD. A first follow up after 3 years of a large cohort of at baseline extrapyramidally healthy individuals revealed a relative risk for incident PD 17.37 times higher in subjects with SN hyperechogenicity at baseline compared to those without this echomarker. Taken together, there is encouraging evidence to implement TCS in a screening battery to identify subjects at risk for the development of PD.

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References

  • Abbott RD, Ross GW, White LR, Sanderson WT, Burchfiel CM, Kashon M, Sharp DS, Masaki KH, Curb JD, Petrovitch H (2003) Environmental, life-style, and physical precursors of clinical Parkinson’s disease: recent findings from the Honolulu-Asia Aging Study. J Neurol 250(Suppl 3):30–39

    Google Scholar 

  • Baumer T, Pramstaller PP, Siebner HR, Schippling S, Hagenah J, Peller M, Gerloff C, Klein C, Munchau A (2007) Sensorimotor integration is abnormal in asymptomatic Parkin mutation carriers: a TMS study. Neurology 69:1976–1981

    Article  PubMed  CAS  Google Scholar 

  • Becker G, Seufert J, Bogdahn U, Reichmann H, Reiners K (1995) Degeneration of substantia nigra in chronic Parkinson’s disease visualized by transcranial color-coded real-time sonography. Neurology 45:182–184

    PubMed  CAS  Google Scholar 

  • Becker G, Muller A, Braune S, Buttner T, Benecke R, Greulich W, Klein W, Mark G, Rieke J, Thumler R (2002) Early diagnosis of Parkinson’s disease. J Neurol 249(Suppl 3):40–48

    Google Scholar 

  • Behnke S, Double KL, Duma S, Broe GA, Guenther V, Becker G, Halliday GM (2007) Substantia nigra echomorphology in the healthy very old: correlation with motor slowing. Neuroimage 34:1054–1059

    Article  PubMed  CAS  Google Scholar 

  • Berg D (2006a) In vivo detection of iron and neuromelanin by transcranial sonography—a new approach for early detection of substantia nigra damage. J Neural Transm 113:775–780

    Article  PubMed  CAS  Google Scholar 

  • Berg D (2006b) Marker for a preclinical diagnosis of Parkinson’s disease as a basis for neuroprotection. J Neural Transm Suppl 71:123–132

    Google Scholar 

  • Berg D (2010) Hyperechogenicity of the substantia nigra: pitfalls in assessment and specificity for Parkinson's disease. J Neural Transm [Epub ahead of print]

  • Berg D, Becker G, Zeiler B, Tucha O, Hofmann E, Preier M, Benz P, Jost W, Reiners K, Lange KW (1999a) Vulnerability of the nigrostriatal system as detected by transcranial ultrasound. Neurology 53:1026–1031

    PubMed  CAS  Google Scholar 

  • Berg D, Grote C, Rausch WD, Maurer M, Wesemann W, Riederer P, Becker G (1999b) Iron accumulation in the substantia nigra in rats visualized by ultrasound. Ultrasound Med Biol 25:901–904

    Article  PubMed  CAS  Google Scholar 

  • Berg D, Jabs B, Merschdorf U, Beckmann H, Becker G (2001a) Echogenicity of substantia nigra determined by transcranial ultrasound correlates with severity of parkinsonian symptoms induced by neuroleptic therapy. Biol Psychiatry 50:463–467

    Article  PubMed  CAS  Google Scholar 

  • Berg D, Siefker C, Becker G (2001b) Echogenicity of the substantia nigra in Parkinson’s disease and its relation to clinical findings. J Neurol 248:684–689

    Article  PubMed  CAS  Google Scholar 

  • Berg D, Roggendorf W, Schroder U, Klein R, Tatschner T, Benz P, Tucha O, Preier M, Lange KW, Reiners K, Gerlach M, Becker G (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 

  • Berg D, Merz B, Reiners K, Naumann M, Becker G (2005a) Five-year follow-up study of hyperechogenicity of the substantia nigra in Parkinson’s disease. Mov Disord 20:383–385

    Article  PubMed  Google Scholar 

  • Berg D, Schweitzer K, Leitner P, Zimprich A, Lichtner P, Belcredi P, Brussel T, Schulte C, Maass S, Nagele T (2005b) Type and frequency of mutations in the LRRK2 gene in familial and sporadic Parkinson’s disease. Brain 128:3000–3011

    PubMed  Google Scholar 

  • Berg D, Hochstr asser H, Schweitzer KJ, Riess O (2006) Disturbance of iron metabolism in Parkinson’s disease—ultrasonography as a biomarker. Neurotox Res 9:1–13

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Berg D, Godau J, Riederer P, Gerlach M, Arzberger T (2010) Microglia activation is related to substantia nigra echogenicity. J Neural Transm 117(11):1287–1292

    Google Scholar 

  • Binkofski F, Reetz K, Gaser C, Hilker R, Hagenah J, Hedrich K, van Eimeren T, Thiel A, Buchel C, Pramstaller PP, Siebner HR, Klein C (2007) Morphometric fingerprint of asymptomatic Parkin and PINK1 mutation carriers in the basal ganglia. Neurology 69:842–850

    Article  PubMed  CAS  Google Scholar 

  • Braak H, Del 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

    Article  PubMed  Google Scholar 

  • Brockmann K, Hagenah J (2010) TCS in monogenic forms of Parkinson's disease. Int Rev Neurobiol 90:157–164

    Google Scholar 

  • Brueggemann N, Odin P, Gruenewald A, Tadic V, Hagenah J, Seidel G, Lohmann K, Klein C, Djarmati A (2008) Re: Alpha-synuclein gene duplication is present in sporadic Parkinson disease. Neurology 71:1294 (author reply 1294)

    Google Scholar 

  • Budisic M, Trkanjec Z, Bosnjak J, Lovrencic-Huzjan A, Vukovic V, Demarin V (2009) Distinguishing Parkinson’s disease and essential tremor with transcranial sonography. Acta Neurol Scand 119:17–21

    Article  PubMed  CAS  Google Scholar 

  • Buhmann C, Binkofski F, Klein C, Buchel C, van Eimeren T, Erdmann C, Hedrich K, Kasten M, Hagenah J, Deuschl G, Pramstaller PP, Siebner HR (2005) Motor reorganization in asymptomatic carriers of a single mutant Parkin allele: a human model for presymptomatic parkinsonism. Brain 128:2281–2290

    Article  PubMed  CAS  Google Scholar 

  • de Lau LM, Koudstaal PJ, Hofman A, Breteler MM (2006) Subjective complaints precede Parkinson disease: the Rotterdam study. Arch Neurol 63:362–365

    Article  PubMed  Google Scholar 

  • Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 114(Pt 5):2283–2301

    Article  PubMed  Google Scholar 

  • Gaenslen A, Unmuth B, Godau J, Liepelt I, Di Santo A, Schweitzer KJ, Gasser T, Machulla HJ, Reimold M, Marek K, Berg D (2008) The specificity and sensitivity of transcranial ultrasound in the differential diagnosis of Parkinson’s disease: a prospective blinded study. Lancet Neurol 7:417–424

    Article  PubMed  Google Scholar 

  • Gaig C, Tolosa E (2009) When does Parkinson’s disease begin? Mov Disord 24(Suppl 2):S656–S664

    Google Scholar 

  • Haehner A, Hummel T, Hummel C, Sommer U, Junghanns S, Reichmann H (2007) Olfactory loss may be a first sign of idiopathic Parkinson’s disease. Mov Disord 22:839–842

    Article  PubMed  Google Scholar 

  • Hagenah JM, Konig IR, Becker B, Hilker R, Kasten M, Hedrich K, Pramstaller PP, Klein C, Seidel G (2007) Substantia nigra hyperechogenicity correlates with clinical status and number of Parkin mutated alleles. J Neurol 254:1407–1413

    Article  PubMed  CAS  Google Scholar 

  • Hagenah JM, Becker B, Bruggemann N, Djarmati A, Lohmann K, Sprenger A, Klein C, Seidel G (2008) Transcranial sonography findings in a large family with homozygous and heterozygous PINK1 mutations. J Neurol Neurosurg Psychiatry 79:1071–1074

    Article  PubMed  CAS  Google Scholar 

  • Hedrich K, Winkler S, Hagenah J, Kabakci K, Kasten M, Schwinger E, Volkmann J, Pramstaller PP, Kostic V, Vieregge P, Klein C (2006) Recurrent LRRK2 (Park8) mutations in early-onset Parkinson’s disease. Mov Disord 21:1506–1510

    Article  PubMed  Google Scholar 

  • Hornykiewicz O, Kish SJ (1987) Biochemical pathophysiology of Parkinson’s disease. Adv Neurol 45:19–34

    PubMed  CAS  Google Scholar 

  • Huang YW, Jeng JS, Tsai CF, Chen LL, Wu RM (2007) Transcranial imaging of substantia nigra hyperechogenicity in a Taiwanese cohort of Parkinson’s disease. Mov Disord 22:550–555

    Article  PubMed  Google Scholar 

  • Iranzo A, Molinuevo JL, Santamaria J, Serradell M, Marti MJ, Valldeoriola F, Tolosa E (2006) Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol 5:572–577

    Article  PubMed  Google Scholar 

  • Kim JY, Kim ST, Jeon SH, Lee WY (2007) Midbrain transcranial sonography in Korean patients with Parkinson’s disease. Mov Disord 22:1922–1926

    Article  PubMed  Google Scholar 

  • Kolevski G, Petrov I, Petrova V (2007) Transcranial sonography in the evaluation of Parkinson disease. J Ultrasound Med 26:509–512

    PubMed  Google Scholar 

  • Lees AJ, Hardy J, Revesz T (2009) Parkinson’s disease. Lancet 373:2055–2066

    Article  PubMed  CAS  Google Scholar 

  • Liepelt I, Wendt A, Schweitzer KJ, Wolf B, Godau J, Gaenslen A, Bruessel T, Berg D (2008) Substantia nigra hyperechogenicity assessed by transcranial sonography is related to neuropsychological impairment in the elderly population. J Neural Transm 115:993–999

    Article  PubMed  Google Scholar 

  • Liepelt I, Behnke S, Schweitzer K, Wolf B, Godau J, Wollenweber F, Dillmann U, Gaenslen A, Di Santo A, Maetzler W, Berg D (2009) Pre-motor signs of PD are r elated to SN hyperechogenicity assessed by TCS in an elderly population. Neurobiol Aging [Epub ahead of print]

  • Marder K, Tang MX, Mejia H, Alfaro B, Cote L, Louis E, Groves J, Mayeux R (1996) Risk of Parkinson’s disease among first-degree relatives: a community-based study. Neurology 47:155–160

    PubMed  CAS  Google Scholar 

  • Mijajlovic M, Dragasevic N, Stefanova E, Petrovic I, Svetel M, Kostic VS (2008) Transcranial sonography in spinocerebellar ataxia type 2. J Neurol 255:1164–1167

    Article  PubMed  Google Scholar 

  • Okawa M, Miwa H, Kajimoto Y, Hama K, Morita S, Nakanishi I, Kondo T (2007) Transcranial sonography of the substantia nigra in Japanese patients with Parkinson’s disease or atypical parkinsonism: clinical potential and limitations. Intern Med 46:1527–1531

    Article  PubMed  Google Scholar 

  • Ressner P, Skoloudik D, Hlustik P, Kanovsky P (2007) Hyper echogenicity of the substantia nigra in Parkinson’s disease. J Neuroimaging 17:164–167

    Article  PubMed  Google Scholar 

  • Riederer P, Wuketich S (1976) Time course of nigrostriatal degeneration in Parkinson’s disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm 38:277–301

    Article  PubMed  CAS  Google Scholar 

  • Ruprecht-Dorfler P, Berg D, Tucha O, Benz P, Meier-Meitinger M, Alders GL, Lange KW, Becker G (2003) Echogenicity of the substantia nigra in relatives of patients with sporadic Parkinson’s disease. Neuroimage 18:416–422

    Article  PubMed  Google Scholar 

  • Schweitzer KJ, Behnke S, Liepelt I, Wolf B, Grosser C, Godau J, Gaenslen A, Bruessel T, Wendt A, Abel F, Muller A, Gasser T, Berg D (2007a) Cross-sectional study discloses a positive family history for Parkinson’s disease and male gender as epidemiological risk factors for substantia nigra hyperechogenicity. J Neural Transm 114:1167–1171

    Article  PubMed  CAS  Google Scholar 

  • Schweitzer KJ, Brussel T, Leitner P, Kruger R, Bauer P, Woitalla D, Tomiuk J, Gasser T, Berg D (2007b) Transcranial ultrasound in different monogenetic subtypes of Parkinson’s disease. J Neurol 254:613–616

    Article  PubMed  Google Scholar 

  • Semchuk KM, Love EJ, Lee RG (1993) Parkinson’s disease: a test of the multifactorial etiologic hypothesis. Neurology 43:1173–1180

    PubMed  CAS  Google Scholar 

  • Spiegel J, Hellwig D, Mollers MO, Behnke S, Jost W, Fassbender K, Samnick S, Dillmann U, Becker G, Kirsch CM (2006) Transcranial sonography and [123I] FP-CIT SPECT disclose complementary aspects of Parkinson’s disease. Brain 129:1188–1193

    Article  PubMed  Google Scholar 

  • Stockner H, Iranzo A, Seppi K, Serradell M, Gschliesser V, Sojer M, Valldeoriola F, Molinuevo JL, Frauscher B, Schmidauer C, Santamaria J, Hogl B, Tolosa E, Poewe W (2009) Midbrain hyperechogenicity in idiopathic REM sleep behavior disorder. Mov Disord 24:1906–1909

    Article  PubMed  Google Scholar 

  • Tolosa E, Compta Y, Gaig C (2007) The premotor phase of Parkinson’s disease. Parkinsonism Relat Disord 13(Suppl):S2–S7

    Google Scholar 

  • Tsai CF, Wu RM, Huang YW, Chen LL, Yip PK, Jeng JS (2007) Transcranial color-coded sonography helps differentiation between idiopathic Parkinson’s disease and vascular parkinsonism. J Neurol 254:501–507

    Article  PubMed  Google Scholar 

  • Unger MM, Moller JC, Ohletz T, Stiasny-Kolster K, Oertel WH, Mayer G (2009) Transcranial midbrain sonography in narcoleptic subjects with and without concomitant REM sleep behaviour disorder. J Neurol 256:874–877

    Article  PubMed  Google Scholar 

  • van de Loo S, Walter U, Behnke S, Hagenah J, Lorenz M, Sitzer M, Hilker R, Berg D (2010) Reproducibility and diagnostic accuracy of substantia nigra sonography for the diagnosis of Parkinson's disease. J Neurol Neurosurg Psychiatry 81(10):1087–1092

    Google Scholar 

  • Vlaar AM, Bouwmans A, Mess WH, Tromp SC, Weber WE (2009) Transcranial duplex in the differential diagnosis of parkinsonian syndromes: a systematic review. J Neurol 256:530–538

    Article  PubMed  Google Scholar 

  • Walter U, Wittstock M, Benecke R, Dressler D (2002) Substantia nigra echogenicity is normal in non-extrapyramidal cerebral disorders but increased in Parkinson’s disease. J Neural Transm 109:191–196

    Article  PubMed  CAS  Google Scholar 

  • Walter U, Klein C, Hilker R, Benecke R, Pramstaller PP, Dressler D (2004) Brain parenchyma sonography detects preclinical parkinsonism. Mov Disord 19:1445–1449

    Article  PubMed  Google Scholar 

  • Walter U, Behnke S, Eyding J, Niehaus L, Postert T, Seidel G, Berg D (2007a) Transcranial brain parenchyma sonography in movement disorders: state of the art. Ultrasound Med Biol 33:15–25

    Article  PubMed  Google Scholar 

  • Walter U, Hoeppner J, Prudente-Morrissey L, Horowski S, Herpertz SC, Benecke R (2007b) Parkinson’s disease-like midbrain sonography abnormalities are frequent in depressive disorders. Brain 130:1799–1807

    Article  PubMed  Google Scholar 

  • Weise D, Lorenz R, Schliesser M, Schirbel A, Reiners K, Classen J (2009) Substantia nigra echogenicity: a structural correlate of functional impairment of the dopaminergic striatal projection in Parkinson’s disease. Mov Disord 24:1669–1675

    Article  PubMed  Google Scholar 

  • Zecca L, Berg D, Arzberger T, Ruprecht P, Rausch WD, Musicco M, Tampellini D, Riederer P, Gerlach M, Becker G (2005) In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage. Mov Disord 20:1278–1285

    Article  PubMed  Google Scholar 

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  1. Department of Neurodegeneration, Hertie-Institute of Clinical Brain Research and German Center for Neurodegenerative Diseases (DZNE), University of Tuebingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany

    Daniela Berg

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Berg, D. Substantia nigra hyperechogenicity is a risk marker of Parkinson’s disease: yes. J Neural Transm 118, 613–619 (2011). https://doi.org/10.1007/s00702-010-0565-6

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