Abstract
Preclinical Parkinson’s disease (PD) can be defined as a state that precedes the diagnosis of PD but without the presence of the characteristic motor features of the disorder. In such a situation, subtle non-motor features may be present or subclinical abnormalities may exist that can be detected only by physiologic testing. Alternatively, lifelong traits such as genetic mutations may predict the onset of PD in the absence of any clinical or physiologic abnormalities. A number of diagnostic technologies are currently available that can detect both preclinical states and traits that will lead to PD in the future. The current challenges are to refine these technologies and to determine how they should be employed so that their use is ethical, practical, and meaningful to at-risk individuals.
Similar content being viewed by others
References and Recommended Reading
Polymeropoulos MH, Lavedan C, Leroy E, et al.: Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 1997, 276:2045–2047.
Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R: Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews [see comment]. N Engl J Med 2004, 351:1972–1977.
Lucking CB, Durr A, Bonifati V, et al.: Association between early-onset Parkinson’s Disease and mutations in the parkin gene. N Engl J Med 2000, 342:1560–1567.
Genetic screening for a single common LRRK2 mutation in familial Parkinson’s disease. Lancet 2005, 365:410–411.
Piccini P, Burn DJ, Ceravolo R, et al.: The role of inheritance in sporadic Parkinson’s Disease: Evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol 1999, 45:577–582.
Marek KL, Seibyl JP, Zoghbi SS, et al.: [123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson’s disease. Neurology 1996, 46:231–237.
Montgomery EB, Baker KB, Lyons K, Koller WC: Abnormal performance on the PD test battery by asymptomatic first-degree relatives. Neurology 1999, 52:757–762.
Ponsen MM, Stoffers D, Booij J, et al.: Idiopathic Hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 2004, 56:173–181. This study describes the prospective identification of individuals with preclinical PD. At-risk individuals were first identified using a combination of olfactory testing and SPECT imaging and then followed prospectively to determine if they developed clinical PD.
Stern MB: The preclinical detection of Parkinson’s disease: ready for prime time? Ann Neurol 2004, 56:169–171.
Armstrong K, Calzone K, Stopfer J, et al.: Factors associated with decisions about clinical BRCA1/2 testing. Cancer Epidemiol Biomarkers Prevention 2000, 9:1251–1254.
Quaid KA, Morris M: Reluctance to undergo predictive testing - the case of Huntington disease. Am J Med Genet 1993, 45:41–45.
Parkinson Study Group: A controlled, randomized, delayed-start study of rasagilinie in early Parkinson’s disease. Arch Neurol 2004, 61:561–566.
Ravina BM, Fagan SC, Hart RG, et al.: Neuroprotective agents for clinical trials in Parkinson’s disease: a systematic assessment. Neurology 2003, 60:1234–1240. This is a systematic review of compounds with potential neuroprotective properties. The paper describes the preclinical and clinical evidence for efficacy.
Shults CW, Oakes D, Kieburtz K, et al.: Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002, 59:1541–1550.
Lang AE, Gill SS, Patel NK, et al.: Randomized, controlled trial of intraputamenal GDNF infusion in Parkinson’s disease. Ann Neurol 2006, 59:459–466.
Hughes AJ, Daniel SE, Kilford L, Lees AJ: Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992, 55:181–184.
Gelb DJ, Oliver E, Gilman S: Diagnostic criteria for Parkinson disease. Archives of Neurology 1999, 56:33–39.
Petersen RC, Smith GE, Waring SC, et al.: Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999, 56:303–308.
Morrish PK, Sawle GV, Brooks DJ: The rate of progression of Parkinson’s disease. A longitudinal [18F]DOPA PET study. Adv Neurol 1996, 69:427–431.
Marek KL, Seibyl JP, Zoghbi SS, et al.: [123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson’s disease. Neurology 1996, 46:231–237.
Dekker MC, Bonifati V, van Duijn CM: Parkinson’s disease: piecing together a genetic jigsaw. Brain 2003, 126(Pt 8):1722–1733.
Braak H, Del Tredici K, Rub U, et al.: Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003, 24:197–211. This paper describes a staging system for Lewy body pathology. The authors suggest that the earliest pathology in PD may not be in the substantia nigra.
Piccini P, Burn DJ, Ceravolo R, et al.: The role of inheritance in sporadic Parkinson’s Disease: Evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol 1999, 45:577–582.
Jennings DL, Seibyl JP, Oakes D, et al.: (123I) beta-CIT and single-photon emission computed tomographic imaging vs clinical evaluation in Parkinsonian syndrome: unmasking an early diagnosis. Arch Neurol 2004, 61:1224–1229.
Mozley PD, Schneider JS, Acton PD, et al.: Binding of [99mTc]TRODAT-1 to dopamine transporters in patients with Parkinson’s disease and in healthy volunteers. J Nucl Med 2000, 41:584–589.
Chou KL, Hurtig HI, Stern MB, et al.: Diagnostic accuracy of [99mTc]TRODAT-1 SPECT imaging in early Parkinson’s disease. Parkinsonism Related Disord 2004, 10:375–379.
Becker G, Seufert J, Bogdahn U, et al.: Degeneration of substantia nigra in chronic Parkinson’s disease visualized by transcranial color-coded real-time sonography. Neurology 1995, 45:182–184.
Berg D, Siefker C, Becker G: Echogenicity of the substantia nigra in Parkinson’s disease and its relation to clinical findings. J Neurol 2001, 248:684–689. This is the first report of abnormal transcranial sonography in PD.
Walter U, Niehaus L, Probst T, et al.: Brain parenchyma sonography discriminates Parkinson’s disease and atypical parkinsonian syndromes. Neurology 2003, 60:74–77.
Berg D, Roggendorf W, Schroder U, et al.: Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol 2002, 59:999–1005.
Ruprecht-Dorfier P, Berg D, Tucha O, et al.: Echogenicity of the substantia nigra in relatives of patients with sporadic Parkinson’s disease. Neuroimage 2003, 18:416–422.
Braune S, Reinhardt M, Bathmann J, et al.: Impaired cardiac uptake of meta-[123I]iodobenzylguanidine in Parkinson’s disease with autonomic failure. Acta Neurol Scand 1998, 97:307–314.
Braune S, Reinhardt M, Schnitzer R, et al.: Cardiac uptake of [123I]MIBG separates Parkinson’s disease from multiple system atrophy. Neurology 1999, 53:1020–1025.
Yoshita M: Differentiation of idiopathic Parkinson’s disease from striatonigral degeneration and progressive supranuclear palsy using iodine-123 meta-iodobenzylguanidine myocardial scintigraphy. J Neurol Sci 1998, 155:60–67.
Courbon F, Brefel-Courbon C, Thalamas C, et al.: Cardiac MIBG scintigraphy is a sensitive tool for detecting cardiac sympathetic denervation in Parkinson’s disease. Mov Disord 2003, 18:890–897.
Muller A, Reichmann H, Livermore A, Hummel T: Olfactory function in idiopathic Parkinson’s disease (IPD): results from cross-sectional studies in IPD patients and longterm follow-up of de-novo IPD patients. J Neural Transm 2002, 109:805–811.
Doty RL, Deems DA, Stellar S: Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 1988, 38:1237–1244.
Doty RL, Golbe LI, McKeown DA, et al.: Olfactory testing differentiates between progressive supranuclear palsy and idiopathic Parkinson’s disease. Neurology 1993, 43:962–965.
Stern MB, Doty RL, Dotti M, et al.: Olfactory function in Parkinson’s disease subtypes. Neurology 1994, 44:266–268.
Khan NL, Katzenschlager R, Watt H, et al.: Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease. Neurology 2004, 62:1224–1226.
Doty RL, Shaman P, Dann M: Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol Behav 1984, 32:489–502.
Doty RL, Bromley SM, Stern MB: Olfactory testing as an aid in the diagnosis of Parkinson’s disease: development of optimal discrimination criteria. Neurodegeneration 1995, 4:93–97.
Siderowf A, Newberg AB, Chou KL, et al.: TRODAT-1 SPECT imaging correlates with odor identification in early Parkinson’s disease. Neurology 2005, 64:1716–1720.
Weintraub D, Moberg PJ, Duda JE, et al.: Effect of psychiatric and other nonmotor symptoms on disability in Parkinson’s disease. J Am Geriatr Soc 2004, 52:784–788.
Menza MA, Mark MH, Burn DJ, Brooks DJ: Personalitycorrelates of [F-18] dopa striatal uptake—results of positron-emission tomography in Parkinsons disease. J Neuropsychiatry Clin Neurosci 1995, 7:176–179.
Glosser G, Clark C, Freundlich B, et al.: Controlled investigation of current and premorbid personality: characteristics of Parkinson’s disease patients. Mov Disord 1995, 10:201–206.
Hubble JP, Venkatesh R, Hassanein RE, et al.: Personality and depression in Parkinson’s disease. J Nervous Mental Dis 1993, 181:657–662.
Leentjens AF, Van den AkkerM, Metsemakers JF, et al.: Higher incidence of depression preceding the onset of Parkinson’s disease: a register study. Mov Disord 2003, 18:414–418.
Shiba M, Bower JH, Maraganore DM, et al.: Anxiety disorders and depressive disorders preceding Parkinson’s disease: a case-control study. Mov Disord 2000, 15:669–677.
Gonera EG, van HofM, Berger HJ, et al.: Symptoms and duration of the prodromal phase in Parkinson’s disease. Mov Disord 1997, 12:871–876.
Schenck CH, Bundlie SR, Mahowald MW: Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. Neurology 1996, 46:388–393.
Eisensehr I, Linke R, Noachtar S, et al.: Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson’s disease and controls. Brain 2000, 123:1155–1160.
Plazzi G, Cortelli P, Montagna P, et al.: REM sleep behaviour disorder differentiates pure autonomic failure from multiple system atrophy with autonomic failure. J Neurol Neurosurg Psychiatry 1998, 64:683–685.
Kessler S, Field T, Worth L, Mosbarger H: Attitudes of persons at risk for Huntington disease toward predictive testing. Am J Med Genet 1987, 26:259–270.
Markel DS, Young AB, Penney JB: At-risk persons’ attitudes toward presymptomatic and prenatal testing of Huntington disease in Michigan. Am J Med Genet 1987, 26:295–305.
Mastromauro C, Myers RH, Berkman B: Attitudes toward presymptomatic testing in Huntington disease. Am J Med Genet 1987, 26:271–282.
Babul R, Adam S, Kremer B, et al.: Attitudes toward direct predictive testing for the huntington disease gene—relevance for other adult-onset disorders. JAMA 1993, 270:2321–2325.
Parkinson Study Group: Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1993, 328:176–183.
McKinnon WC, Baty BJ, Bennett RL, et al.: Predisposition genetic testing for late-onset disorders in adults—a position paper of the National Society of Genetic Counselors. JAMA 1997, 278:1217–1220.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Siderowf, A., Stern, M.B. Preclinical diagnosis of parkinson’s disease: Are we there yet?. Curr Neurol Neurosci Rep 6, 295–301 (2006). https://doi.org/10.1007/s11910-006-0021-z
Issue Date:
DOI: https://doi.org/10.1007/s11910-006-0021-z