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Parkinson disease (PD) is a late onset disorder with age‐dependent penetrance that may confound genetic studies, since affected individuals may not demonstrate clinical manifestations at the time of evaluation. The use of endophenotypes, biologic surrogates for clinical disease diagnoses, may permit more accurate classification of at‐risk subjects. Positron emission tomography (PET) measurements of 6‐(18F)fluorodopa ((18F)FDOPA) uptake indicate nigrostriatal neuronal integrity and may provide a useful endophenotype for PD linkage studies. We performed (18F)FDOPA PET in 11 members of a large, multi‐incident Amish family with PD, 24 normals and 48 people with clinically definite idiopathic PD (PD controls). Clinical diagnoses in the Amish were clinically definite PD in four, clinically probable in one, clinically possible in five, and normal in one. Abnormal (18F)FDOPA posterior putamen uptake was defined as less than 3 standard deviations below the normal mean. The criteria were applied to the Amish sample to determine a PET endophenotype for each. We performed genetic simulations using SLINK to model the effect phenoconversion with the PET endophenotype had on logarithm of odds (LOD) scores. PET endophenotype confirmed the status of two clinically definite subjects. Two clinically definite Amish PD subjects had normal PETs. Two possible PD were converted to “PET definite PD.” The remainder had normal PETs. The average maximum LOD score with the pre‐PET was 6.14 ± 0.84. Simulating phenoconversion of subjects with unknown phenotypes increased the LOD score to 7.36 ± 1.23. The (18F)FDOPA PET endophenotype permits phenoconversion in multi‐incident PD families and may increase LOD score accuracy and power of an informative pedigree. © 2006 Wiley‐Liss, Inc.
American Journal of Medical Genetics part B – Wiley
Published: Apr 5, 2006
Keywords: Parkinson's disease; positron emission tomography; linkage; endophenotype; Amish
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