Imaging prodromal Parkinson disease: The Parkinson Associated Risk Syndrome Study

Abstract

Objectives: The purpose of this study is to evaluate the relative risk of abnormal dopamine transporter (DAT) imaging for subjects with and without hyposmia and the feasibility of acquiring a large, community-based, 2-tiered biomarker assessment strategy to detect prodromal Parkinson disease (PD).Methods: In this observational study, individuals without a diagnosis of PD, recruited through 16 movement disorder clinics, underwent tier 1 assessments (olfactory testing, questionnaires). Tier 2 assessments (neurologic examination, DAT imaging, and other biomarker assessments) were completed by 303 subjects. The main outcome of the study is to compare age-expected [ 123 I]b-CIT striatal binding ratio in hyposmic and normosmic subjects.Results: Tier 1 assessments were mailed to 9,398 eligible subjects and returned by 4,999; 669 were hyposmic. Three hundred three subjects (203 hyposmic, 100 normosmic) completed baseline evaluations. DAT deficit was present in 11% of hyposmic subjects compared with 1% of normosmic subjects. Multiple logistic regression demonstrates hyposmia (odds ratio [OR] 12.4; 95% confidence interval [CI] 1.6, 96.1), male sex (OR 5.5; 95% CI 1.7, 17.2), and constipation (OR 4.3; 95% CI 1.6, 11.6) as factors predictive of DAT deficit. Combining multiple factors (hyposmia, male sex, and constipation) increased the percentage of subjects with a DAT deficit to .40%. Conclusion:Subjects with DAT deficit who do not meet criteria for a diagnosis of PD can be identified by olfactory testing. Sequential biomarker assessment may identify those at risk of PD. Selecting hyposmic individuals enriches the population for DAT deficit, and combining hyposmia with other potential risk factors (male sex, constipation) increases the percentage of subjects with a DAT deficit compatible with prodromal PD. The prodromal stage of Parkinson disease (PD) occurs several years in advance of typical motor symptoms and involves nigral dopamine degeneration and likely brainstem and olfactory bulb pathology. Detecting loss of dopaminergic integrity during the prodromal period offers the possibility to test potential disease-modifying therapies in the earliest stages of disease.Studies have highlighted the pathologic, clinical, and imaging manifestations of prodromal PD. Braak has proposed that prodromal neuropathologic changes in PD may begin in extranigral structures, including the olfactory bulb or brainstem nuclei.1-4 Early nonmotor symptoms may precede motor symptoms and allow identification of individuals with early neurodegeneration. [5][6][7] Imaging studies have demonstrated a 40% to 60% loss of dopaminergic neuronal integrity at PD motor symptom threshold. 8,9 Studies in unaffected subjects with PD mutations, hyposmia, and a first-degree relative with PD or REM behavior disorder (RBD) demonstrate

Application of the movement disorder society prodromal Parkinson's disease research criteria in 2 independent prospective cohorts

“…The inclusion of video‐polysomnography (PSG), quantitative imaging, and genetic data (the markers with highest LR + for developing PD in previous studies and in the criteria) will probably be necessary in further longitudinal validations, as their evaluation deeply influences the total LR. For example, using the variables available in the TREND study, a 60‐year‐old male nonsmoker with hyposmia, depression, constipation, SN hyperechogenicity, and a first‐degree relative with PD would still not reach the threshold of prodromal PD (77.7%).…”

Abnormal dopamine transporter imaging in pure autonomic failure: a potential biomarker of central nervous system involvement

“…Müller et al. previously described abnormal DaTscans in patients up to 5 years before clinical manifestation of PD [21]. Our patients with a reduction in presynaptic DAT availability and no concurrent motor symptoms or signs were followed up to a maximum of 2 years after their DaTscans.…”