Longitudinal follow-up of SWEDD subjects in the PRECEPT Study

Abstract

Objective: To compare the clinical and imaging characteristics of those PRECEPT (Parkinson Research Examination of CEP-1347 Trial) subjects with a scan without evidence of dopaminergic deficit (SWEDD) to those with dopamine transporter (DAT) deficit scans at study baseline and during a 22-month follow-up.Methods: Baseline (n 5 799) and 22-month follow-up (n 5 701) [123 I] b-CIT SPECT scans were acquired. The percent change in [123 I] b-CIT striatal binding ratio, the percentage of subjects requiring dopaminergic therapy, the change in Unified Parkinson's Disease Rating Scale (UPDRS) score, and the PRECEPT Study investigators' diagnosis at study termination were compared between SWEDD and DAT deficit subjects.Results: SWEDD subjects (n 5 91) compared with DAT deficit subjects (n 5 708) showed reduced .9], p , 0.0001) at follow-up assessments. At PRECEPT termination, the diagnosis by study investigators was changed from Parkinson disease (PD) to other disorders not associated with DAT deficit in 44% (95% confidence interval 34.2, 54.7) of SWEDD subjects compared with 3.6% (95% confidence interval 2.3, 5.1) of DAT deficit subjects. Conclusion:These results indicate that subjects identified as having a SWEDD, with DAT imaging within the normal range, have minimal evidence of clinical or imaging PD progression. These data strongly suggest that SWEDD subjects are unlikely to have idiopathic PD. In several recent Parkinson disease (PD) clinical trials, dopaminergic imaging has been used as a tool to assess PD progression. Both dopamine transporter (DAT) SPECT and [ 18 F] fluoro-Ldopa PET imaging identified research subjects having a scan without evidence of dopaminergic deficit (SWEDD) enrolled in PD clinical trials of newly diagnosed untreated patients. [1][2][3][4] In PD studies enrolling participants within 9 months of PD diagnosis, approximately 10% to 15% of the research subjects have a SWEDD. Longitudinal assessment has demonstrated that those subjects with a SWEDD at baseline continue to have a SWEDD in follow-up scans for at least a 4-year period. 5The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) was a multicenter, randomized, double-masked, placebo-controlled study to examine the efficacy and long-term safety of CEP-1347 as a potential disease-modifying treatment in patients with early PD.

The Parkinson's progression markers initiative (PPMI) – establishing a PD biomarker cohort

“…The eligibility assessment for DAT was based on visual assessment (the regulatory approved strategy for 123I Ioflupane) and comparison of the visual and quantitative outcomes shows outstanding agreement (Table S1). The imaging characteristics of the SWEDD subjects confirm prior reports that quantitative dopamine transporter assessments in this population are comparable to HC subjects 4. The wide range of DAT deficit among PD subjects (30–80% loss at baseline) suggest that additional characteristics may define subsets of PD that manifest PD symptoms after modest DAT loss compared to those requiring more severe DAT deficit 36, 37, 47.…”

“…While recent data from clinical trials have demonstrated that subjects enrolled with SWEDD are unlikely to have PD,4 the clinical and biomarker characteristics of subjects with SWEDD have not been reported. The baseline PPMI data suggest that subjects with SWEDD have increased MDS‐UPDRS part 1 scores and greater degrees of depression, anxiety, and autonomic dysfunction compared to PD subjects.…”

“…Study investigators evaluated enrolled PD subjects to assess absence of current or imminent (6 months) disability requiring PD medications, though subjects could initiate PD medications at any time after enrollment if the subject or investigator deemed it clinically necessary. Those subjects screened as potential PD subjects who were ineligible due to DAT or VMAT‐2 scans without evidence of dopaminergic deficit (SWEDD) were eligible to be enrolled in a SWEDD cohort 4. HC subjects were required to be age 30 years or older without an active, clinically significant neurological disorder or a first‐degree relative with PD.…”

Combining clinical and biofluid markers for early Parkinson's disease detection

“…The four‐factor model could also differentiate SWEDD from PD, and likely predicted the conversion of SWEDD to PD. Of 31 SWEDD subjects, four converted to PD over the next 1–2 years, consistent with previous studies showing a conversion rate between 2 and 12% 14, 15, 16. All four were classified as “PD‐like” by the model, while none of those classified as “normal” converted to PD.…”

Scan without evidence of dopaminergic deficit: A 10-year retrospective study

“…However, assessments taken in combination allow a greater sensitivity for determination of nigro-striatal impairment. In previous studies, an incorrect initial diagnosis of degenerative parkinsonism seems to account for a significant proportion of SWEDDs [12,13,23] and, in those studies where a second, follow-up scan has been performed, conversion from normal to abnormal was rather uncommon (8.3% in Ref. [13] and 12.5% in Ref.…”