Dopaminergic responsiveness and dopaminergic challenge tests of Parkinson's disease: a systematic review and...

The assessment and quantification of dopaminergic responsiveness are crucial for the diagnosis and management of Parkinson's disease (PD). This study aimed to summarize and compare motor improvements in patients with PD and atypical parkinsonian syndromes (APS) across three types of dopaminergic challenge tests, as well as evaluate their diagnostic performance.

PubMed, Embase, Cochrane Library, and Web of Science were searched to identify eligible studies reporting the improvement rate of the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) or MDS-UPDRS-III in dopaminergic challenge tests for PD or APS, or diagnostic outcomes in differential diagnosis between PD and APS. A random-effects model was conducted to pool improvement rates and standardized mean differences (SMDs) in patients with PD or APS during dopaminergic challenge tests. Subgroup analysis and meta-regression were used to investigate the sources of heterogeneity. A bivariate mixed-effects model was employed to evaluate the diagnostic performance of these tests.

A total of 58 studies (3641 PD and 711 APS) were included. In the acute levodopa challenge test, patients with PD, APS, and multiple system atrophy (MSA) demonstrated pooled UPDRS-III improvement rates of 41.5% [95% confidence interval (CI) 38.5%-44.5%; I² = 98.8%], 14.7% (95% CI 6.8%-22.7%; I² = 96.5%), and 6.3% (95% CI - 4.0% to 16.7%), respectively. Subgroup analyses showed the pooled improvement rate of de novo PD patients (25.9%; 95% CI 15.1%-36.7%) was significantly lower than treated PD patients (42.4%; 95% CI 38.6%-46.2%) (p = 0.005), overlapping with APS patients with off-state H-Y stage ≤ 2.5 (21.2%; 95% CI 14.5%-27.9%). PD patients with off-state H-Y stage ≤ 2.5 (35.4%; 95% CI 31.1%-39.7%) or UPDRS-III score ≤ 30 (30.5%; 95% CI 23.4%-35.7%) had significantly lower improvement rate than PD patients with off-state H-Y stage > 2.5 (44.1%; 95% CI 37.0%-51.3%) (p = 0.041) or UPDRS-III scores > 30 (47.0%; 95% CI 43.7%-50.4%) (p < 0.001). The pooled improvement rate in acute levodopa challenge tests of PD with 100 mg levodopa (17.0%; 95% CI 11.3%-22.8%) was significantly lower than that in tests with 200-250 mg levodopa (34.3%; 95% CI 30.6%-38.0%) (p < 0.001). Meta-regression showed the improvement rate of PD was positively correlated with off-state UPDRS-III scores (p = 0.007). In the acute apomorphine challenge test, PD patients showed a pooled UPDRS-III improvement rate of 40.1% (95% CI 36.9%-43.3%). To differentiate between PD and APS, the pooled sensitivity, specificity, diagnostic odds ratio (DOR), and area under the curve (AUC) for the acute levodopa challenge test were 0.81, 0.77, 13.91, and 0.85; for the acute apomorphine challenge test, they were 0.84, 0.85, 29.94, and 0.91; and for chronic levodopa therapy, they were 0.82, 0.71, 11.54, and 0.72. The pooled sensitivity, specificity, DOR, and AUC of the acute levodopa challenge test for distinguishing PD from MSA were 0.82, 0.78, 15.74, and 0.79; for PD vs. PSP, they were 0.77, 0.78, 11.54, and 0.84; and for PD vs. DLB, they were 0.65, 0.58, 2.65, and 0.64.

The overall dopaminergic responsiveness is greater in PD patients compared to those with APS. However, there is significant heterogeneity in the pooled motor improvement of dopaminergic responsiveness within PD or APS, with overlap between de novo PD and early-stage APS. All three types of dopaminergic challenge tests demonstrate moderate diagnostic performance in differentiating PD from APS.