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

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.

Kou W ，Cai H ，Cui Y ，Zhu J ，Li S ，Yang C ，Chen H ，Feng T ... -  《-》

Acute challenge with apomorphine and levodopa in Parkinsonism.

The diagnosis of different parkinsonian syndromes and the ability to predict long-term drug efficacy constitute important clinical issues. Motor responses to the acute administration of levodopa and apomorphine were analyzed in a series of 134 parkinsonian patients, including 83 patients with a clinical diagnosis of idiopathic Parkinson's disease (PD), 28 patients with multiple-system atrophy (MSA), 6 with progressive supranuclear palsy, and 17 with an unclassified parkinsonian syndrome. The patients received oral levodopa/carbidopa (250/25 mg) and subcutaneous apomorphine (1.5, 3 and 4.5 mg). Clinical variations of the Unified Parkinson's Disease Rating Scale (UPDRS) motor score were evaluated 1 h following levodopa administration or 20 min following apomorphine. The motor improvement produced by each acute challenge was matched with the clinical diagnosis and with the response to chronic levodopa treatment. The diagnosis was verified by repeated clinical assessments or by autopsy in 2 cases. A receiver operating characteristics curve was plotted comparing PD vs. non-PD, PD vs. MSA and chronic responders vs. nonresponders. Cutoff threshold improvement was defined as the value closest to the crossing point for 80% sensitivity and 80% specificity, corresponding to the best trade-off for a predictive evaluation. UPDRS motor score improvement was on average higher in PD than in non-PD patients (levodopa: 29.8 vs. 12.2%; apomorphine 1.5 mg: 27.1 vs. 10.5%; apomorphine 3 mg: 27.7 vs. 9.7%; apomorphine 4.5 mg: 28.8 vs. 11.8%; p < 0.01 with Student's t test). When PD patients were compared to non-PD patients, levodopa challenge had the best diagnostic accuracy with a threshold improvement of 16%. Apomorphine had the best diagnostic accuracy with a threshold improvement of 13.5% for 1.5 mg, 13% for 3 mg, and 16% for 4.5 mg. This meant that patients improving at least 16% in all tests had the highest probability of having PD. When PD patients were compared to MSA patients, levodopa acute challenge had the best diagnostic accuracy with a threshold improvement of 17%. Apomorphine had the best diagnostic accuracy with an improvement of 13% for 1.5 mg, 15% for 3 mg, and 18% for 4.5 mg. This meant that patients improving at least 18% in all tests had the highest probability of having PD rather than MSA. When patients who responded to chronic levodopa treatment were compared to those who did not, acute challenge with levodopa had the best predictive accuracy with a threshold improvement of 14.5%. Apomorphine had the best predictive accuracy with an improvement of 13% for 1.5 mg, and 14% for 3 and 4.5 mg. This meant that patients improving at least 14.5% in all tests had the highest probability of responding to chronic treatment. A good agreement was found between acute challenges with levodopa/carbidopa and apomorphine, and the use of both improved the reliability of the test. Different threshold improvements after acute challenges would support a diagnosis of PD or the exclusion of MSA, and would have a predictive value for subsequent response to chronic levodopa therapy.

Rossi P ，Colosimo C ，Moro E ，Tonali P ，Albanese A ... -  《-》

Cerebrospinal fluid and blood neurofilament light chain in Parkinson's disease and atypical parkinsonian syndromes: a systematic review and Bayesian network meta-analysis.

The value of neurofilament light chain (NfL) levels as a biomarker for the diagnosis and differential diagnosis in patients with Parkinson's disease (PD) and atypical parkinsonian syndromes (APS) remains controversial. Furthermore, few studies have directly compared NfL levels among specific APS categories. This study aimed to compare cerebrospinal fluid (CSF) and blood NfL levels among PD, APS, other PD-related disorders, and controls, as well as rank NfL levels across these groups. PubMed, Embase, Web of Science, and the Cochrane Library were searched from the inception up to November 1st, 2024, to identify eligible studies reporting CSF or blood NfL concentrations in PD, PD dementia (PDD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB), corticobasal syndrome (CBS), vascular parkinsonism (VP), essential tremor (ET), idiopathic rapid eye movement sleep behavior disorder (iRBD), and controls. The Bayesian approach was utilized to estimate the standardized mean difference (SMD) and the associated 95% credible intervals (CrIs) of NfL levels. The surface under the cumulative ranking curve (SUCRA) was employed to evaluate the ranking probabilities of NfL levels. Subgroup analysis and meta-regression were conducted to explore the sources of heterogeneity. The present network meta-analysis (NMA) included 78 studies with 13,120 participants (4050 controls, 5021 PD, 191 PDD, 1173 MSA, 887 PSP, 1254 DLB, 319 CBS, 160 ET, 65 iRBD, and 0 VP). Of these, the NMA of CSF NfL included 34 studies with 6,013 participants, while the NMA of blood NfL included 49 studies with 7,787 participants. Both CSF and blood NfL levels were significantly elevated in patients with PD and APS compared to controls. Compared to PD patients, CSF NfL levels were significantly elevated in MSA (SMD 1.85; 95% CrI 1.55-2.15), CBS (1.42; 1.08-1.75), PSP (1.35; 1.06-1.64), and DLB 0.52; 0.20-0.85) patients. Similarly, blood NfL levels were significantly higher in patients with MSA (1.36; 1.02-1.71), PDD (1.19; 0.65-1.72), PSP (1.15; 0.77-1.54), CBS (0.92; 0.11-1.72), and DLB (0.63; 0.14-1.12) compared to PD. Among APS, CSF NfL levels in MSA patients were significantly higher than those in PSP, DLB, and CBS patients, while blood NfL levels in MSA patients were significantly higher only compared to DLB. In both CSF and blood NfL, MSA patients exhibited the highest probability of ranking first for NfL level elevations (CSF: SUCRA = 0.998; blood: SUCRA = 0.925). Age significantly influenced the SMD of the comparison between MSA and PD in CSF NfL (β = -0.15; p = 0.016). CSF and blood NfL levels in PD and APS are higher than those in controls, and all APS categories show higher levels than PD, suggesting that NfL levels may serve as a potential biomarker for the differential diagnosis between PD and APS. However, caution is warranted when using NfL as a diagnostic biomarker for PD. Significant differences in NfL levels are also observed between certain APS categories. Patients with MSA exhibit the highest NfL levels among PD and related disorders.

Kou W ，Li S ，Yan R ，Zhang J ，Wan Z ，Feng T ... -  《-》

Overall Efficacy and Safety of Safinamide in Parkinson's Disease: A Systematic Review and a Meta-analysis.

Giossi R ，Carrara F ，Mazzari M ，Lo Re F ，Senatore M ，Schicchi A ，Corrù F ，Fittipaldo VA ，Pani A ，Tramacere I ，Elia AE ，Scaglione F ... -  《-》

[Acute dopaminergic responsiveness test in diagnosis of Parkinson's disease and Parkinsonian disorders].

Li W ，Feng T ，Wang YJ ，Lin JX ，Xu XT ... -  《-》