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Heterozygous mutations in the GBA1 gene, encoding the enzyme glucocerebrosidase (GCase), are major risk factors for Parkinson’s Disease (PD). Ambroxol, a small chaperone originally used as a mucolytic agent, has been shown to cross the blood–brain barrier, enhance GCase activity, and reduce α-synuclein levels, making it a promising therapeutic candidate for disease-modifying effects in GBA1-associated PD (GBA1-PD). This study aimed to develop a method to quantify ambroxol levels in human plasma and cerebrospinal fluid (CSF) using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Ambroxol was determined by online solid-phase extraction (SPE), coupled with LC-MS/MS, by gradient elution on a monolithic column. Detection employed a 3200 QTRAP tandem mass spectrometer in the positive electrospray ionization mode. Calibration curves exhibited linearity across the analyzed ranges in both plasma and CSF. The recovery rate ranged from 106.7% to 113.5% in plasma and from 99.0% to 103.0% in CSF. No significant matrix effect was observed. Intra-day and inter-day precisions were below 11.8% in both matrices, and accuracy ranged from 89.9% to 103.1% in plasma and from 96.3% to 107.8% in CSF. We evaluated and confirmed the stability of the analyte in plasma and CSF across various storage conditions. The method was successfully validated according to European Medicine Agency (EMA) guidelines and its applicability was confirmed in the context of a multicenter, randomized, double-blind, placebo-controlled, phase II study, designed to monitor the ambroxol levels in the plasma and CSF of GBA1-PD.

Variants in the GBA1 gene are the commonest genetic risk factor for Parkinson disease (PD). Genotype-phenotype correlations exist but with conflicting data. Here, we compared the clinical phenotype of 183 idiopathic PD (iPD) patients, 39 severe GBA1 -PD, 24 mild GBA1 -PD, and 55 risk GBA1 -PD. Compared to iPD, we observed that only severe GBA1 -PD patients had a distinctive, more several clinical profile, characterised by worse depression, hyposmia, cognitive dysfunction, and possibly constipation.

Background GBA variants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBA carriers are scarce.ObjectiveTo elucidate the impact of GBA variants on long-term DBS outcome in a large Italian cohort.MethodsWe retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBA prevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS.ResultsWe included 365 patients with PD, of whom 73 (20%) carried GBA variants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms.At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up.ConclusionsEvaluation of long-term impact of GBA variants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up.

To explore the relationship between dopaminergic denervation and motor impairment in two de novo Parkinson's disease (PD) cohorts. n = 249 PD patients from Parkinson's Progression Markers Initiative (PPMI) and n = 84 from an external clinical cohort. Clustering analysis stratified dopaminergic denervation, measured with I-FP-CIT-SPECT, and motor impairment into mild [D and M] and severe [D+ and M+]. Differences in terms of biomarkers and clinical progression were assessed across subgroups. Causal mediation analysis evaluated the effect of co-pathology on the relationship between subgroups and cognitive decline. Four subgroups were identified. Two subgroups showed concordant profiles: the severe dopaminergic and motor impairment subgroup [D+/M+] exhibited poorer memory performance, pathological Aβ , as well as higher longitudinal Levodopa equivalent daily dose (LEDD) values and faster progression of motor disability; the mild dopaminergic and motor deficits [D/M] subgroup displayed a benign clinical profile and stable disease progression. Two subgroups exhibited dopaminergic and motor severity mismatch: the mild dopaminergic but severe motor impairment [D/M+] subgroup showed severe and rapidly progressive rigidity. CSF Aβ levels mediated the association between D+/M+ and cognitive decline in patients who were cognitively preserved at onset, accounting for 13% of the total effect. The external cohort supported the malignancy of D+/M+ and the presence of rigidity in D/M+. Concordant severe impairment reflects a malignant profile linked to Aβ-related cognitive decline, while mild concordant cases show stable progression. Mismatch subgroups display distinct clinical patterns, underscoring the value of integrating imaging and motor features for early disease stratification.