Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced Parkinson’s Disease (PD). However, the effects of STN-DBS on freezing of gait (FOG) are still debated, particularly in the long-term follow-up (≥5-years). The main aim of the current study is to evaluate the long-term effects of STN-DBS on FOG. Twenty STN-DBS treated PD patients were included. Each patient was assessed before surgery through a detailed neurological evaluation, including FOG score, and revaluated in the long-term (median follow-up: 5-years) in different stimulation and drug conditions. In the long term follow-up, FOG score significantly worsened in the off-stimulation/off-medication condition compared with the pre-operative off-medication assessment (z = −1.930; p = 0.05) but not in the on-stimulation/off-medication (z = −0.357; p = 0.721). There was also a significant improvement of FOG at long-term assessment by comparing on-stimulation/off-medication and off-stimulation/off-medication conditions (z = −2.944; p = 0.003). These results highlight the possible beneficial long-term effects of STN-DBS on FOG.

(1) Background: Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is characterized by late-onset cerebellar ataxia, bilateral vestibulopathy, and sensory neuronopathy mostly due to biallelic RFC1 expansion. (2) Objectives: The aim of this case series is to describe vestibular, gait, and speech alterations in CANVAS via a systematic approach. (3) Methods: All patients (n = 5) underwent a standardized clinical–instrumental examination, including the perceptual and acoustic analysis of speech, instrumental gait, and balance analysis (posturographic data were acquired using a force plate [Kistler, Winterthur, Switzerland] while 3D gait analysis, inclusive of surface electromyography, was acquired using a motion capture system [SMART DX, BTS Bioengineering, Milan, Italy], a wireless electromyograph [FreeEMG, BTS Bioengineering, Milan, Italy]), and vestibular assessment with video-oculography. (4) Results: Five patients were included in the analysis: three females (patients A, B, C) and two males (patients D and E) with a mean age at evaluation of 62 years (SD ± 15.16, range 36–74). The mean age of symptoms’ onset was 55.6 years (SD ± 15.04, range 30–68), and patients were clinically and instrumentally evaluated with a mean disease duration of 6.4 years (SD ± 0.54, range 6–7). Video-Frenzel examination documented spontaneous downbeat nystagmus enhanced on bilateral gaze in all patients, except for one presenting with slight downbeat nystagmus in the supine position. All patients exhibited different degrees of symmetrically reduced VOR gain for allsix semicircular canals on the video-head impulse test and an unexpectedly normal (“false negative”) VOR suppression, consistent with combined cerebellar dysfunction and bilateral vestibular loss. Posturographic indices were outside their age-matched normative ranges in all patients, while 3D gait analysis highlighted a reduction in ankle dorsiflexion (limited forward rotation of the tibia over the stance foot during the stance phase of gait and fatigue of the dorsiflexor muscles) and variable out-of-phase activity of plantar flexors during the swing phase. Finally, perceptual-acoustic evaluation of speech showed ataxic dysarthria in three patients. Dysdiadochokinesis, rhythm instability, and irregularity were observed in the oral diadochokinesis task. (5) Conclusions: CANVAS is a recently discovered syndrome that is gaining more and more relevance within late-onset ataxias. In this paper, we aimed to contribute to a detailed description of its phenotype.

Neurosteroids are pleiotropic molecules involved in various neurodegenerative diseases with neuroinflammation. We assessed neurosteroids’ serum levels in a cohort of Parkinson’s Disease (PD) patients with heterozygous glucocerebrosidase (GBA) mutations (GBA-PD) compared with matched cohorts of consecutive non-mutated PD (NM-PD) patients and healthy subjects with (GBA-HC) and without (NM-HC) GBA mutations. A consecutive cohort of GBA-PD was paired for age, sex, disease duration, Hoehn and Yahr stage, and comorbidities with a cohort of consecutive NM-PD. Two cohorts of GBA-HC and HC were also considered. Clinical assessment included the Movement Disorder Society revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and the Montreal Cognitive Assessment (MoCA). Serum samples were processed and analyzed by liquid chromatography coupled with the triple quadrupole mass spectrometry. Twenty-two GBA-PD (males: 11, age: 63.68), 22 NM-PD (males: 11, age: 63.05), 14 GBA-HC (males: 8; age: 49.36), and 15 HC (males: 4; age: 60.60) were studied. Compared to NM-PD, GBA-PD showed more hallucinations and psychosis (p < 0.05, Fisher’s exact test) and higher MDS-UPDRS part-II (p < 0.05). Most of the serum neurosteroids were reduced in both GBA-PD and NM-PD compared to the respective control cohorts, except for 5α-dihydroprogesterone. Allopregnanolone was the only neurosteroid significantly lower (p < 0.01, Dunn’s test) in NM-PD compared to GBA-PD patients. Only in GBA-PD, allopregnanolone, and pregnanolone levels correlated (Spearman) with a more severe MDS-UPDRS part-III. Allopregnanolone levels also negatively correlated with MoCA scores, and pregnanolone levels correlated with more pronounced bradykinesia. This pilot study provides the first observation of changes in neurosteroid peripheral levels in GBA-PD. The involvement of the observed changes in the development of neuropsychological and motor symptoms of GBA-PD deserves further attention.

Background: Biallelic mutations in the PRKN gene are a common cause of early‐onset Parkinson's disease (EOPD). In addition to single nucleotide variants, structural variants contribute substantially to the mutational profile of PRKN . A significant portion of patients with EOPD remains genetically unsolved. Objectives: By using short‐read whole genome sequencing (sr‐WGS), we aimed to uncover complex genetic alterations at the PRKN locus in EOPD cases which tested negative for mutations in Mendelian PD genes with clinical exome sequencing (CES) and multiplex ligation‐dependent probe amplification (MLPA). Methods: We evaluated 498 unrelated EOPD patients, who tested negative using gold‐standard diagnostic methods, using sr‐WGS. In selected cases, long‐read whole genome sequencing (lr‐WGS) with Oxford Nanopore technology was employed for an in‐depth analysis and validation. The Parkinson's Progression Markers Initiative (PPMI) dataset was interrogated to assess the prevalence of any newly identified elusive pathogenic genetic configurations. Results: sr‐WGS revealed elusive compound heterozygous structural variations, consisting of partially overlapping deletions and duplications within the PRKN gene in three unrelated EOPD cases (two familial, one sporadic). In familial cases, biallelic PRKN structural variants co‐segregated with the disease. The exact structure of each variant was resolved using lr‐WGS. Similar variants were absent in the large PPMI database, suggesting that they are a rare occurrence. Conclusions: In this article we describe a rare configuration of compound heterozygous structural variations involving partially overlapping chromosomal regions at the PRKN locus, which are difficult to detect through standard diagnostic genetic technologies. This study highlights the importance of integrating WGS into clinical practice. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.