Levodopa is the standard long-term dopamine replacement therapy to treat Parkinson's disease (PD) symptoms. With time, levodopa may induce debilitating dyskinesias (LID), the treatment of which ...represents a large clinically unmet need. However, time-to-LID onset varies between patients, reflecting a possible genetic component. We performed an hypothesis-free whole-exome sequencing (WES)-based screening of time-to-LID onset and attempted replication of previously published candidate gene studies. A WES association analysis was carried out in 134 PD patients in a meta-analytical framework. Replication was attempted in an independent study of 97 PD patients. Variants from previously reported candidate genes (OPRM1, COMT, BDNF) were also specifically examined. We significantly replicated, for the first time, an association of variant rs1799971 in the OPRM1 gene with time-to-LID onset. Furthermore, we identified two novel potentially functional variants, in the MAD2L2 (rs2233019) and MAP7 (rs35350783) genes, which were significantly associated at the discovery stage. In the replication study, the two variants showed direction-consistent effects but did not achieve the replication significance threshold. Our study provides the first WES results for time-to-LID onset, where we replicate association at OPRM1, and suggest new variants in MAD2L2 and MAP7 genes that are significant in discovery, but require larger datasets for replication. The results are being made publicly available to allow for independent external validation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The TANDEM investigation was carried out in 17 Italian Movement Disorder centers on behalf of a joint initiative of neurologist members of the Italian Academy for Parkinson’s disease and Movement ...Disorders (LIMPE-DISMOV Academy) and gastroenterologist members of the Italian Society of Digestive Endoscopy (SIED) to evaluate the efficacy and tolerability of levodopa-carbidopa intestinal gel (LCIG) in patients with advanced Parkinson's disease (PD) in routine medical care. Motor scores in “ON” and OFF” state (UPDRS-III), complications of therapy (UPDRS-IV), activities of daily living, sleep disorders and quality of life were evaluated at baseline and at two follow-up assessments (FUV1 and FUV2) within the initial 12-month LCIG treatment. In 159 patients (55% males) with a mean age of 69.1 ± 6.6 years and a diagnosis of PD since 13.6 ± 5.5 years, the UPDRS-III total score (in “OFF”) decreased from baseline (45.8 ± 13.2) to FUV1 (41.0 ± 17.4;
p
< 0.001) and FUV2 (40.5 ± 15.5;
p
< 0.001), the UPDRS-IV total score decreased from baseline (8.8 ± 2.9) to FUV1 (5.1 ± 3.4;
p
< 0.001) and FUV2 (5.5 ± 3.2;
p
< 0.001). The percentage of patients exhibiting freezing, dystonia, gait/walking disturbances, falls, pain and sleep disorders was significantly reduced. Twenty-eight device complications were reported and 11 (6.9%) patients prematurely terminated the study. LCIG after 12-month treatment led to sustained improvement of time spent in “OFF”, complications of therapy, PD-associated symptoms and sleep disorders. LCIG tolerability was consistent with the established safety profile of LCIG.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Whole-body electromyostimulation (WB-EMS) was never previously applied to Parkinson's disease (PD) patients. This randomized controlled study aimed to find the most effective and safe WB-EMS training ...protocol for this population.
Twenty-four subjects (age: 72.13 ± 6.20 years), were randomly assigned to three groups: a high-frequency WB-EMS strength training group (HFG) (rectangular stimulation at 85 Hz, 350 μs, 4 s stimulation/4 s rest), a low-frequency WB-EMS aerobic training group (LFG) (rectangular stimulation 7 Hz, 350 μs, with a continuous pulse duration), and an inactive control group (CG). Participants of the two experimental groups underwent 24 controlled WB-EMS training sessions, with a duration of 20 min each, during 12-week intervention. Serum growth factors (BDNF, FGF-21, NGF and proNGF), α-synuclein, physical performance and Parkinson's Disease Fatigue Scale (PFS-16) responses were analyzed to evaluate the pre-post variation and differences among groups.
Significant interactions of Time*Groups were detected for BDNF (Time*Groups
= 0.024; Time*CG,
= -628, IC95% = -1,082/-174,
= 0.008), FGF-21 (Time*Groups
= 0.009; Time*LFG
= 1,346, IC95% = 423/2268,
= 0.005), and α-synuclein (Time*Groups
= 0.019; Time*LFG
= -1,572, IC95% = -2,952/-192,
= 0.026).
analyses and comparisons of ΔS (post-pre), performed independently for each group, showed that LFG increased serum BDNF levels (+ 203 pg/ml) and decreased α-synuclein levels (-1,703 pg/ml), while HFG showed the opposite effects (BDNF: -500 pg/ml; α-synuclein: + 1,413 pg/ml). CG showed a significant BDNF reduction over time. Both LFG and HFG showed significant improvements in several physical performance outcomes and the LFG showed better results than HFG. Concerning PFS-16, significant differences over time (
= -0.4, IC95% = -0.8/-0.0,
= 0.046) and among groups (among all groups
< 0.001) were found, and the LFG exhibited better results than the HFG (
= -1.0, IC95% = -1.3/-0.7,
< 0.001), and CG (
= -1.7, IC95% = -2.0/-1.4,
< 0.001) with this last one that worsened over time.
LFG training was the best choice for improving or maintaining physical performance, fatigue perception and variation in serum biomarkers.
https://www.clinicaltrials.gov/ct2/show/NCT04878679, identifier NCT04878679.
Introduction
Deep brain stimulation of the subthalamic nucleus (STN-DBS) can exert relevant effects on the voice of patients with Parkinson's disease (PD). In this study, we used artificial ...intelligence to objectively analyze the voices of PD patients with STN-DBS.
Materials and methods
In a cross-sectional study, we enrolled 108 controls and 101 patients with PD. The cohort of PD was divided into two groups: the first group included 50 patients with STN-DBS, and the second group included 51 patients receiving the best medical treatment. The voices were clinically evaluated using the Unified Parkinson's Disease Rating Scale part-III subitem for voice (UPDRS-III-v). We recorded and then analyzed voices using specific machine-learning algorithms. The likelihood ratio (LR) was also calculated as an objective measure for clinical-instrumental correlations.
Results
Clinically, voice impairment was greater in STN-DBS patients than in those who received oral treatment. Using machine learning, we objectively and accurately distinguished between the voices of STN-DBS patients and those under oral treatments. We also found significant clinical-instrumental correlations since the greater the LRs, the higher the UPDRS-III-v scores.
Discussion
STN-DBS deteriorates speech in patients with PD, as objectively demonstrated by machine-learning voice analysis.
Ataxia management is mainly based on rehabilitation, symptomatic management, and functional improvement. Therefore, it is important to comprehensively assess ataxic symptoms and their impact on ...function. Recently, the movement disorders society recommended four generic ataxia rating scales: scale for assessment and rating of ataxia (SARA), international cooperative ataxia rating scales, Friedreich's ataxia rating scale (FARS), and unified multiple system atrophy rating scale (UMSARS). The aim of the study was to analyze and compare the content of the recommended ataxia rating scales by linking them to the international classification of functioning, disability and health (ICF). A total of 125 meaningful concepts from 93 items of the four included scales were linked to 57 different ICF categories. The ICF categories were distributed in body structure (
= 8), body function (
= 26), activity and participation (
= 20), and environmental factors (
= 3) components. UMSARS and FARS were the only ones that have addressed the body structure or environmental factors component. The content analysis of ataxia rating scales would help clinicians and researchers select the most appropriate scale and understand ataxic symptoms and their impact on function. It seems that SARA is the optimal scale for rapid assessment of ataxia or in busy clinical settings. UMSARS or FARS are more appropriate for the investigating the impact of ataxia on overall health, and monitoring ataxia progression and disability.
Background
To date, there are no large studies delineating the clinical correlates of “pure” essential tremor (ET) according to its new definition.
Methods
From the ITAlian tremor Network (TITAN) ...database, we extracted data from patients with a diagnosis of “pure” ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum.
Results
Out of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) “pure” ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options.
Discussion
The findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of “pure” ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of “pure” ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies.
Mutations of PLA2G6 gene are responsible for PARK14, an autosomal recessive L-DOPA responsive dystonia/parkinsonism with early/adult onset. This phenotype possesses an high clinical variability, ...which consists in the occurrence of cerebral and cerebellar atrophy, iron accumulation in the basal ganglia, and cognitive decline. This report describes a PD patient carrying an heterozygous PLA2G6 mutation, which was identified also in his PD affected sister. This patient is characterized by a L-DOPA responsive typical parkinsonian syndrome without the occurrence of dystonia, a slight cognitive decline, presence of iron accumulation both in neo and paleostriatum while cerebellar atrophy was absent. Clinical and imaging features are compatible with the PARK14 phenotype. Although PARK14 has been previously reported to be inherited as a recessive disorder, clinical and genetic analysis of this proband and his family rise the hypothesis that even heterozygous PLA2G6 mutations may cause PARK14. It remains to be analyzed whether these heterozygous variants may act as dominant mutations, or they merely increase the risk to develop PD by acting within a context of synergistic genetic and/or environmental backgrounds.
Parkinson Disease (PD) is a complex neurodegenerative disorder characterized by large genetic heterogeneity and missing heritability. Since the genetic background of PD can partly vary among ...ethnicities and neurological scales have been scarcely investigated in a PD setting, we performed an exploratory Whole Exome Sequencing (WES) analysis of 123 PD patients from mainland Italy, investigating scales assessing motor (UPDRS), cognitive (MoCA), and other non-motor symptoms (NMS). We performed variant prioritization, followed by targeted association testing of prioritized variants in 446 PD cases and 211 controls. Then we ran Exome-Wide Association Scans (EWAS) within sequenced PD cases (
= 113), testing both motor and non-motor PD endophenotypes, as well as their associations with Polygenic Risk Scores (PRS) influencing brain subcortical volumes. We identified a variant associated with PD, rs201330591 in
(5q13; alternative T allele: OR CI = 8.161.08; 61.52, FDR = 0.048), which was not replicated in an independent cohort of European ancestry (1,148 PD cases, 503 controls). In the EWAS, polygenic analyses revealed statistically significant multivariable associations of amygdala- β(SE) = -0.039(0.013); FDR = 0.039 and caudate-PRS 0.043(0.013); 0.028 with motor symptoms. All subcortical PRSs in a multivariable model notably increased the variance explained in motor (adjusted-R
= 38.6%), cognitive (32.2%) and other non-motor symptoms (28.9%), compared to baseline models (~20%). Although, the small sample size warrants further replications, these findings suggest shared genetic architecture between PD symptoms and subcortical structures, and provide interesting clues on PD genetic and neuroimaging features.
Postural instability (PI) in Parkinson’s disease (PD) exposes patients to an increased risk of falls (RF). While dopaminergic therapy and deep brain stimulation (DBS) improve motor performance in ...advanced PD patients, their effects on PI and RF remain elusive. PI and RF were assessed using a stabilometric platform in six advanced PD patients. Patients were evaluated in OFF and ON dopaminergic medication and under four DBS settings: with DBS off, DBS bilateral, and unilateral DBS of the more- or less-affected side. Our findings indicate that dopaminergic medication by itself exacerbated PI and RF, and DBS alone led to a decline in RF. No combination of medication and DBS yielded a superior improvement in postural control compared to the baseline combination of OFF medication and the DBS-off condition. Yet, for ON medication, DBS significantly improved both PI and RF. Among DBS conditions, DBS bilateral provided the most favorable outcomes, improving PI and RF in the ON medication state and presenting the smallest setbacks in the OFF state. Conversely, the more-affected side DBS was less beneficial. These preliminary results could inform therapeutic strategies for advanced PD patients experiencing postural disorders.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Functional Motor Disorders (FMDs) represent nosological entities with no clear phenotypic characterization, especially in patients with multiple (combined FMDs) motor manifestations. A data-driven ...approach using cluster analysis of clinical data has been proposed as an analytic method to obtain non-hierarchical unbiased classifications. The study aimed to identify clinical subtypes of combined FMDs using a data-driven approach to overcome possible limits related to "a priori" classifications and clinical overlapping.
Data were obtained by the Italian Registry of Functional Motor Disorders. Patients identified with multiple or "combined" FMDs by standardized clinical assessments were selected to be analyzed. Non-hierarchical cluster analysis was performed based on FMDs phenomenology. Multivariate analysis was then performed after adjustment for principal confounding variables.
From a study population of
= 410 subjects with FMDs, we selected
= 188 subjects women: 133 (70.7%); age: 47.9 ± 14.4 years; disease duration: 6.4 ± 7.7 years presenting combined FMDs to be analyzed. Based on motor phenotype, two independent clusters were identified: Cluster C1 (
= 82; 43.6%) and Cluster C2 (
= 106; 56.4%). Cluster C1 was characterized by functional tremor plus parkinsonism as the main clinical phenotype. Cluster C2 mainly included subjects with functional weakness. Cluster C1 included older subjects suffering from anxiety who were more treated with botulinum toxin and antiepileptics. Cluster C2 included younger subjects referring to different associated symptoms, such as pain, headache, and visual disturbances, who were more treated with antidepressants.
Using a data-driven approach of clinical data from the Italian registry, we differentiated clinical subtypes among combined FMDs to be validated by prospective studies.
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