Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review.

OBJECTIVE: We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature. METHODS: A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high-resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed. RESULTS: Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively. CONCLUSIONS: There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult-onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT-TOR1A and DYT-GNAL, with DYT-THAP1 likely to be an intermediate phenotype.

Lack of validation of variants associated with cervical dystonia risk: a GWAS replication study.

BACKGROUND: A recent genome-wide association study (GWAS) has identified a putative association, not statistically confirmed, of cervical dystonia within several regions in a British population. Hence, the authors proposed dysfunction of the ion channel NALCN (for sodium leak channel, nonselective) as a plausible cause of cervical dystonia. The objective of our study was to investigate the association of five single nucleotide polymorphisms (SNPs) previously reported with high signals as putative genetic risk factors for cervical dystonia in a British GWAS, including two located in the NALCN gene region. METHODS: We performed a case-control association study in a Spanish population. The SNPs selected for genotyping were two SNPS in the NALCN gene (rs61973742 and rs1338041), one SNP in the OR4X2 gene (rs67863238), one SNP in the COL4A1 region (rs619152), and one intergenic SNP (rs1249277). Genomic DNA was collected from 252 patients with cervical dystonia, with a mean age of 55.3 ± 14.1 years (mean age at onset, 43.5 ± 15.7 years), and 342 unrelated control subjects with a mean age of 56.3 ± 14.3 years. Genotyping of SNPs was performed using TaqMan assays and SimpleProbe assays. RESULTS: The SNP rs619152 had to be excluded because of assay failure. No significant differences were found in allele distribution between cases and controls for all analyzed SNPs. Therefore, we found no association with cervical dystonia for the analyzed SNPs in our Spanish population. CONCLUSIONS: We did not find any evidence supporting the association of NALCN with cervical dystonia, indicating that this gene is not implicated in the pathogenesis of this disorder in our cervical dystonia population.

BDNF Val66Met polymorphism in primary adult-onset dystonia: a case-control study and meta-analysis.

BACKGROUND: A polymorphism in brain-derived neurotrophic factor (BDNF) (Val66Met) has been reported as a risk factor in primary dystonia. However, overall the results have been inconclusive. Our aim was to clarify the association of Val66Met with primary dystonia, and with the most prevalent clinical subtypes, cervical dystonia and blepharospasm. METHODS: We conducted a Spanish multicenter case-control study (including 680 primary dystonia patients and 788 healthy controls) and performed a meta-analysis integrating our study and six previously published studies (including a total of 1,936 primary dystonia patients and 2,519 healthy controls). RESULTS: We found no allelic or genotypic association with primary dystonia, cervical dystonia, or blepharospasm risks, for the allele A (Met) from a BDNF Val66Met polymorphism in our case-control study. This was confirmed by results from our meta-analysis in white and mixed ethnic populations in any genetic model. CONCLUSION: We did not find any evidence supporting the association of the BDNF Val66Met polymorphism with primary dystonia.

Neuropsychological deficits associated with destruction of the right nigrostriatal pathway.

Hemiparkinsonism secondary to a vascular mesencephalic lesion is infrequent; these patients offer an exceptional opportunity to study neuropsychological alterations attributable to unilateral dopaminergic denervation, shedding light on the pathophysiology of cognitive disorders in early-stage idiopathic Parkinson's disease (PD). From the investigation of our case, we conclude that destruction of the right nigrostriatal pathway is accompanied by deficits in executive functioning and verbal/visual memory similar to those observed in many patients with early-stage idiopathic PD. The more complex neuropsychological dysfunction developed by other PD patients must therefore be related to the additional involvement of other brain structures.

Neuropsychological assessment protocol in an ongoing randomized controlled trial on posterior subthalamic area vs. ventral intermediate nucleus deep brain stimulation for essential tremor.

Objective: Patients with essential tremor (ET) may experience cognitive-affective impairment. Deep brain stimulation (DBS) of different targets, such as the ventral intermediate nucleus (VIM) of the thalamus or the posterior subthalamic area (PSA), has been shown to be beneficial for refractory ET. However, there is little evidence regarding the possible neuropsychological effects of PSA-DBS on patients with ET, and there are few studies comparing it with VIM-DBS in this population.In this study, we aim to present the evaluation protocol and neuropsychological battery as used in an ongoing trial of DBS for ET comparing the already mentioned targets. Methods: As part of a randomized, double-blind, crossover clinical trial comparing the effectiveness and safety of PSA-DBS vs. VIM-DBS, 11 patients with refractory ET will undergo a multi-domain neuropsychological battery assessment. This will include a pre-/post-implantation assessment (3 months after the stimulation of each target and 6 months after an open stage of DBS on the most optimal target). Conclusion: Evidence on the neuropsychological effects of DBS in patients with refractory ET is very scarce, particularly in lesser-explored targets such as PSA. This study could contribute significantly in this field, particularly on pre-procedure safety analysis for tailored patient/technique selection, and to complete the safety analysis of the procedure. Moreover, if proven useful, this proposed neuropsychological assessment protocol could be extensible to other surgical therapies for ET.

Staging Parkinson's Disease According to the MNCD (Motor/Non-motor/Cognition/Dependency) Classification Correlates with Disease Severity and Quality of Life.

BACKGROUND: Recently, a novel simple classification called MNCD, based on 4 axes (Motor; Non-motor; Cognition; Dependency) and 5 stages, has been proposed to classify Parkinson's disease (PD). OBJECTIVE: Our aim was to apply the MNCD classification in a cohort of PD patients for the first time and also to analyze the correlation with quality of life (QoL) and disease severity. METHODS: Data from the baseline visit of PD patients recruited from 35 centers in Spain from the COPPADIS cohort fromJanuary 2016 to November 2017 were used to apply the MNCD classification. Three instruments were used to assess QoL:1) the 39-item Parkinson's disease Questionnaire [PDQ-39]); PQ-10; the EUROHIS-QOL 8-item index (EUROHIS-QOL8). RESULTS: Four hundred and thirty-nine PD patients (62.05±7.84 years old; 59% males) were included. MNCD stage was:stage 1, 8.4% (N = 37); stage 2, 62% (N = 272); stage 3, 28.2% (N = 124); stage 4-5, 1.4% (N = 6). A more advancedMNCD stage was associated with a higher score on the PDQ39SI (p < 0.0001) and a lower score on the PQ-10 (p< 0.0001) and EUROHIS-QOL8 (p< 0.0001). In many other aspects of the disease, such as disease duration, levodopa equivalent daily dose, motor symptoms, non-motor symptoms, and autonomy for activities of daily living, an association between the stage and severity was observed, with data indicating a progressive worsening related to disease progression throughout the proposed stages. CONCLUSION: Staging PD according to the MNCD classification correlated with QoL and disease severity. The MNCD could be a proper tool to monitor the progression of PD.

Cognitive effects of subthalamic nucleus stimulation in Parkinson's disease: a controlled study.

BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor function in selected patients with Parkinson's disease (PD) but can be associated with variable changes in cognitive functions. METHODS: We studied 21 patients selected for STN-DBS and compared 6-month clinical and neuropsychological outcomes between those who underwent surgery (n = 9) and those who voluntarily refused it (n = 12). RESULTS: Motor and quality of life outcomes were markedly superior in the STN-DBS group versus controls. A wide neuropsychological battery was administered, and the whole sample showed a statistically significant worsening in phonemic verbal fluency, time to perform the Trail Making Test part B, Digit Symbol score of WAIS-III and color-naming score of the Stroop Test. In comparison to controls, a trend to a slightly worse deterioration in phonemic verbal fluency was observed in the STN-DBS patients and was significantly correlated with reductions in the L-dopa-equivalent daily dose (r = 0.850, p = 0.007). CONCLUSION: Our study confirms the safety of STN-DBS from a cognitive standpoint; a reduction in verbal fluency at 6 months after surgery can also be related to PD progression and medication reduction.

Opicapone Improves Global Non-Motor Symptoms Burden in Parkinson's Disease: An Open-Label Prospective Study.

Patients with Parkinson's disease (PD) can improve some non-motor symptoms (NMS) after starting treatment with opicapone. The aim of this study was to analyze the effectiveness of opicapone on global NMS burden in PD. OPEN-PD (Opicapone Effectiveness on Non-motor symptoms in Parkinson's Disease) is a prospective open-label single-arm study conducted in 5 centers from Spain. The primary efficacy outcome was the change from baseline (V0) to the end of the observational period (6 months ± 30 days) (V2) in the Non-Motor Symptoms Scale (NMSS) total score. Different scales were used for analyzing the change in motor, NMS, quality of life (QoL), and disability. Thirty-three patients were included between JUL/2019 and JUN/2021 (age 63.3 ± 7.91; 60.6% males; 7.48 ± 4.22 years from symptoms onset). At 6 months, 30 patients completed the follow-up (90.9%). The NMSS total score was reduced by 27.3% (from 71.67 ± 37.12 at V0 to 52.1 ± 34.76 at V2; Cohen's effect size = −0.97; p = 0.002). By domains, improvement was observed in sleep/fatigue (−40.1%; p < 0.0001), mood/apathy (−46.6%; p = 0.001), gastrointestinal symptoms (−20.7%; p = 0.029), and miscellaneous (−44.94%; p = 0.021). QoL also improved with a 18.4% reduction in the 39-item Parkinson's Disease Quality of Life Questionnaire Summary Index (from 26.67 ± 17.61 at V0 to 21.75 ± 14.9 at V2; p = 0.001). A total of 13 adverse events in 11 patients (33.3%) were reported, 1 of which was severe (not related to opicapone). Dyskinesias and nausea were the most frequent (6.1%). Opicapone is well tolerated and improves global NMS burden and QoL in PD patients at 6 months.

Balance Ability and Occupational Performance in Patients With Parkinson's Disease and On-Medication-State Freezing of Gait.

PURPOSE: The aim of this study was to examine balance ability and occupational performance in patients with Parkinson's disease (PD) and on-medication-state freezing of gait (FOG). DESIGN: A cohort study with three groups was conducted. METHODS: Seven patients with PD and on-medication-state FOG with optimized pharmacological therapy; seven patients with PD matched by age, gender, length of time since diagnosis, and Hoehn and Yahr stage; and seven controls were included. Outcomes included balance and occupational performance. Nonparametric analyses were used. FINDINGS: Significant differences were found between the two subgroups of patients with PD in the Timed Up & Go Test when adding a cognitive task, dual-task interference, and self-confidence in balance. CONCLUSIONS: Patients with PD and on-medication-state FOG had lower scores on dual-task interference and self-confidence than matched PD patients. CLINICAL RELEVANCE: The assessment and rehabilitation approach for patients with PD and on-medication-state FOG should include balance confidence and dual-task interference.

Patient and caregiver outcomes with levodopa-carbidopa intestinal gel in advanced Parkinson's disease.

Levodopa-carbidopa intestinal gel (LCIG) has shown to be efficacious in motor and non-motor symptoms (NMS). Nevertheless, studies with patient Quality of Life (QoL) as a primary endpoint are scarce. To assess the effect of LCIG on Advanced Parkinson's Disease (APD) patients QoL. Secondarily, the impact on motor symptoms and NMS, emotional well-being, treatment satisfaction, and caregiver QoL, stress, disease burden, anxiety, depression, and work impairment were also investigated. In this prospective, 6-month multicenter postmarketing observational study, LCIG was administered to 59 patients with APD. Endpoints were assessed using validated scales and questionnaires. LCIG significantly improved patient QoL (PDQ-39 mean change ± standard deviation from baseline, -12.8 ± 14.6; P < 0.0001), motor symptoms (UPDRS-III in "On," -6.5 ± 11.8; P = 0.0002), NMS (NMSS, -35.7 ± 31.1; P < 0.0001), mood (Norris/Bond-Lader VAS, -6.6 ± 21.1; P = 0.0297), fatigue (PFS-16, -0.6 ± 1.0; P = 0.0003), depression (BDI-II, -5.1 ± 9.4; P = 0.0002), anxiety (BAI, -6.2 ± 9.6; P < 0.0001), and patient treatment satisfaction (SATMED-Q, 16.1 ± 16.8; P < 0.0001). There were significant correlations between the change from baseline to 6 months between PDQ-39 and UPDRS-IV, NMSS, BAI, BDI-II, AS, and PFS-16 scores, and Norris/Bond-Lader alertness/sedation factor. Caregiver anxiety also improved (Goldberg anxiety scale, -1.1 ± 1.0; P = 0.0234), but the clinical relevance of this finding is questionable. The serious adverse events reported were similar to those previously described for LCIG. In patients with APD, LCIG improves QoL, motor symptoms and NMS, emotional well-being, and satisfaction with the treatment. Improvement in patient QoL is associated with improvements in motor complications, NMS, anxiety, depression, apathy and fatigue. Improvements in patients' QoL does not correspond with improvements in caregivers' QoL or burden.

MNCD: A New Tool for Classifying Parkinson's Disease in Daily Clinical Practice.

Background and objective: Parkinson's disease (PD) is a clinically heterogeneous disorder in which the symptoms and prognosis can be very different among patients. We propose a new simple classification to identify key symptoms and staging in PD. Patients and Methods: Sixteen movement disorders specialists from Spain participated in this project. The classification was consensually approved after a discussion and review process from June to October 2021. The TNM classification and the National Institutes of Health Stroke Scale (NIHSS) were considered as models in the design. Results: The classification was named MNCD and included 4 major axes: (1) motor symptoms; (2) non-motor symptoms; (3) cognition; (4) dependency for activities of daily living (ADL). Motor axis included 4 sub-axes: (1) motor fluctuations; (2) dyskinesia; (3) axial symptoms; (4) tremor. Four other sub-axes were included in the non-motor axis: (1) neuropsychiatric symptoms; (2) autonomic dysfunction; (3) sleep disturbances and fatigue; (4) pain and sensory disorders. According to the MNCD, 5 stages were considered, from stage 1 (no disabling motor or non-motor symptoms with normal cognition and independency for ADL) to 5 (dementia and dependency for basic ADL). Conclusions: A new simple classification of PD is proposed. The MNCD classification includes 4 major axes and 5 stages to identify key symptoms and monitor the evolution of the disease in patients with PD. It is necessary to apply this proof of concept in a properly designed study.

Present and Future of Parkinson's Disease in Spain: PARKINSON-2030 Delphi Project.

Parkinson's disease (PD) is a chronic progressive and irreversible disease and the second most common neurodegenerative disease worldwide. In Spain, it affects around 120.000-150.000 individuals, and its prevalence is estimated to increase in the future. PD has a great impact on patients' and caregivers' lives and also entails a substantial socioeconomic burden. The aim of the present study was to examine the current situation and the 10-year PD forecast for Spain in order to optimize and design future management strategies. This study was performed using the modified Delphi method to try to obtain a consensus among a panel of movement disorders experts. According to the panel, future PD management will improve diagnostic capacity and follow-up, it will include multidisciplinary teams, and innovative treatments will be developed. The expansion of new technologies and studies on biomarkers will have an impact on future PD management, leading to more accurate diagnoses, prognoses, and individualized therapies. However, the socio-economic impact of the disease will continue to be significant by 2030, especially for patients in advanced stages. This study highlighted the unmet needs in diagnosis and treatment and how crucial it is to establish recommendations for future diagnostic and therapeutic management of PD.

Validation of a Device for the Ambulatory Monitoring of Sleep Patterns: A Pilot Study on Parkinson's Disease.

The development of wearable devices has increase interest in the use of ambulatory methods to detect sleep disorders more objectively than those permitted by subjective scales evaluating sleep quality, while subjects maintain their usual lifestyle. This study aims to validate an ambulatory circadian monitoring (ACM) device for the detection of sleep and wake states and apply it to the evaluation of sleep quality in patients with Parkinson disease (PD). A polysomnographic validation study was conducted on a group of patients with different sleep disorders in a preliminary phase, followed by a pilot study to apply this methodology to PD patients. The ACM device makes it possible to estimate the main sleep parameters very accurately, as demonstrated by: (a) the lack of significant differences between the mean values detected by PSG and ACM in time in bed (TIB), total sleep time (TST), sleep efficiency (SE), and time awake after sleep onset (WASO); (b) the slope of the correlation lines between the parameters estimated by the two procedures, very close to 1, which demonstrates the linearity of the predictions; (c) the low bias value in the estimates obtained through ACM. Sleep in PD is associated with lower distal skin temperature, efficiency and overall sleep time; greater WASO, activity during sleep and duration of naps and a worse circadian function index. In summary, the ACM device has proven to be clinically useful to evaluate sleep in an objective manner, thanks to the integrated management of different complementary variables, having advantages over conventional actigraphy.

Association of Parkinson's disease and treatment with aminosalicylates in inflammatory bowel disease: a cross-sectional study in a Spain drug dispensation records.

OBJECTIVES: To analyse the association between aminosalicylate-treated inflammatory bowel disease (IBD) and Parkinson's disease (PD) at population level. DESIGN: Cross-sectional study. SETTING: The study was performed based on electronic drug prescription and dispensation records of the Andalusian Public Health System. PARTICIPANTS: All individuals aged ≥50 years with at least one drug dispensation during December 2014 were identified from the records. PRIMARY AND SECONDARY OUTCOME MEASURES: Groups were formed: 'possible PD' group, including all who received an anti-Parkinson agent; 'possible IBD' group, those treated with mesalazine and/or derivatives (5-aminosalicylic acid (5-ASA)); and 'possible PD and IBD', including those receiving both anti-Parkinson agent and 5-ASA. Prevalence of possible PD was determined among those with possible IBD and among those without this condition. The age-adjusted and sex-adjusted OR was calculated. RESULTS: We recorded 2 020 868 individuals (68±11 years, 56% female), 19 966 were included in possible PD group (75±9 years, 53% female) and 7485 in possible IBD group (64±10 years, 47% female); only 56 were included in both groups (76±8 years, 32% female). The prevalence of possible PD was 0.7% among those with possible IBD and 1% among those without this condition (adjusted OR=0.94; 95% CI 0.72 to 1.23; p=0.657). OR was 0.28 in individuals aged ≤65 years (95% CI 0.10 to 0.74; p=0.01) and 1.17 in older individuals (95% CI 0.89 to 1.54; p=0.257). CONCLUSIONS: Within the limitations of this study, the results suggest a protective role for IBD and/or 5-ASA against PD development, especially among under 65-year olds. Further studies are warranted to explore this association given its scientific and therapeutic implications.

Multidimensional Circadian Monitoring by Wearable Biosensors in Parkinson's Disease.

Parkinson's disease (PD) is associated with several non-motor symptoms that may precede the diagnosis and constitute a major source of frailty in this population. The digital era in health care has open up new prospects to move forward from the qualitative and subjective scoring for PD with the use of new wearable biosensors that enable frequent quantitative, reliable, repeatable, and multidimensional measurements to be made with minimal discomfort and inconvenience for patients. A cross-sectional study was conducted to test a wrist-worn device combined with machine-learning processing to detect circadian rhythms of sleep, motor, and autonomic disruption, which can be suitable for the objective and non-invasive evaluation of PD patients. Wrist skin temperature, motor acceleration, time in movement, hand position, light exposure, and sleep rhythms were continuously measured in 12 PD patients and 12 age-matched healthy controls for seven consecutive days using an ambulatory circadian monitoring device (ACM). Our study demonstrates that a multichannel ACM device collects reliable and complementary information from motor (acceleration and time in movement) and common non-motor (sleep and skin temperature rhythms) features frequently disrupted in PD. Acceleration during the daytime (as indicative of motor impairment), time in movement during sleep (representative of fragmented sleep) and their ratio (A/T) are the best indexes to objectively characterize the most common symptoms of PD, allowing for a reliable and easy scoring method to evaluate patients. Chronodisruption score, measured by the integrative algorithm known as the circadian function index is directly linked to a low A/T score. Our work attempts to implement innovative technologies based on wearable, multisensor, objective, and easy-to-use devices, to quantify PD circadian rhythms in huge populations over extended periods of time, while controlling at the same time exposure to exogenous circadian synchronizers.

Carotid body autotransplantation in Parkinson disease: a clinical and positron emission tomography study.

BACKGROUND: Carotid body (CB) glomus cells are highly dopaminergic and express the glial cell line derived neurotrophic factor. The intrastriatal grafting of CB cell aggregates exerts neurotrophic actions on nigrostriatal neurons in animal models of Parkinson disease (PD). OBJECTIVE: We conducted a phase I-II clinical study to assess the feasibility, long term safety, clinical and neurochemical effects of intrastriatal CB autotransplantation in patients with PD. METHODS: Thirteen patients with advanced PD underwent bilateral stereotactic implantation of CB cell aggregates into the striatum. They were assessed before surgery and up to 1-3 years after surgery according to CAPIT (Core Assessment Programme for Intracerebral Transplantation) and CAPSIT-PD (Core Assessment Programme for Surgical Interventional Therapies in Parkinson's Disease) protocols. The primary outcome measure was the change in video blinded Unified Parkinson's Disease Rating Scale III score in the off-medication state. Seven patients had 18F-dopa positron emission tomography scans before and 1 year after transplantation. RESULTS: Clinical amelioration in the primary outcome measure was observed in 10 of 12 blindly analysed patients, which was maximal at 6-12 months after transplantation (5-74%). Overall, mean improvement at 6 months was 23%. In the long term (3 years), 3 of 6 patients still maintained improvement (15-48%). None of the patients developed off-period dyskinesias. The main predictive factors for motor improvement were the histological integrity of the CB and a milder disease severity. We observed a non-significant 5% increase in mean putaminal 18F-dopa uptake but there was an inverse relationship between clinical amelioration and annual decline in putaminal 18F-dopa uptake (r = -0.829; p = 0.042). CONCLUSIONS: CB autotransplantation may induce clinical effects in patients with advanced PD which seem partly related to the biological properties of the implanted glomus cells.

Structural genomic variations and Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease, whose prevalence is projected to be between 8.7 and 9.3 million by 2030. Until about 20 years ago, PD was considered to be the textbook example of a "non-genetic" disorder. Nowadays, PD is generally considered a multifactorial disorder that arises from the combination and complex interaction of genes and environmental factors. To date, a total of 7 genes including SNCA, LRRK2, PARK2, DJ-1, PINK 1, VPS35 and ATP13A2 have been seen to cause unequivocally Mendelian PD. Also, variants with incomplete penetrance in the genes LRRK2 and GBA are considered to be strong risk factors for PD worldwide. Although genetic studies have provided valuable insights into the pathogenic mechanisms underlying PD, the role of structural variation in PD has been understudied in comparison with other genomic variations. Structural genomic variations might substantially account for such genetic substrates yet to be discovered. The present review aims to provide an overview of the structural genomic variants implicated in the pathogenesis of PD.