RESUMEN
OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.
Asunto(s)
Amantadina , Antiparkinsonianos , Enfermedad de Parkinson , Amantadina/uso terapéutico , Amantadina/efectos adversos , Humanos , Masculino , Femenino , Francia/epidemiología , Anciano , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Antiparkinsonianos/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología , Persona de Mediana Edad , Estudios Prospectivos , Discinesia Inducida por Medicamentos/epidemiología , Discinesia Inducida por Medicamentos/etiología , Estudios Transversales , Levodopa/efectos adversos , Levodopa/administración & dosificación , Estudios Longitudinales , Estudios de CohortesRESUMEN
BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).
Asunto(s)
Antiparkinsonianos , Agonistas Receptor de Péptidos Similares al Glucagón , Enfermedad de Parkinson , Péptidos , Humanos , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Personas con Discapacidad , Método Doble Ciego , Trastornos Motores/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Péptidos/administración & dosificación , Péptidos/efectos adversos , Péptidos/uso terapéutico , Resultado del Tratamiento , Agonistas Receptor de Péptidos Similares al Glucagón/administración & dosificación , Agonistas Receptor de Péptidos Similares al Glucagón/efectos adversos , Agonistas Receptor de Péptidos Similares al Glucagón/uso terapéutico , Progresión de la Enfermedad , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/efectos adversos , Fármacos Neuroprotectores/uso terapéutico , Inyecciones SubcutáneasRESUMEN
BACKGROUND: Although the group of paroxysmal kinesigenic dyskinesia (PKD) genes is expanding, the molecular cause remains elusive in more than 50% of cases. OBJECTIVE: The aim is to identify the missing genetic causes of PKD. METHODS: Phenotypic characterization, whole exome sequencing and association test were performed among 53 PKD cases. RESULTS: We identified four causative variants in KCNJ10, already associated with EAST syndrome (epilepsy, cerebellar ataxia, sensorineural hearing impairment and renal tubulopathy). Homozygous p.(Ile209Thr) variant was found in two brothers from a single autosomal recessive PKD family, whereas heterozygous p.(Cys294Tyr) and p.(Thr178Ile) variants were found in six patients from two autosomal dominant PKD families. Heterozygous p.(Arg180His) variant was identified in one additional sporadic PKD case. Compared to the Genome Aggregation Database v2.1.1, our PKD cohort was significantly enriched in both rare heterozygous (odds ratio, 21.6; P = 9.7 × 10-8) and rare homozygous (odds ratio, 2047; P = 1.65 × 10-6) missense variants in KCNJ10. CONCLUSIONS: We demonstrated that both rare monoallelic and biallelic missense variants in KCNJ10 are associated with PKD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Distonía , Mutación Missense , Canales de Potasio de Rectificación Interna , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Distonía/genética , Secuenciación del Exoma , Mutación Missense/genética , Linaje , Canales de Potasio de Rectificación Interna/genéticaRESUMEN
BACKGROUND: Acting on the main target of dopaminergic cells, the striatal γ-aminobutyric acid (GABA)-ergic cells, might be a new way to treat persons with Parkinson's disease (PD). OBJECTIVE: The objective of this study was to assess the efficacy of bumetanide, an Na-K-Cl cotransporter (NKCC1) inhibitor, to improve motor symptoms in PD. METHODS: This was a 4-month double-blind, randomized, parallel-group, placebo-controlled trial of 1.75 to 3 mg/day bumetanide as an adjunct to levodopa in 44 participants with PD and motor fluctuations. RESULTS: Compared to the baseline, the mean change in OFF Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score after 4 months of treatment (primary endpoint) did not improve significantly compared with placebo. No changes between participants treated with bumetanide and those treated with placebo were observed for most other outcome measures. Despite no relevant safety signals, bumetanide was poorly tolerated. CONCLUSIONS: There was no evidence in this study that bumetanide has efficacy in improving motor symptoms of PD. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Antiparkinsonianos , Bumetanida/uso terapéutico , Levodopa/uso terapéutico , Evaluación de Resultado en la Atención de Salud , Método Doble Ciego , Resultado del TratamientoRESUMEN
[This corrects the article DOI: 10.5334/tohm.464.].
RESUMEN
Background: Monoallelic pathogenic variants of PRRT2 often result in paroxysmal kinesigenic dyskinesia (PKD). Little is known about health-related quality of life (HrQoL), non-motor manifestations, self-esteem, and stigma in patients with PKD. Objectives: We investigated non-motor symptoms and how they related to HrQoL in a genetically homogeneous group of PRRT2-PKD patients. We paid special attention to perceived stigmatization and self-esteem. Methods: We prospectively enrolled 21 consecutive PKD patients with a pathogenic variant of PRRT2, and 21 healthy controls matched for age and sex. They were evaluated with dedicated standardized tests for non-motor symptoms, HrQoL, anxiety, depression, stigma, self-esteem, sleep, fatigue, pain, and psychological well-being. Results: Patients reported an alteration of the physical aspects of HrQoL, regardless of the presence of residual paroxysmal episodes. Non-motor manifestations were frequent, and were an important determinant of the alteration of HrQoL. In addition, patients perceived a higher level of stigmatization which positively correlated with a delay in diagnosis (ρ = 0.615, P = 0.003) and the fear of being judged (ρ = 0.452, P = 0.04), but not with the presence of paroxysmal episodes (ρ = 0.203, P = 0.379). Conclusions: Our findings have important implications for care givers concerning patient management and medical education about paroxysmal dyskinesia. PRRT2-PKD patients should be screened for non-motor disorders in routine care. A long history of misdiagnosis may play a role in the high level of perceived stigmatization. Improving knowledge about diagnostic clues suggestive of PKD is mandatory.
RESUMEN
Paroxysmal kinesigenic dyskinesia (PKD) are movement disorders triggered by sudden voluntary movement. Variants in the TMEM151A gene have recently been associated with the development of PKD. We report three patients presenting PKD with different TMEM151A mutations, two of which have not been described yet.
Asunto(s)
Distonía , Proteínas de la Membrana , Humanos , Proteínas de la Membrana/genética , Proteínas del Tejido Nervioso/genética , Mutación , Distonía/genéticaRESUMEN
BACKGROUND: The EARLYSTIM trial demonstrated for Parkinson's disease patients with early motor complications that deep brain stimulation of the subthalamic nucleus (STN-DBS) and best medical treatment (BMT) was superior to BMT alone. OBJECTIVE: This prospective, ancillary study on EARLYSTIM compared changes in blinded speech intelligibility assessment between STN-DBS and BMT over 2 years, and secondary outcomes included non-speech oral movements (maximum phonation time [MPT], oral diadochokinesis), physician- and patient-reported assessments. METHODS: STN-DBS (n = 102) and BMT (n = 99) groups underwent assessments on/off medication at baseline and 24 months (in four conditions: on/off medication, ON/OFF stimulation-for STN-DBS). Words and sentences were randomly presented to blinded listeners, and speech intelligibility rate was measured. Statistical analyses compared changes between the STN-DBS and BMT groups from baseline to 24 months. RESULTS: Over the 2-year period, changes in speech intelligibility and MPT, as well as patient-reported outcomes, were not different between groups, either off or on medication or OFF or ON stimulation, but most outcomes showed a nonsignificant trend toward worsening in both groups. Change in oral diadochokinesis was significantly different between STN-DBS and BMT groups, on medication and OFF STN-DBS, with patients in the STN-DBS group performing slightly worse than patients under BMT only. A signal for clinical worsening with STN-DBS was found for the individual speech item of the Unified Parkinson's Disease Rating Scale, Part III. CONCLUSION: At this early stage of the patients' disease, STN-DBS did not result in a consistent deterioration in blinded speech intelligibility assessment and patient-reported communication, as observed in studies of advanced Parkinson's Disease. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/complicaciones , Estudios Prospectivos , Núcleo Subtalámico/fisiología , Movimiento , Inteligibilidad del Habla/fisiología , Estimulación Encefálica Profunda/métodos , Resultado del TratamientoRESUMEN
In recent decades, numerous studies have found that smoking or the intake of any form of nicotine, such as smokeless tobacco, exposure to environmental tobacco smoke, or even dietary sources such as peppers, reduces the risk of developing Parkinson's disease.1 Such observations suggest a potential disease-modifying effect of nicotine in Parkinson's disease. Many experimental studies, some of them supported by grants from the tobacco industry, have lent support for such a hypothesis.
Asunto(s)
Enfermedad de Parkinson , Contaminación por Humo de Tabaco , Tabaco sin Humo , Humanos , Nicotina/análisis , Enfermedad de Parkinson/tratamiento farmacológico , Contaminación por Humo de Tabaco/análisisRESUMEN
Introduction: In Parkinson's disease (PD), the quality of life of both patients and caregivers is affected. While key issues relating to quality of life may not emerge in conversations with healthcare professionals (HCPs), unguarded social media conversations can provide insight into how people with Parkinson's disease (PwPD) and their caregivers are affected. We conducted a qualitative and quantitative netnographic study of PD conversations posted on social media sites over a 12-month period. Objective: To identify key themes and issues for PwPD. Methods: Using predefined and piloted search terms, we identified 392,962 social media posts (between March 31, 2020, and March 31, 2021, for the UK and France, and between September 30, 2019, and March 31, 2021, for Italy, Spain, and Germany). A random sample of these posts was then analyzed using natural language processing (NLP), and quantitative, qualitative,in-depth contextual analysis was also performed. Results: Key themes that emerged in the PD conversation related to the changing experience of symptoms over time are the physical, emotional, and cognitive impact of symptoms, the management and treatment of PD, disease awareness among the general public, and the caregiver burden. The emotional impact of motor symptoms on PwPD is significant, particularly when symptoms increase and PwPD lose their independence, which may exacerbate existing anxiety and depression. Nonmotor symptoms can also compound the difficulties with managing the physical impact of motor symptoms. The burden of nonmotor symptoms is felt by both PwPD and their caregivers, with the impact of nonmotor symptoms on cognitive processes particularly frustrating for caregivers. The experience of off-time was also featured in the online conversation. Some PwPD believe there is a lack of adequate management from healthcare professionals, who may not appreciate their concerns or take sufficient time to discuss their needs. Conclusion: This study identified key themes that PwPD and their caregivers discuss online. These findings help signpost issues of importance to PwPD and areas in which their care may be improved.
RESUMEN
PURPOSE: The decision for subthalamic deep brain stimulation (STN-DBS) in Parkinson's disease (PD) relies on clinical predictors. Whether genetic variables could predict favourable or unfavourable decisions is under investigation. OBJECTIVE: First, we aimed to reproduce the previous observation that SNCA rs356220 was associated with favourable STN-DBS motor response. In additional exploratory analyses, we studied if other PD risk and progression variants from the latest GWAS are associated with therapeutic outcome. Further, we evaluated the predictive value of polygenic risk scores. METHODS: We comprehensively genotyped patients from the EarlyStim cohort using NeuroChip, and assessed the clinico-genetic associations with longitudinal outcome parameters. RESULTS: The SNCA rs356220 variant did not predict UPDRS III outcomes. However, it was associated with quality of life improvement in secondary analyses. Several polymorphisms from previously identified GWAS hits predicted motor or quality of life outcomes in DBS patients. Polygenic risk scores did not predict any outcome parameter. CONCLUSIONS: Our findings support the hypothesis that different common genetic markers are associated with favourable quality of life outcomes of STN-DBS in PD. These findings can be the basis for further validation in larger and independent cohorts.
Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Núcleo Subtalámico/fisiología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/complicaciones , Calidad de Vida , Marcadores Genéticos , Resultado del TratamientoRESUMEN
AIM: Deep brain stimulation (DBS) has proven to be an effective therapy of some treatment-resistant psychiatric disorders and movement disorders. Comorbid depressive symptoms are common and difficult to manage. Treatment with electroconvulsive therapy (ECT) may be required. There are few published cases describing the safety and efficacy of ECT for patients with DBS implants, and there are no available guidelines for administration of ECT in patients with DBS and mood disorders. The current study had 3 aims: (i) to conduct a systematic review of case reports on patients with DBS implants who received ECT; (ii) to report the case of a 69-year-old man with a DBS implant for essential tremor, who required ECT; and (iii) to provide practical recommendations for ECT in patients with DBS implants. METHODS: We conducted a systematic review, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, of existing case reports on patients with DBS implants administered ECT for psychiatric disorders. RESULTS: Our search yielded 25 cases of ECT in patients implanted with DBS systems. In addition, we here describe successful ECT management of major depressive disorder in a patient treated by DBS. We also set forth ECT management guidelines based on points of consensus. The 2 most important practical recommendations are to make sure the DBS system is set to 0 V and turned off before ECT, and to avoid sites near the DBS electrodes. CONCLUSIONS: Electroconvulsive therapy may be an effective and safe treatment for DBS patients with MDD.
Asunto(s)
Estimulación Encefálica Profunda , Trastorno Depresivo Mayor , Terapia Electroconvulsiva , Temblor Esencial , Anciano , Comorbilidad , Humanos , Masculino , Resultado del TratamientoRESUMEN
BACKGROUND: Deep brain stimulation (DBS) is an effective technique to treat patients with advanced Parkinson's disease. The surgical procedure of DBS implantation is generally performed under local anesthesia due to the need for intraoperative clinical testing. However, this procedure is long (5-7 h on average) and, therefore, the objective that the patient remains co-operative and tolerates the intervention well is a real challenge. OBJECTIVE: To evaluate the additional benefit of electroacupuncture (EA) performed intraoperatively to improve the comfort of parkinsonian patients during surgical DBS implantation. METHODS: This single-center randomized study compared two groups of patients. In the first group, DBS implantation was performed under local anesthesia alone, while the second group received EA in addition. The patients were evaluated preoperatively, during the different stages of the surgery, and 2 days after surgery, using the 9-item Edmonton Symptom Assessment System (ESAS), including a total sum score and physical and emotional subscores. RESULTS: The data of nine patients were analyzed in each group. Although pain and tiredness increased in both groups after placement of the stereotactic frame, the ESAS item "lack of appetite", as well as the ESAS total score and physical subscore increased after completion of the first burr hole until the end of the surgical procedure in the control group only. ESAS total score and physical subscore were significantly higher at the end of the intervention in the control group compared to the EA group. After the surgical intervention (D2), anxiety and ESAS emotional subscore were improved in both groups, but the feeling of wellbeing improved in the EA group only. Finally, one patient developed delirium during the intervention and none in the EA group. DISCUSSION: This study shows that intraoperative electroacupuncture significantly improves the tolerance of DBS surgery in parkinsonian patients. This easy-to-perform procedure could be fruitfully added in clinical practice.
RESUMEN
BACKGROUND: ADCY5-related dyskinesia is characterized by early-onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine. OBJECTIVE: The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5-related dyskinesia. METHODS: A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire. RESULTS: Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality-of-life improvement. Three patients reported worsening. CONCLUSION: Our findings suggest that caffeine should be considered as a first-line therapeutic option in ADCY5-related dyskinesia. © 2022 International Parkinson and Movement Disorder Society.
Asunto(s)
Discinesias , Trastornos del Movimiento , Adenilil Ciclasas/genética , Cafeína/uso terapéutico , Niño , Discinesias/etiología , Discinesias/genética , Humanos , Trastornos del Movimiento/genética , Estudios RetrospectivosRESUMEN
OBJECTIVE: To assess the long-term effects of multi-site repetitive transcranial magnetic stimulation combined with cognitive training (NeuroAD procedure) on cognitive symptoms and apathy in patients with Alzheimer's disease (AD) as part of a 4-year chart review. METHODS: The study included the 30 AD patients who underwent NeuroAD treatment between 2015 and 2019 at our center. The clinical evaluation was based on the Mini Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Apathy Inventory (AI). Assessment was performed before treatment (baseline), after an initial 6-week protocol of 30 sessions (M1.5), then 3 months (M3), 1 year (M12), and between 1.5 and 4 years (mean 28 months, M28) after treatment initiation. RESULTS: During the first year of follow-up, the AI score improved at all time points (M1.5, M3, M12, p < 0.0001), the ADAS-Cog score improved at the end of the initial procedure (M1.5, p = 0.003) then deteriorated (M12, p = 0.01), while the MMSE score did not change. At final assessment (M28), the AI score was still improved from baseline (p < 0.0001), while the MMSE and ADAS-Cog scores worsened (p < 0.0001). Regarding the ADAS-Cog score, the prolonged improvement at M12 or M28 was correlated with the initial improvement at M1.5. CONCLUSION: The NeuroAD procedure produced long-term improvement in apathy and more general cognitive improvement only in patients who responded well to the initial 6-week protocol. SIGNIFICANCE: Our results suggest long-term beneficial effects of the NeuroAD procedure on apathy, which need to be confirmed in controlled studies. The criteria for predicting a good outcome before starting the procedure remain to be defined.
Asunto(s)
Enfermedad de Alzheimer , Apatía , Trastornos del Conocimiento , Enfermedad de Alzheimer/diagnóstico , Cognición , Humanos , Pruebas Neuropsicológicas , Estimulación Magnética Transcraneal/métodosRESUMEN
BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) effectively treats motor symptoms and quality of life (QoL) of advanced and fluctuating early Parkinson's disease. Little is known about the relation between electrode position and changes in symptom control and ultimately QoL. OBJECTIVES: The relation between the stimulated part of the STN and clinical outcomes, including the motor score of the Unified Parkinson's Disease Rating Scale (UPDRS) and the quality-of-life questionnaire, was assessed in a subcohort of the EARLYSTIM study. METHODS: Sixty-nine patients from the EARLYSTIM cohort who underwent DBS, with a comprehensive clinical characterization before and 24 months after surgery, were included. Intercorrelations of clinical outcome changes, correlation between the affected functional parts of the STN, and changes in clinical outcomes were investigated. We further calculated sweet spots for different clinical parameters. RESULTS: Improvements in the UPDRS III and Parkinson's Disease Questionnaire (PDQ-39) correlated positively with the extent of the overlap with the sensorimotor STN. The sweet spots for the UPDRS III (x = 11.6, y = -13.1, z = -6.3) and the PDQ-39 differed (x = 14.8, y = -12.4, z = -4.3) ~3.8 mm. CONCLUSIONS: The main influence of DBS on QoL is likely mediated through the sensory-motor basal ganglia loop. The PDQ sweet spot is located in a posteroventral spatial location in the STN territory. For aspects of QoL, however, there was also evidence of improvement through stimulation of the other STN subnuclei. More research is necessary to customize the DBS target to individual symptoms of each patient. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Humanos , Enfermedad de Parkinson/terapia , Calidad de Vida , Núcleo Subtalámico/fisiología , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: The main culprit gene for paroxysmal kinesigenic dyskinesia, characterized by brief and recurrent attacks of involuntary movements, is PRRT2. The location of the primary dysfunction associated with paroxysmal dyskinesia remains a matter of debate and may vary depending on the etiology. While striatal dysfunction has often been implicated in these patients, evidence from preclinical models indicates that the cerebellum could also play a role. We aimed to investigate the role of the cerebellum in the pathogenesis of PRRT2-related dyskinesia in humans. METHODS: We enrolled 22 consecutive right-handed patients with paroxysmal kinesigenic dyskinesia with a pathogenic variant of PRRT2 and their matched controls. Participants underwent a multimodal neuroimaging protocol. We recorded anatomic and diffusion-weighted MRI, as well as resting-state fMRI, during which we tested the aftereffects of sham and repetitive transcranial magnetic stimulation applied to the cerebellum on endogenous brain activity. We quantified the structural integrity of gray matter using voxel-based morphometry, the structural integrity of white matter using fixel-based analysis, and the strength and direction of functional cerebellar connections using spectral dynamic causal modeling. RESULTS: Patients with PRRT2 had decreased gray matter volume in the cerebellar lobule VI and in the medial prefrontal cortex, microstructural alterations of white matter in the cerebellum and along the tracts connecting the cerebellum to the striatum and the cortical motor areas, and dysfunction of cerebellar motor pathways to the striatum and the cortical motor areas, as well as abnormal communication between the associative cerebellum (Crus I) and the medial prefrontal cortex. Cerebellar stimulation modulated communication within the motor and associative cerebellar networks and tended to restore this communication to the level observed in healthy controls. DISCUSSION: Patients with PRRT2-related dyskinesia have converging structural alterations of the motor cerebellum and related pathways with a dysfunction of cerebellar output toward the cerebello-thalamo-striato-cortical network. We hypothesize that abnormal cerebellar output is the primary dysfunction in patients with a PRRT2 pathogenic variant, resulting in striatal dysregulation and paroxysmal dyskinesia. More broadly, striatal dysfunction in paroxysmal dyskinesia might be secondary to aberrant cerebellar output transmitted by thalamic relays in certain disorders. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier: NCT03481491.
Asunto(s)
Enfermedades Cerebelosas , Corea , Distonía , Cerebelo/patología , Corea/diagnóstico por imagen , Corea/genética , Distonía/diagnóstico por imagen , Distonía/genética , Distonía/metabolismo , Humanos , Imagen por Resonancia Magnética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismoRESUMEN
Idiopathic normal pressure hydrocephalus has a complex multifactorial pathogenesis and is associated with Alzheimer's disease in many patients. To date, it is not well known if a similar association exists with behavioural variant of frontotemporal lobar degeneration. In a first step, we compare the prevalence of idiopathic normal pressure hydrocephalus in two groups of patients, one with behavioural variant of frontotemporal lobar degeneration (n = 69) and the other with Alzheimer's disease (n = 178). In the second step, we describe more precisely the phenotype of patients with the association of idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration. Firstly, we report that the prevalence of idiopathic normal pressure hydrocephalus was far higher in the group of patients with behavioural variant of frontotemporal lobar degeneration than in the group of patients with Alzheimer's disease (7.25% and 1.1%, respectively, P = 0.02). Secondly, we show that patients with the double diagnosis share common clinical and para-clinical features of both idiopathic normal pressure hydrocephalus and behavioural variant of frontotemporal lobar degeneration patients, including CSF shunting efficacy in real-life experience. Overall, our results suggest a link between these two conditions and should encourage neurologists to look for idiopathic normal pressure hydrocephalus in their behavioural variant of frontotemporal lobar degeneration patients in the event of gait disturbances; the benefit/risk balance could indeed be in favour of shunt surgery for selected patients with this newly described entity.