RESUMEN
BACKGROUND: Using 11 C-(R)-PK11195-PET, we found increased microglia activation in isolated REM sleep behavior disorder (iRBD) patients. Their role remains to be clarified. OBJECTIVES: The objective is to assess relationships between activated microglia and progression of nigrostriatal dysfunction in iRBD. METHODS: Fifteen iRBD patients previously scanned with 11 C-(R)-PK11195 and 18 F-DOPA-PET underwent repeat 18 F-DOPA-PET after 3 years. 18 F-DOPA Ki changes from baseline were evaluated with volumes-of-interest and voxel-based analyses. RESULTS: Significant 18 F-DOPA Ki reductions were found in putamen and caudate. Reductions were larger and more widespread in patients with increased nigral microglia activation at baseline. Left nigral 11 C-(R)-PK11195 binding at baseline was a predictor of 18 F-DOPA Ki reduction in left caudate (coef = -0.0426, P = 0.016). CONCLUSIONS: Subjects with increased baseline 11 C-(R)-PK11195 binding have greater changes in nigrostriatal function, suggesting a detrimental rather than protective effect of microglial activation. Alternatively, both phenomena occur in patients with prominent nigrostriatal dysfunction without a causative link. The clinical and therapeutic implications of these findings need further elucidation. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
RESUMEN
Parkinson's disease (PD) is a neurodegenerative disease associated with progressive death of midbrain dopamine (DAn) neurons in the substantia nigra (SN). Since it has been proposed that patients with PD exhibit an overall proinflammatory state, and since astrocytes are key mediators of the inflammation response in the brain, here we sought to address whether astrocyte-mediated inflammatory signaling could contribute to PD neuropathology. For this purpose, we generated astrocytes from induced pluripotent stem cells (iPSCs) representing patients with PD and healthy controls. Transcriptomic analyses identified a unique inflammatory gene expression signature in PD astrocytes compared with controls. In particular, the proinflammatory cytokine IL-6 was found to be highly expressed and released by PD astrocytes and was found to induce toxicity in DAn. Mechanistically, neuronal cell death was mediated by IL-6 receptor (IL-6R) expressed in human PD neurons, leading to downstream activation of STAT3. Blockage of IL-6R by the addition of the FDA-approved anti-IL-6R antibody, Tocilizumab, prevented PD neuronal death. SN neurons overexpressing IL-6R and reactive astrocytes expressing IL-6 were detected in postmortem brain tissue of patients at early stages of PD. Our findings highlight the potential role of astrocyte-mediated inflammatory signaling in neuronal loss in PD and pave the way for the design of future therapeutics.
Asunto(s)
Células Madre Pluripotentes Inducidas , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , Astrocitos/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Interleucina-6/metabolismo , Enfermedades Neurodegenerativas/patología , Neuronas Dopaminérgicas/metabolismoRESUMEN
Parkinson's disease and dementia with Lewy bodies are currently defined by their clinical features, with α-synuclein pathology as the gold standard to establish the definitive diagnosis. We propose that, given biomarker advances enabling accurate detection of pathological α-synuclein (ie, misfolded and aggregated) in CSF using the seed amplification assay, it is time to redefine Parkinson's disease and dementia with Lewy bodies as neuronal α-synuclein disease rather than as clinical syndromes. This major shift from a clinical to a biological definition of Parkinson's disease and dementia with Lewy bodies takes advantage of the availability of tools to assess the gold standard for diagnosis of neuronal α-synuclein (n-αsyn) in human beings during life. Neuronal α-synuclein disease is defined by the presence of pathological n-αsyn species detected in vivo (S; the first biological anchor) regardless of the presence of any specific clinical syndrome. On the basis of this definition, we propose that individuals with pathological n-αsyn aggregates are at risk for dopaminergic neuronal dysfunction (D; the second biological anchor). Our biological definition establishes a staging system, the neuronal α-synuclein disease integrated staging system (NSD-ISS), rooted in the biological anchors (S and D) and the degree of functional impairment caused by clinical signs or symptoms. Stages 0-1 occur without signs or symptoms and are defined by the presence of pathogenic variants in the SNCA gene (stage 0), S alone (stage 1A), or S and D (stage 1B). The presence of clinical manifestations marks the transition to stage 2 and beyond. Stage 2 is characterised by subtle signs or symptoms but without functional impairment. Stages 2B-6 require both S and D and stage-specific increases in functional impairment. A biological definition of neuronal α-synuclein disease and an NSD-ISS research framework are essential to enable interventional trials at early disease stages. The NSD-ISS will evolve to include the incorporation of data-driven definitions of stage-specific functional anchors and additional biomarkers as they emerge and are validated. Presently, the NSD-ISS is intended for research use only; its application in the clinical setting is premature and inappropriate.
Asunto(s)
Enfermedad por Cuerpos de Lewy , Enfermedad de Parkinson , Sinucleinopatías , Humanos , alfa-Sinucleína/genética , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/genética , Enfermedad por Cuerpos de Lewy/diagnóstico , Sinucleinopatías/diagnóstico , Cuerpos de Lewy , SíndromeRESUMEN
BACKGROUND: Reduced cortical acetylcholinesterase activity, as measured by 11 C-donepezil positron emission tomography (PET), has been reported in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD). However, its progression and clinical implications have not been fully investigated. Here, we explored the relationship between longitudinal changes in brain acetylcholinesterase activity and cognitive function in iRBD. METHODS: Twelve iRBD patients underwent 11 C-donepezil PET at baseline and after 3 years. PET images were interrogated with statistical parametric mapping (SPM) and a regions of interest (ROI) approach. Clinical progression was assessed with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). Cognitive function was rated using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). RESULTS: From baseline to follow-up, the mean 11 C-donepezil distribution volume ratio (DVR) decreased in the cortex (p = 0.006), thalamus (p = 0.013), and caudate (p = 0.013) ROI. Despite no significant changes in the group mean MMSE or MoCA scores being observed, individually, seven patients showed a decline in their scores on these cognitive tests. Subgroup analysis showed that only the subgroup of patients with a decline in cognitive scores had a significant reduction in mean cortical 11 C-donepezil DVR. CONCLUSIONS: Our results show that severity of brain cholinergic dysfunction in iRBD patients increases significantly over 3 years, and those changes are more severe in those with a decline in cognitive test scores.
Asunto(s)
Enfermedad de Parkinson , Trastorno de la Conducta del Sueño REM , Humanos , Trastorno de la Conducta del Sueño REM/psicología , Acetilcolinesterasa , Donepezilo , Encéfalo/diagnóstico por imagenRESUMEN
Background: Multiple system atrophy (MSA) is a devastating disease characterized by a variable combination of motor and autonomic symptoms. Previous studies identified numerous clinical factors to be associated with shorter survival. Objective: To enable personalized patient counseling, we aimed at developing a risk model of survival based on baseline clinical symptoms. Methods: MSA patients referred to the Movement Disorders Unit in Innsbruck, Austria, between 1999 and 2016 were retrospectively analyzed. Kaplan-Meier curves and multivariate Cox regression analysis with least absolute shrinkage and selection operator penalty for variable selection were performed to identify prognostic factors. A nomogram was developed to estimate the 7 years overall survival probability. The performance of the predictive model was validated and calibrated internally using bootstrap resampling and externally using data from the prospective European MSA Study Group Natural History Study. Results: A total of 210 MSA patients were included in this analysis, of which 124 patients died. The median survival was 7 years. The following clinical variables were found to significantly affect overall survival and were included in the nomogram: age at symptom onset, falls within 3 years of onset, early autonomic failure including orthostatic hypotension and urogenital failure, and lacking levodopa response. The time-dependent area under curve for internal and external validation was >0.7 within the first 7 years of the disease course. The model was well calibrated showing good overlap between predicted and actual survival probability at 7 years. Conclusion: The nomogram is a simple tool to predict survival on an individual basis and may help to improve counseling and treatment of MSA patients.
RESUMEN
Background: On-demand treatments can treat OFF episodes in Parkinson's disease, however, there is limited information regarding when to prescribe them. Objective: Develop expert consensus to determine appropriate clinical factors for considering on-demand treatments. Methods: Using a RAND/UCLA modified Delphi panel method, a panel developed consensus on the use of on-demand treatments for OFF episodes. Results: The panel agreed on-demand treatments were appropriate when OFF episodes were associated with greater functional impact and interfered with basic daily activities. The panel also agreed on-demand treatment may be appropriate for patients with morning akinesia and/or delayed ON of first levodopa dose and >1 type of OFF episode (eg, early morning OFF or wearing OFF regardless of frequency). Conclusions: Experts agreed on-demand treatment is appropriate for many patients with OFF episodes. The greater the functional impact of OFF episodes, the more likely experts agreed that on-demand treatment is appropriate to prescribe.
RESUMEN
Elevated urine bis(monoacylglycerol)phosphate (BMP) levels have been found in gain-of-kinase function LRRK2 G2019S mutation carriers. Here, we have expanded urine BMP analysis to other Parkinson's disease (PD) associated mutations and found them to be consistently elevated in carriers of LRRK2 G2019S and R1441G/C as well as VPS35 D620N mutations. Urine BMP levels are promising biomarkers for patient stratification and potentially target engagement in clinical trials of emerging targeted PD therapies.
RESUMEN
The LRRK2 G2019S pathogenic mutation causes LRRK2-associated Parkinson's disease (L2PD) with incomplete penetrance. LRRK2 non-manifesting carriers (L2NMC) are at PD high risk but predicting pheno-conversion is challenging given the lack of progression biomarkers. To investigate novel biomarkers for PD premotor stages, we performed a longitudinal microRNA (miRNA) assessment of serum samples from G2019S L2NMC followed-up over 8 years. Our cohort consisted of G2019S L2NMC stratified by dopamine transporter single-photon emission computed tomography (DaT-SPECT) into DaT-negative (n = 20) and DaT-positive L2NMC (n = 20), pheno-converted G2019S L2PD patients (n = 20), idiopathic PD (iPD) (n = 19), and controls (n = 40). We also screened a second cohort of L2PD patients (n = 19) and controls (n = 20) (Total n = 158). Compared to healthy controls, we identified eight deregulated miRNAs in DaT-negative L2NMC, six in DaT-positive L2NMC, and one in L2PD. Between groups, the highest miRNA differences, 24 candidate miRNAs, occurred between DaT-positive L2NMC and L2PD. Longitudinally, we found 11 common miRNAs with sustained variation in DaT-negative and DaT-positive L2NMCs compared to their baselines. Our study identifies novel miRNA alterations in premotor stages of PD co-occurring with progressive DaT-SPECT decline before motor manifestation, whose deregulation seems to attenuate after the diagnosis of L2PD. Moreover, we identified four miRNAs with relatively high discriminative ability (AUC = 0.82) between non-pheno-converted DaT-positive G2019S carriers and pheno-converted L2PD patients (miR-4505, miR-8069, miR-6125, and miR-451a), which hold potential as early progression biomarkers for PD.
RESUMEN
INTRODUCTION: There is currently a resurgence of levodopa as the initial treatment of choice for most patients with Parkinson's disease, albeit at lower doses than previously used. The addition of adjuvant treatments (including MAO-B inhibitors, COMT inhibitors and dopamine agonists) is an established strategy to reduce motor complications that develop with sustained levodopa therapy. AREAS COVERED: In this narrative review, the authors discuss the evidence underpinning current levodopa optimization strategies, during early disease and once motor complications occur. To support the discussion, the authors performed a broad PubMed search with the terms 'levodopa/L-dopa/L-Dopa, and Parkinson's disease,' restricted to clinical trials. There is now a wealth of evidence that improving levodopa delivery to the brain improves outcomes and we discuss how agents can be combined earlier in the course of disease to leverage the full potential of this strategy. EXPERT OPINION: Levodopa remains the cornerstone of antiparkinsonian therapy. Several promising advances in formulation have been made and include novel extended-release oral drugs as well as non-oral delivery systems. However, evidence has long suggested that anti-parkinsonian medications may be better used in combination earlier in the disease, and consequently patients will benefit from low doses of several agents rather than ever larger levodopa doses.
Asunto(s)
Levodopa , Enfermedad de Parkinson , Humanos , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/complicaciones , Antiparkinsonianos/efectos adversos , Agonistas de Dopamina/uso terapéuticoRESUMEN
BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 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/genética , MutaciónRESUMEN
BACKGROUND: The neuropathology of Parkinson's disease (PD) associated with leucine-rich repeat kinase 2 (LRRK2) mutations (LRRK2-PD) is heterogeneous and varies with the type of mutation. There are only a few studies evaluating seeding aggregation assays to detect α-synuclein (α-syn) in patients with LRRK2-PD. OBJECTIVE: We aimed to investigate whether α-syn real-time quaking induced conversion (RT-QuIC) is a sensitive biomarker of synucleinopathy in LRRK2-PD. METHODS: We studied α-syn RT-QuIC in brain tissue and postmortem ventricular cerebrospinal fluid (CSF) of LRRK2-PD cases with and without Lewy-type pathology. RESULTS: The accuracy of α-syn RT-QuIC in substantia nigra and CSF samples of patients with LRRK2-PD was 100%. The test also obtained 100% sensitivity to detect misfolded α-syn in substantia nigra of cases with idiopathic PD and was negative in the substantia nigra of all the control brains without Lewy-type pathology. CONCLUSIONS: Substantia nigra and ventricular CSF RT-QuIC discriminates with high sensitivity and specificity LRRK2 cases with Lewy-type pathology from those without it. RT-QuIC assay could be of particular interest in the selection of cases for clinical trials in this genetic form of PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Enfermedad de Parkinson , Sinucleinopatías , Humanos , Enfermedad de Parkinson/genética , alfa-Sinucleína/metabolismo , Cuerpos de Lewy/patología , Encéfalo/patología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genéticaRESUMEN
Leucine-rich repeat kinase 2 (LRRK2) gene, which is the gene most commonly associated with Parkinson's disease (PD), is also a susceptibility gene for Crohn's disease, thereby suggesting that LRRK2 may sit at the crossroads of gastrointestinal inflammation, Parkinson's, and Crohn's disease. LRRK2 protein has been studied intensely in both CNS neurons and in immune cells, but there are only few studies on LRRK2 in the enteric nervous system (ENS). LRRK2 is present in ENS ganglia and the existing studies on LRRK2 expression in colonic biopsies from PD subjects have yielded conflicting results. Herein, we propose to extend these findings by studying in more details LRRK2 expression in the ENS. LRRK2 expression was evaluated in full thickness segments of colon of 16 Lewy body, 12 non-Lewy body disorders cases, and 3 non-neurodegenerative controls and in various enteric neural cell lines. We showed that, in addition to enteric neurons, LRRK2 is constitutively expressed in enteric glial cells in both fetal and adult tissues. LRRK2 immunofluorescence intensity in the myenteric ganglia was not different between Lewy body and non-Lewy body disorders. Additionally, we identified the cAMP pathway as a key signaling pathway involved in the regulation of LRRK2 expression and phosphorylation in the enteric glial cells. Our study is the first detailed characterization of LRRK2 in the ENS and the first to show that enteric glial cells express LRRK2. Our findings provide a basis to unravel the functions of LRRK2 in the ENS and to further investigate the pathological changes in enteric synucleinopathies.
Asunto(s)
Enfermedad de Crohn , Sistema Nervioso Entérico , Enfermedad de Parkinson , Adulto , Humanos , Animales , Enfermedad de Crohn/metabolismo , Enfermedad de Crohn/patología , Sistema Nervioso Entérico/metabolismo , Enfermedad de Parkinson/metabolismo , Neuronas/metabolismo , Línea Celular , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismoRESUMEN
Mitochondrial dysfunction happens in both idiopathic (iPD) and LRRK2-related Parkinson's disease (LRRK2-PD). Nonetheless, previous studies suggested that a different type of mitochondrial pathology underlies the neurodegeneration in these two disorders. To further explore this hypothesis, we developed a novel multiplex digital PCR assay that allows the absolute quantification of cell-free mitochondrial DNA (cf-mtDNA) copy number and deletion ratio directly in cerebrospinal fluid (CSF) by simultaneously measuring two opposed regions of the mtDNA circular molecule, one of them in the commonly deleted major arc. The results confirmed that the content of cf-mtDNA in CSF was statistically significantly different between iPD and LRRK2-PD patients. Moreover, we found high cf-mtDNA deletion levels in CSF from patients with iPD, but not LRRK2-PD. The high cf-mtDNA deletion frequency in iPD was validated in an independent cohort. These results indicated that the content and deletion ratio of cf-mtDNA may differentiate iPD from LRRK2-PD, and provides further evidence of the different mitochondrial pathophysiology between these two forms of the disease.
Asunto(s)
Enfermedad de Parkinson , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/líquido cefalorraquídeo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/líquido cefalorraquídeo , ADN Mitocondrial/genética , Mitocondrias/genética , Estudios de Cohortes , MutaciónRESUMEN
Background: ATP13A2 holds promise as biomarker for Parkinsons disease (PD). No study has examined how salivary ATP13A2 is related to motor features in idiopathic PD. Methods: Salivary ATP13A2 concentration was evaluated with ELISA, and statistical correlations of ATP13A2 level with PD parameters were examined. The dose intensity of the dopaminergic medication regimen was expressed as levodopa equivalent daily dose (LEDD). ATP13A2 expression on histological sections of submandibular glands was evaluated using immunohistochemistry. Results: Salivary ATP13A2 was undetectable in many subjects (28 % of patients, 43.7 % of controls). However, all the patients with motor complications (n = 28) showed quantifiable levels of ATP13A2, that positively correlated with MDS-UPDRS (total, parts III and IV), and LEDD (p < 0.05). Dyskinetic patients showed the highest LEDD values (p < 0.05). The histological study revealed: a) ATP13A2 staining was very intense in duct cells and vascular endothelium, and b) two patterns of ATP13A2-positive deposits are observed: rounded inclusions of 10-20 µm in diameter located in the interlobular tissue of the patients, and amorphous aggregates inside duct lumen in controls and patients. Conclusions: The sensitivity of the ELISA assay was a major limitation for quantifying ATP13A2. However, salivary ATP13A2 was detected in all patients with motor complications, where a direct relationship among ATP13A2 concentration, levodopa equivalent daily dose, and MDS-UPDRS was found. Therefore, salivary ATP13A2 might be a reliable index of therapy-induced motor complications. ATP13A2 was expressed by rounded inclusions in the submandibulary gland of patients. This is the first description of ATP13A2-positive inclusions outside the nervous system.
RESUMEN
Introduction: Post-hoc analyses of the BIPARK-I and II trials previously demonstrated that opicapone (OPC) 50 mg was efficacious over the whole trajectory of motor fluctuation evolution in patients with Parkinson's disease (PD) and end-of-dose motor fluctuations, with enhanced efficacy in patients who were earlier vs. later in their disease course and levodopa treatment pathway. Complementary post-hoc analyses were performed to evaluate the safety/tolerability of OPC following the same pre-defined segmentation of the wide spectrum of duration of both PD and levodopa therapy, as well as of motor fluctuation history, in this patient population. Materials and methods: Data from matching treatment arms in BIPARK-I and II were combined for the placebo (PLC) and OPC 50 mg groups and exploratory post-hoc analyses were performed to investigate the safety/tolerability of OPC 50 mg and PLC in 22 subgroups of patients who were in "earlier" vs. "later" stages of both their disease course (e.g., duration of PD <6 years vs. ≥6 years) and levodopa treatment pathway (e.g., levodopa treatment duration <4 vs. ≥4 years). Safety/tolerability assessments included evaluation of treatment-emergent adverse events (TEAEs). Results: The Safety Set included 522 patients (PLC, n = 257; OPC 50 mg, n = 265). For OPC 50 mg, incidences of TEAEs, related TEAEs, related serious TEAEs, and related TEAEs leading to discontinuation were lower for patients in earlier vs. later stages of their disease course and levodopa treatment pathway in 86.4, 86.4, 63.6, and 68.2% of the 22 pairwise comparisons conducted, respectively (compared with 63.6, 77.3, 18.2, and 45.5%, respectively, in the 22 corresponding PLC comparisons). Conclusion: OPC 50 mg was generally well-tolerated when used to treat patients with PD with end-of-dose fluctuations, with an even more favorable tolerability profile in patients who were earlier, as opposed to later, in their disease course and levodopa treatment pathway, further supporting its use as an early adjunct to levodopa in PD.
RESUMEN
The purpose of this study was to investigate whether âdifferential phosphorylation states of blood markers can identify patients with LRRK2 Parkinson's disease (PD). We assessed phospho(P)-Ser-935-LRRK2 and P-Ser-473-AKT levels in peripheral blood cells from patients with G2019S LRRK2-associated PD (L2PD, n = 31), G2019S LRRK2 non-manifesting carriers (L2NMC, n = 26), idiopathic PD (iPD, n = 25), and controls (n = 40, total n = 122). We found no differences at P-Ser-935-LRRK2 between groups but detected a specific increase of P-Ser-473-AKT levels in all G2019S carriers, either L2PD or L2NMC, absent in iPD. Although insensitive to LRRK2 inhibition, our study identifies P-Ser-473-AKT as an endogenous candidate biomarker for peripheral inflammation in G2019S carriers using accessible blood cells. ANN NEUROL 2022;92:888-894.
Asunto(s)
Enfermedad de Parkinson , Proteínas Proto-Oncogénicas c-akt , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Proteínas Proto-Oncogénicas c-akt/genética , Mutación/genética , Enfermedad de Parkinson/genética , Biomarcadores , Células SanguíneasRESUMEN
BACKGROUND: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. METHODS: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT). RESULTS: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls. CONCLUSIONS: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).
Asunto(s)
Anticuerpos Monoclonales Humanizados , Antiparkinsonianos , Enfermedad de Parkinson , alfa-Sinucleína , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antiparkinsonianos/efectos adversos , Método Doble Ciego , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Resultado del Tratamiento , alfa-Sinucleína/inmunologíaRESUMEN
The role of somatic mutations in complex diseases, including neurodevelopmental and neurodegenerative disorders, is becoming increasingly clear. However, to date, no study has shown their relation to Parkinson disease's phenotype. To explore the relevance of embryonic somatic mutations in sporadic Parkinson disease, we performed whole-exome sequencing in blood and four brain regions of ten patients. We identified 59 candidate somatic single nucleotide variants (sSNVs) through sensitive calling and a careful filtering strategy (COSMOS). We validated 27 of them with amplicon-based ultra-deep sequencing, with a 70% validation rate for the highest-confidence variants. The identified sSNVs are in genes with synaptic functions that are co-expressed with genes previously associated with Parkinson disease. Most of the sSNVs were only called in blood but were also found in the brain tissues with ultra-deep amplicon sequencing, demonstrating the strength of multi-tissue sampling designs.
RESUMEN
BACKGROUND: The second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages. OBJECTIVE: To develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence-based and consensus-based methodology. METHODS: We identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference. RESULTS: The criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow. CONCLUSIONS: This set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.