| 131. |
- Ran, Caroline, et al.
(författare)
-
Glucocerebrosidase variant T369M is not a risk factor for Parkinson's disease in Sweden.
- 2022
-
Ingår i: Neuroscience Letters. - : Elsevier. - 0304-3940 .- 1872-7972. ; 784
-
Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Genetic variants in the Beta-glucocerebrosidase gene (GBA1) is a known risk factor for Parkinson's disease. The GBA1 mutations L444P, N370S and many other have been shown to associate with the disease in populations with diverse background. Some GBA1 polymorphisms have a less pronounced effect, and their pathogenicity has been debated. We have previously found associations with L444P, N370S and E326K and Parkinson's disease in Sweden.METHOD: In this study we used pyrosequencing to genotype the T369M variant in a large Swedish cohort consisting of 1,131 patients with idiopathic Parkinson's disease, and 1,594 control subjects to evaluate the possibility of this variant conferring an increased risk for Parkinson's disease.RESULTS: The minor allele frequency was 2.15% in patients and 1.76% in controls. Statistical analysis showed that there was no significant difference in allele frequency between patients and control subjects, p-value 0.37, Odds Ratio 1.23 with a 95% confidence interval of 0.82-1.83.CONCLUSION: Our results suggest that T369M is not a risk factor for Parkinson's disease in the Swedish population.
|
|
| 132. |
- Remnestål, Julia, et al.
(författare)
-
CSF profiling of the human brain enriched proteome reveals associations of neuromodulin and neurogranin to Alzheimer's disease
- 2016
-
Ingår i: PROTEOMICS - Clinical Applications. - : Wiley-VCH Verlagsgesellschaft. - 1862-8346 .- 1862-8354. ; 10:12, s. 1242-1253
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study is part of a larger effort aiming to expand the knowledge of brain-enriched proteins in human cerebrospinal fluid (CSF) and to provide novel insight into the relation between such proteins and different neurodegenerative diseases. Experimental design: Here 280 brain-enriched proteins in CSF from patients with Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are profiled. In total, 441 human samples of ventricular CSF collected post mortem and lumbar CSF collected ante mortem are analyzed using 376 antibodies in a suspension bead array setup, utilizing a direct labelling approach. Results: Among several proteins displaying differentiated profiles between sample groups, we focus here on two synaptic proteins, neuromodulin (GAP43) and neurogranin (NRGN). They are both found at elevated levels in CSF from AD patients in two independent cohorts, providing disease-associated profiles in addition to verifying and strengthening previously observed patterns. Increased levels are also observed for patients for whom the AD diagnosis was not established at the time of sampling. Conclusions and clinical relevance: These findings indicate that analyzing the brain-enriched proteins in CSF is of particular interest to increase the understanding of the CSF proteome and its relation to neurodegenerative disorders. In addition, this study lends support to the notion that measurements of these synaptic proteins could potentially be of great relevance in future diagnostic tests for AD.
|
|
| 133. |
- Reyes, Juan, et al.
(författare)
-
Binding of alfa-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes
- 2019
-
Ingår i: Acta Neuropathologica. - : SPRINGER. - 0001-6322 .- 1432-0533. ; 138:1, s. 23-47
-
Tidskriftsartikel (refereegranskat)abstract
- The intercellular transfer of alpha-synuclein (-syn) has been implicated in the progression of Parkinson's disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of -syn oligomeric assemblies (o-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and o-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked o-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with -syn accumulation. Notably, we could alsodemonstrate a direct interaction between -syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related -synucleinopathies.
|
|
| 134. |
- Riggare, Sara, et al.
(författare)
-
Patient-driven N-of-1 in Parkinson's Disease. Lessons Learned from a Placebo-controlled Study of the Effect of Nicotine on Dyskinesia
- 2017
-
Ingår i: Methods of information in medicine. - 2511-705X. ; 56:99, s. e123-e128
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: New insights and knowledge in biomedical science often come from observation and experimentation. Methods traditionally used include self-experimentation, case reports, randomised controlled trials, and N-of-1 studies. Technological advances have lead to an increasing number of individuals and patients engaging in self-tracking. We use the term patient-driven N-of-1 for self-tracking performed with the explicit intention to disseminate the results by academic publishing.OBJECTIVES: The aim of the study was to: 1) explore the potential role for patient-driven N-of-1 studies as a tool for improving self-management in Parkinson's disease (PD) using the example of managing levodopa-induced dyskinesia (LID) with nicotine, and 2) based on this example; identify some specific challenges of patient-driven N-of-1 studies.METHODS: We used a placebo controlled patient-driven N-of-1 study with nicotine administered via e-cigarette to treat LID. The first author initiated and conducted the experiment on herself and noted her observations. The evaluations of the potential of N-of-1 for improving self-management of PD as well as the effects of nicotine on dyskinesia were based on the perception of the subject. During the planning and undertaking of the experiment, notes were made to identify challenges specific to patient-driven N-of-1 studies.RESULTS: The subject was able to distinguish a decrease of her LID from nicotine but no effect from placebo. The main challenges of patient-driven N-of-1 studies were identified to be associated with planning of the study, recruiting a suitable research team, making sure the data collection is optimal, analysis of data, and publication of results.CONCLUSIONS: Our study indicates that nicotine administered via e-cigarette may have an effect on levodopa-induced dyskinesia in individual patients with PD. The main contribution is however highlighting the work done by patients on a daily basis for understanding their conditions and conducting self-tracking experiments. More work is needed to further develop methods around patient-driven N-of-1 studies for PD.
|
|
| 135. |
- Riggare, Sara, et al.
(författare)
-
Patients are doing it for themselves : A survey on disease-specific knowledge acquisition among people with Parkinson's disease in Sweden.
- 2017
-
Ingår i: Health Informatics Journal. - : SAGE Publications. - 1460-4582 .- 1741-2811.
-
Tidskriftsartikel (refereegranskat)abstract
- Effective self-management is key to living well with Parkinson's disease and one important aspect is disease-specific knowledge. This article explores how people with Parkinson's disease in Sweden (1) acquire disease-specific knowledge and (2) use Parkinson's disease-related healthcare. Data were collected through an online survey, which had 346 respondents (16-87 years old, median age: 68 years, 51% male; time since diagnosis: 0-31 years, median time: 7 years). Our results show that disease-specific knowledge is mainly found online, especially for women with Parkinson's disease and people with Parkinson's disease of working age, that most people with Parkinson's disease in Sweden see their neurologist for 1 h or less per year and only one in two people with Parkinson's disease has regular contact with other Parkinson's disease-related healthcare professionals. We also find that people with Parkinson's disease reporting higher levels of specific knowledge also are more likely to be satisfied with the amount of time they get with their neurologist, regardless of the amount of time.
|
|
| 136. |
- Saarinen, Marcus, et al.
(författare)
-
TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT1A receptor agonist SEP-383856
- 2022
-
Ingår i: Neuropsychopharmacology. - : Springer Nature. - 0893-133X .- 1740-634X. ; 47, s. 2319-2329
-
Tidskriftsartikel (refereegranskat)abstract
- SEP-383856 (SEP-856) is a novel antipsychotic under clinical development. It displays a unique pattern of receptor interaction, with only weak (partial agonist) activity at dopamine D2 receptors, yet more potent agonist activity at the trace amine associated receptor (TAAR1) and 5-hydroxytryptamine 1 A receptor (5-HT1A). Nonetheless, these observations await independent confirmation and more detailed characterization of the in vitro and in vivo actions of SEP-856 at TAAR1 and 5-HT1A receptors would be instructive. Herein, we employed luminescence complementation technology in heterologous live cell systems, confocal microscopy, voltage clamp electrophysiology, behavioral readouts and TAAR1 knockout (KO) mice to study SEP-856 in further detail. We provide evidence for the ability of SEP-856 to activate TAAR1 at the surface plasma membrane, and show that this interaction results in Gαs recruitment (pEC50: 6.08 ± 0.22 EMAX: 96.41% ± 15.26) and by extension, to G-protein inwardly rectifying potassium (GIRK) channel activation. Using TAAR1-KO mice, we find TAAR1 to be indispensable for SEP-856 control of body temperature, baseline locomotion reduction and for “antipsychotic-like” efficacy as characterized by a reversal of dizocilipine (MK-801) mediated disruption of pre-pulse inhibition. Conversely, the inhibition by SEP-856 of MK-801 induced locomotion was unaffected in TAAR1 KO mice. SEP-856 behaved as a low-potency, partial agonist at the 5-HT1A receptor, while it partially inhibited recruitment of D2 receptor-coupled Gα and GIRK by DA and acted as a weak partial agonist with low potency at the same receptor when applied alone. Our findings corroborate and extend previous observations on the molecular substrates engaged by this unique, dual TAAR1/5-HT1A receptor agonist and potential antipsychotic that could prove to have major advantages in the treatment of schizophrenia and other psychotic disorders.
|
|
| 137. |
- Senek, Marina, et al.
(författare)
-
First clinical experience with levodopa/carbidopa microtablets in Parkinson’s disease
- 2017
-
Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 136:6, s. 727-731
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Levodopa is the most effective symptomatic treatment throughout thecourse of Parkinson’s disease, but as the disease progresses, there may be a need forindividualized, fine-tunedtreatments.Aim: To evaluate individualized levodopa/carbidopa dosing using microtablets dispensedwith a dose dispenser, with respect to efficacy and usability as perceived bypatients.Methods: Patient records and dose dispenser reports from patients previously or currentlytreated with microtablets and a dose dispenser were reviewed, and a patientquestionnaire concerning effect and usability was sent to patients.Results: Eleven patient records, four dose dispenser reports and nine survey responseswere obtained. The treatment effect was considered to be improved by six of ninepatients. One-thirdfound their bradykinesia to be improved, and the non-troublesomedyskinesia was unchanged according to a majority of patients; however, some experiencedthe duration and magnitude of troublesome dyskinesia to be worse. The usabilitywas generally rated as good. The four dose dispenser reports obtained showed97(±5)% total adherence.Conclusions: The experienced effect of treatment can, for some patients, be improvedby the use of microtablets, and the dose dispenser was considered user-friendly.Further studies with a larger study population and prospective design are needed toconfirm the results.
|
|
| 138. |
- Siebzehnrübl, Florian A., et al.
(författare)
-
Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition
- 2018
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 115:37, s. 8765-8774
-
Tidskriftsartikel (refereegranskat)abstract
- Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.
|
|
| 139. |
- Sjögren, Magnus, et al.
(författare)
-
Genetically targeted clinical trials in parkinson's disease : Learning from the successes made in oncology
- 2021
-
Ingår i: Genes. - : MDPI. - 2073-4425. ; 12:10
-
Forskningsöversikt (refereegranskat)abstract
- Clinical trials in neurodegenerative disorders have been associated with high rate of failures, while in oncology, the implementation of precision medicine and focus on genetically defined subtypes of disease and targets for drug development have seen an unprecedented success. With more than 20 genes associated with Parkinson's disease (PD), most of which are highly penetrant and often cause early onset or atypical signs and symptoms, and an increasing understanding of the associated pathophysiology culminating in dopaminergic neurodegeneration, applying the technologies and designs into the field of neurodegeneration seems a logical step. This review describes some of the methods used in oncology clinical trials and some attempts in Parkinson’s disease and the potential of further implementing genetics, biomarkers and smart clinical trial designs in this disease area.
|
|
| 140. |
- Sjöström, Henrik, et al.
(författare)
-
Putaminal T1/T2-weighted ratio is increased in PSP compared to PD and healthy controls, a multi-cohort study
- 2024
-
Ingår i: Parkinsonism and Related Disorders. - 1353-8020 .- 1873-5126. ; 121
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Differentiating Parkinson's disease (PD) from progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) is a common clinical problem. We aimed to apply the T1-/T2-weighted ratio imaging technique, based on standard clinical MRI, to reveal differences in neurodegeneration in three large cohorts. Methods: Three cohorts, with a total of 405 participants (269 PD, 44 PSP, 38 MSA, 54 controls), were combined and T1/T2-weighted ratio image analyses were carried out. A combination of automatic segmentation and atlas-based ROI were used in this study. The cohorts were combined using the ComBat batch correction procedure. Results: Group differences were found in the putamen (p = 0.040), with higher T1/T2-weighted ratio in this region in PSP compared to PD and healthy controls (p-values 0.010 and 0.007 respectively). Using putaminal T1/T2-weighted ratio for diagnostic separation, a fair performance was found in separating PSP from healthy controls, with an area under the receiver operating characteristic curve of 0.701. Conclusion: Different patterns of T1/T2-weighted ratio, reflecting differences in underlying pathophysiology, were found between the groups. Since T1/T2-weighted ratio can be applied to standard clinical MRI sequences to allow more quantitative analyses, this seems to be a promising biomarker for diagnostics and treatment evaluation of parkinsonian disorders for clinical trials.
|
|
