| 1. |
- Carlsson, Thomas, et al.
(författare)
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Systemic administration of Neuregulin-1ß(1) protects dopaminergic neurons in a mouse model of Parkinson's disease.
- 2011
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 117:6, s. 1066-1074
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Tidskriftsartikel (refereegranskat)abstract
- Neuregulin-1 (Nrg1) is genetically linked to schizophrenia, a disease caused by neurodevelopmental imbalance in dopaminergic function. The Nrg1 receptor ErbB4 is abundantly expressed on midbrain dopaminergic neurons. Nrg1 has been shown to penetrate blood-brain barrier, and peripherally administered Nrg1 activates ErbB4 and leads to a persistent hyperdopaminergic state in neonatal mice. These data prompted us to study the effect of peripheral administration of Nrg1 in the context of Parkinson's disease, a neurodegenerative disorder affecting the dopaminergic system in the adult brain. We observed that systemic injections of the extracellular domain of Nrg1ß(1) (Nrg1ß(1) -ECD) increased dopamine levels in the substantia nigra and striatum of adult mice. Nrg1ß(1) -ECD injections also significantly protected the mouse nigrostriatal dopaminergic system morphologically and functionally against 6-hydroxydopamine-induced toxicity in vivo. Moreover, Nrg1ß(1) -ECD also protected human dopaminergic neurons in vitro against 6-hydroxydopamine. In conclusion, we have identified Nrg1ß(1) -ECD as a neurotrophic factor for adult mouse and human midbrain dopaminergic neurons with peripheral administratability, warranting further investigation as therapeutic option for PD patients.
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| 2. |
- Depboylu, Candan, et al.
(författare)
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Neuregulin-1 receptor tyrosine kinase ErbB4 is upregulated in midbrain dopaminergic neurons in Parkinson disease
- 2012
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940. ; 531:2, s. 209-214
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Tidskriftsartikel (refereegranskat)abstract
- Previously we demonstrated that systemically administered neuregulin-1-beta 1, a nerve growth and differentiation factor, passed the blood-brain barrier and accumulated in brain areas with expression of its receptor ErbB4. In substantia nigra (SN), neuregulin-1-beta 1 phosphorylated ErbB4 and protected dopaminergic neurons in a toxin-based mouse model of Parkinson disease (PD). We studied ErbB4 in the context of human midbrain dopaminergic degeneration in vivo and in vitro. Post-mortem ventral midbrain tissue sections of neuropsychiatric healthy individuals and PD patients (matched for age, gender and post-mortem delay) were immunostained for ErbB4. Cultured Lund human mesencephalic (LUHMES) post-mitotic dopaminergic neurons were treated with dopaminergic toxins and analyzed for ErbB4 expression. In control individuals, 85.0 +/- 5.0% of dopaminergic neurons, containing cytoplasmic neuromelanin, expressed ErbB4 in the SN. In PD cases, the percentage of ErbB4-positive nigral dopaminergic neurons was increased to 94.9 +/- 2.5%. The mean ErbB4 immunoreactivity of melanized neurons was higher in PD than controls. LUHMES neurons upregulated ErbB4 when exposed to toxins 1-methyl-4-phenylpyridinium and 6-hydroxydopamine. Increased rate of ErbB4-positive dopaminergic neurons in PD may either reflect a better survival of ErbB4-positive neurons or an increased expression of ErbB4 by remaining neurons to seek trophic support. Enhanced ErbB4 expression in human in vitro toxin-based PD models supports the latter interpretation. Thus, dopaminergic neurons in SN might be susceptible to neuregulin-1 treatment in PD. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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| 3. |
- Hagell, Peter, et al.
(författare)
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Dyskinesias following neural transplantation in Parkinson's disease.
- 2002
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1546-1726 .- 1097-6256. ; 5:7, s. 627-628
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Tidskriftsartikel (refereegranskat)abstract
- Severe dyskinesias during the 'off' phases (periods of increased Parkinson's disease (PD) disability) have been observed following intrastriatal transplantation of human embryonic mesencephalic tissue. Here we retrospectively analyzed 14 patients who were followed for up to 11 years after grafting, and found that dyskinesias (abnormal involuntary movements and postures) increased during postoperative off phases, but were generally of mild to moderate severity. Dyskinesia severity was not related to the magnitude of graft-derived dopaminergic re-innervation, as judged by (18)F-labeled 6-L-fluorodopa (FD) positron emission tomography (PET), indicating that off-phase dyskinesias probably did not result from excessive growth of grafted dopaminergic neurons.
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| 4. |
- Herzog, Jan, et al.
(författare)
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Deep brain stimulation in Parkinson's disease following fetal nigral transplantation
- 2008
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 23:9, s. 1293-1296
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Tidskriftsartikel (refereegranskat)abstract
- OFF-period dyskinesias have been reported as a consequence of fetal nigral transplantation for Parkinson's disease. This type of dyskinesias may appear in patients even in the prolonged absence of antiparkinson medication and be aggravated by levodopa. Therefore, pharmacological therapeutic approaches in these patients are limited. Here we report two patients with bilateral fetal nigral grafts in the caudate and putamen subjected to deep brain stimulation (DBS) of the globus pallidus internus (GPi) or subthalamic nucleus (STN). Clinical assessment was performed according to UPDRS and the clinical dyskinesia rating scale. In both patients, we found significant improvement in OFF-period symptoms as well as levodopa-induced dyskinesias. However, only GPi-DBS led to a significant reduction of OFF-period dyskinesias whereas STN-DBS did not influence dyskinesias unrelated to external dopaminergic application. These findings, based on two case reports, highlight the pivotal role of the GPi in mediating dyskinesia-related neural activity within the basal ganglia loop. (C) 2008 Movement Disorder Society.
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| 5. |
- Hong, Xu, et al.
(författare)
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Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice.
- 2014
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Ingår i: Neuropathology and Applied Neurobiology. - : Wiley. - 0305-1846 .- 1365-2990. ; 40:7, s. 833-843
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Tidskriftsartikel (refereegranskat)abstract
- AIM: P301SMAPT transgenic mice (P301S mice) are a widely used model of frontotemporal dementia and parkinsonism linked to chromosome 17 with tau pathology (FTDP-17-tau). However, a systematic correlation between cognitive deficits and cellular tau pathology at different ages is still missing. Therefore, our study investigated memory deficits of P301S mice in relation to pathological tau species and dendritic spine pathology throughout adulthood. METHODS: We analysed P301S mice behaviourally with the novel open field, rotarod, and Morris water maze tests to measure deficits in locomotion, balance and cognition, respectively; immunohistochemically with different tau antibodies for specific tau species; and with Golgi staining for dendritic spine pathology. RESULTS: We confirmed the occurrence of locomotor deficits at an age of 5months and newly report memory deficits from 2.5months of age onwards. At this early age, MC1 and CP13, but not AT180 immunoreactivity, was prominent in the hippocampus of P301S mice. Neuronal cell loss in the hippocampus of P301S mice was not observed to occur till 6months of age. However, there was a significant reduction in the density of dendritic spines from young adulthood onwards in hippocampal pyramidal neurones. CONCLUSION: In P301S mice, memory deficits precede the onset of locomotor dysfunction and coincide with the appearance of conformationally changed, S202-phosphorylated tau and reduced spine density in the absence of neuronal cell loss in the hippocampus. Our finding provides insights into the toxic effects of different tau species in vivo and may facilitate the development of new therapies against neurodegenerative tauopathies. © 2014 British Neuropathological Society.
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| 6. |
- Höglinger, Günter U, et al.
(författare)
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Clinical diagnosis of progressive supranuclear palsy : The movement disorder society criteria
- 2017
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 32:6, s. 853-864
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Tidskriftsartikel (refereegranskat)abstract
- Background: PSP is a neuropathologically defined disease entity. Clinical diagnostic criteria, published in 1996 by the National Institute of Neurological Disorders and Stroke/Society for PSP, have excellent specificity, but their sensitivity is limited for variant PSP syndromes with presentations other than Richardson's syndrome. Objective: We aimed to provide an evidence- and consensus-based revision of the clinical diagnostic criteria for PSP. Methods: We searched the PubMed, Cochrane, Medline, and PSYCInfo databases for articles published in English since 1996, using postmortem diagnosis or highly specific clinical criteria as the diagnostic standard. Second, we generated retrospective standardized clinical data from patients with autopsy-confirmed PSP and control diseases. On this basis, diagnostic criteria were drafted, optimized in two modified Delphi evaluations, submitted to structured discussions with consensus procedures during a 2-day meeting, and refined in three further Delphi rounds. Results: Defined clinical, imaging, laboratory, and genetic findings serve as mandatory basic features, mandatory exclusion criteria, or context-dependent exclusion criteria. We identified four functional domains (ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction) as clinical predictors of PSP. Within each of these domains, we propose three clinical features that contribute different levels of diagnostic certainty. Specific combinations of these features define the diagnostic criteria, stratified by three degrees of diagnostic certainty (probable PSP, possible PSP, and suggestive of PSP). Clinical clues and imaging findings represent supportive features. Conclusions: Here, we present new criteria aimed to optimize early, sensitive, and specific clinical diagnosis of PSP on the basis of currently available evidence.
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| 7. |
- Politis, Marios, et al.
(författare)
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Graft-Induced Dyskinesias in Parkinson's Disease: High Striatal Serotonin/Dopamine Transporter Ratio
- 2011
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 26:11, s. 1997-2003
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Tidskriftsartikel (refereegranskat)abstract
- Graft-induced dyskinesias are a serious complication after neural transplantation in Parkinson's disease. One patient with Parkinson's disease, treated with fetal grafts 14 years ago and deep brain stimulation 6 years ago, showed marked improvement of motor symptoms but continued to suffer from OFF-medication graft-induced dyskinesias. The patient received a series of clinical and imaging assessments. Positron emission tomography and single-photon emission computed tomography 14 years posttransplantation revealed an elevated serotonin/dopamine transporter ratio in the grafted striatum compatible with serotonergic hyperinnervation. Inhibition of serotonin neuron activity by systemic administration of a 5-HT1A agonist suppressed graft-induced dyskinesias. Our data provide further evidence that serotonergic neurons mediate graft-induced dyskinesias in Parkinson's disease. Achieving a normal striatal serotonin/dopamine transporter ratio following transplantation of fetal tissue or stem cells should be necessary to avoid the development of graft-induced dyskinesias. (C) 2011 Movement Disorder Society
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| 8. |
- Politis, Marios, et al.
(författare)
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Serotonin Neuron Loss and Nonmotor Symptoms Continue in Parkinson's Patients Treated with Dopamine Grafts
- 2012
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 4:128
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Tidskriftsartikel (refereegranskat)abstract
- Cell therapy studies in patients with Parkinson's disease (PD) have been confined to intrastriatal transplantation of dopamine-rich fetal mesencephalic tissue in efforts to improve motor performance. Although some PD patients receiving the dopamine-rich grafts showed improvements in motor symptoms due to replacement of dopaminergic neurons, they still suffered from nonmotor symptoms including depression, fatigue, visual hallucinations, and sleep problems. Using functional imaging and clinical evaluation of motor and nonmotor symptoms in three PD patients transplanted with intrastriatal fetal grafts 13 to 16 years previously, we assessed whether reestablishment of dopaminergic neuronal networks is sufficient to improve a broad range of symptoms. At 13 to 16 years after transplantation, dopaminergic innervation was restored to normal levels in basal ganglia and preserved in a number of extrabasal ganglia areas. These changes were associated with long-lasting relief of motor symptoms. Then, we assessed the integrity of their serotonergic and norepinephrine neuronal systems using [C-11]DASB {[C-11]3-amino-4-(2-dimethylaminomethylphenylthio) benzonitrile} positron emission tomography (PET) and F-18-dopa PET, respectively. F-18-Dopa uptake in the locus coeruleus was within the normal range. In contrast, [C-11] DASB uptake in the raphe nuclei and regions receiving serotonergic projections was markedly reduced. These results indicate ongoing degeneration of serotonergic raphe nuclei and their projections to regions involved in the regulation of sleep, arousal, feeding, satiety, mood, and emotion. Our findings indicate that future cell-based therapies using fetal tissue or stem cells in PD patients may require additional grafts of serotonergic neurons to relieve nonmotor symptoms by restoring serotonergic neurotransmission in specific cerebral targets.
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| 9. |
- Respondek, Gesine, et al.
(författare)
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Which ante mortem clinical features predict progressive supranuclear palsy pathology?
- 2017
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 32:7, s. 995-1005
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Forskningsöversikt (refereegranskat)abstract
- Background: Progressive supranuclear palsy (PSP) is a neuropathologically defined disease presenting with a broad spectrum of clinical phenotypes. Objective: To identify clinical features and investigations that predict or exclude PSP pathology during life, aiming at an optimization of the clinical diagnostic criteria for PSP. Methods: We performed a systematic review of the literature published since 1996 to identify clinical features and investigations that may predict or exclude PSP pathology. We then extracted standardized data from clinical charts of patients with pathologically diagnosed PSP and relevant disease controls and calculated the sensitivity, specificity, and positive predictive value of key clinical features for PSP in this cohort. Results: Of 4166 articles identified by the database inquiry, 269 met predefined standards. The literature review identified clinical features predictive of PSP, including features of the following 4 functional domains: ocular motor dysfunction, postural instability, akinesia, and cognitive dysfunction. No biomarker or genetic feature was found reliably validated to predict definite PSP. High-quality original natural history data were available from 206 patients with pathologically diagnosed PSP and from 231 pathologically diagnosed disease controls (54 corticobasal degeneration, 51 multiple system atrophy with predominant parkinsonism, 53 Parkinson's disease, 73 behavioral variant frontotemporal dementia). We identified clinical features that predicted PSP pathology, including phenotypes other than Richardson's syndrome, with varying sensitivity and specificity. Conclusions: Our results highlight the clinical variability of PSP and the high prevalence of phenotypes other than Richardson's syndrome. The features of variant phenotypes with high specificity and sensitivity should serve to optimize clinical diagnosis of PSP.
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| 10. |
- Rogozinski, Sophia, et al.
(författare)
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Reduction in Volume of Nucleus Basalis of Meynert Is Specific to Parkinson’s Disease and Progressive Supranuclear Palsy but Not to Multiple System Atrophy
- 2022
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To study in vivo gray matter (GM) volumes of the nucleus basalis of Meynert (nbM) in different parkinsonian syndromes and assess their relationship with clinical variables. Methods: T1-weighted magnetic resonance images from patients with progressive supranuclear palsy (PSP, N = 43), multiple system atrophy (MSA, N = 23), Parkinson’s disease (PD, N = 26), and healthy controls (HC, N = 29) were included. T1-weighted images were analyzed using a voxel-based morphometry approach implemented in the VBM8 toolbox, and nbM volumes were extracted from the spatially normalized GM images using a cyto-architectonically-defined nbM mask in stereotactic standard space. NbM volumes were compared between groups, while controlling for intracranial volume. Further, within each group correlation analyses between nbM volumes and the Mini Mental Status Examination (MMSE), Hoehn and Yahr stage, PSP Rating Scale, Unified Parkinson’s Disease Rating Scale part III and Frontal Assessment Battery scores were performed. Results: Significantly lower nbM volumes in patients with PSP and PD compared to HC or patients with MSA were found. No significant correlations between MMSE and nbM volumes were detected in any of the subgroups. No significant correlations were found between clinical scores and nbM volumes in PSP or other groups. Conclusion: nbM volumes were reduced both in PD and PSP but not in MSA. The lack of significant correlations between nbM and cognitive measures suggests that other factors, such as frontal atrophy, may play a more important role than subcortical cholinergic atrophy in PSP patients. These results may indicate that other drug-targets are needed to improve cognitive function in PSP patients.
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