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  • 1
    In: Movement Disorders, Wiley, Vol. 35, No. 4 ( 2020-04), p. 629-639
    Abstract: Although deep brain stimulation of the globus pallidus internus (GPi‐DBS) is an established treatment for many forms of dystonia, including generalized as well as focal forms, its effects on brain (dys‐)function remain to be elucidated, particularly for focal and segmental dystonia. Clinical response to GPi‐DBS typically comes with some delay and lasts up to several days, sometimes even weeks, once stimulation is discontinued. Objective This study investigated how neural activity during rest and motor activation is affected by GPi‐DBS while excluding the potential confound of altered feedback as a result of therapy‐induced differences in dystonic muscle contractions. Methods Two groups of patients with focal or segmental dystonia were included in the study: 6 patients with GPi‐DBS and 8 without DBS (control group). All 14 patients had cervical dystonia. Using H 2 15 O PET, regional cerebral blood flow was measured at rest and during a motor task performed with a nondystonic hand. Results In patients with GPi‐DBS (stimulation ON and OFF), activity at rest was reduced in a prefrontal network, and during the motor task, sensorimotor cortex activity was lower than in patients without DBS. Within‐group contrasts (tapping 〉 rest) showed less extensive task‐induced motor network activation in GPi‐DBS patients than in non‐DBS controls. Reduced sensorimotor activation amounted to a significant group‐by‐task interaction only in the stimulation ON state. Conclusions These findings support previous observations in generalized dystonia that suggested that GPi‐DBS normalizes dystonia‐associated sensorimotor and prefrontal hyperactivity, indicating similar mechanisms in generalized and focal or segmental dystonia. Evidence is provided that these effects extend into the OFF state, which was not previously demonstrated by neuroimaging. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2041249-6
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  • 2
    In: Movement Disorders, Wiley, Vol. 35, No. 12 ( 2020-12), p. 2201-2210
    Abstract: Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. Objective This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. Methods GBA was sequenced in 56 patients with mid‐stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6‐[ 18 F]fluoro‐L‐Dopa positron emission tomography (PET), [ 18 F]fluorodeoxyglucose PET, and resting‐state functional magnetic resonance imaging were performed. Results Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD‐related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [ 18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. Conclusions This is the first study to comprehensively assess (neuro‐)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease‐modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
    Type of Medium: Online Resource
    ISSN: 0885-3185 , 1531-8257
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2041249-6
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  • 3
    In: Human Brain Mapping, Wiley, Vol. 42, No. 8 ( 2021-06), p. 2623-2641
    Abstract: Involvement of the default mode network (DMN) in cognitive symptoms of Parkinson's disease (PD) has been reported by resting‐state functional MRI (rsfMRI) studies. However, the relation to metabolic measures obtained by [18F]‐fluorodeoxyglucose positron emission tomography (FDG‐PET) is largely unknown. We applied multimodal resting‐state network analysis to clarify the association between intrinsic metabolic and functional connectivity abnormalities within the DMN and their significance for cognitive symptoms in PD. PD patients were classified into normal cognition ( n = 36) and mild cognitive impairment (MCI; n = 12). The DMN was identified by applying an independent component analysis to FDG‐PET and rsfMRI data of a matched subset (16 controls and 16 PD patients) of the total cohort. Besides metabolic activity, metabolic and functional connectivity within the DMN were compared between the patients' groups and healthy controls ( n = 16). Glucose metabolism was significantly reduced in all DMN nodes in both patient groups compared to controls, with the lowest uptake in PD‐MCI ( p   〈  .05). Increased metabolic and functional connectivity along fronto‐parietal connections was identified in PD‐MCI patients compared to controls and unimpaired patients. Functional connectivity negatively correlated with cognitive composite z ‐scores in patients ( r = −.43, p = .005). The current study clarifies the commonalities of metabolic and hemodynamic measures of brain network activity and their individual significance for cognitive symptoms in PD, highlighting the added value of multimodal resting‐state network approaches for identifying prospective biomarkers.
    Type of Medium: Online Resource
    ISSN: 1065-9471 , 1097-0193
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 1492703-2
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