| 1. |
- Walton, Lois, et al.
(författare)
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The Effects of Working Memory Updating Training in Parkinson's Disease : A Feasibility and Single-Subject Study on Cognition, Movement and Functional Brain Response
- 2021
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Ingår i: Frontiers in Psychology. - : Frontiers Media S.A.. - 1664-1078. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- In Parkinson's disease (PD), the fronto-striatal network is involved in motor and cognitive symptoms. Working memory (WM) updating training engages this network in healthy populations, as observed by improved cognitive performance and increased striatal BOLD signal. This two-part study aimed to assess the feasibility of WM updating training in PD and measure change in cognition, movement and functional brain response in one individual with PD after WM updating training. A feasibility and single-subject (FL) study were performed in which patients with PD completed computerized WM updating training. The outcome measures were the pre-post changes in criterion and transfer cognitive tests; cognitive complaints; psychological health; movement kinematics; and task-related BOLD signal. Participants in the feasibility study showed improvements on the criterion tests at post-test. FL displayed the largest improvements on the criterion tests and smaller improvements on transfer tests. Furthermore, FL reported improved cognitive performance in everyday life. A shorter onset latency and smoother upper-limb goal-directed movements were measured at post-test, as well as increased activation within the striatum and decreased activation throughout the fronto-parietal WM network. This two-part study demonstrated that WM updating training is feasible to complete for PD patients and that change occurred in FL at post-test in the domains of cognition, movement and functional brain response.
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| 2. |
- Bäckström, David C, et al.
(författare)
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Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease
- 2015
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Ingår i: JAMA Neurology. - : American Medical Association. - 2168-6149 .- 2168-6157. ; 72:10, s. 1175-1182
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Alterations in cerebrospinal fluid (CSF) have been found in Parkinson disease (PD) and in PD dementia (PDD), but the prognostic importance of such changes is not well known. In vivo biomarkers for disease processes in PD are important for future development of disease-modifying therapies. OBJECTIVE: To assess the diagnostic and prognostic value of a panel of CSF biomarkers in patients with early PD and related disorders. DESIGN, SETTING, AND PARTICIPANTS: Regional population-based, prospective cohort study of idiopathic parkinsonism that included patients diagnosed between January 1, 2004, and April 30, 2009, by amovement disorder team at a university hospital that represented the only neurology clinic in the region. Participants were 128 nondemented patients with new-onset parkinsonism (104 with PD, 11 with multiple system atrophy, and 13 with progressive supranuclear palsy) who were followed up for 5 to 9 years. At baseline, CSF from 30 healthy control participants was obtained for comparison. MAIN OUTCOMES AND MEASURES: Cerebrospinal fluid concentrations of neurofilament light chain protein, Aβ1-42, total tau, phosphorylated tau, α-synuclein, and heart fatty acid-binding protein were quantified by 2 blinded measurements (at baseline and after 1 year). Follow-up included an extensive neuropsychological assessment. As PD outcome variables, mild cognitive impairment and incident PDD were diagnosed based on published criteria. RESULTS: Among the 128 study participants, the 104 patients with early PD had a different CSF pattern compared with the 13 patients with progressive supranuclear palsy (baseline area under the receiver operating characteristic curve, 0.87; P < .0001) and the 30 control participants (baseline area under the receiver operating characteristic curve, 0.69; P = .0021). A CSF biomarker pattern associated with the development of PDD was observed. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PDD as analyzed by Cox proportional hazards regression models. Combined, these early biomarkers predicted PDD with high accuracy (hazard ratio, 11.8; 95% CI, 3.3-42.1; P = .0001) after adjusting for possible confounders. CONCLUSIONS AND RELEVANCE: The analyzed CSF biomarkers have potential usefulness as a diagnostic tool in patients with parkinsonism. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein were related to future PDD, providing new insights into the etiology of PDD.
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| 3. |
- Bäckström, David C, M.D. 1978-, et al.
(författare)
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Prediction and early biomarkers of cognitive decline in Parkinson disease and atypical parkinsonism: a population-based study
- 2022
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Backstrom et al. report that, in a population-based cohort of patients with new-onset Parkinson disease, approximately half develop dementia within 10 years. Measurement of CSF biomarkers together with baseline cognitive function, olfaction and motor disease severity has high accuracy for predicting who will develop dementia. The progression of cognitive decline is heterogeneous in the three most common idiopathic parkinsonian diseases: Parkinson disease, multiple system atrophy and progressive supranuclear palsy. The causes for this heterogeneity are not fully understood, and there are no validated biomarkers that can accurately identify patients who will develop dementia and when. In this population-based, prospective study, comprehensive neuropsychological testing was performed repeatedly in new-onset, idiopathic parkinsonism. Dementia was diagnosed until 10 years and participants (N = 210) were deeply phenotyped by multimodal clinical, biochemical, genetic and brain imaging measures. At baseline, before the start of dopaminergic treatment, mild cognitive impairment was prevalent in 43.4% of the patients with Parkinson disease, 23.1% of the patients with multiple system atrophy and 77.8% of the patients with progressive supranuclear palsy. Longitudinally, all three diseases had a higher incidence of cognitive decline compared with healthy controls, but the types and severity of cognitive dysfunctions differed. In Parkinson disease, psychomotor speed and attention showed signs of improvement after dopaminergic treatment, while no such improvement was seen in other diseases. The 10-year cumulative probability of dementia was 54% in Parkinson disease and 71% in progressive supranuclear palsy, while there were no cases of dementia in multiple system atrophy. An easy-to-use, multivariable model that predicts the risk of dementia in Parkinson disease within 10 years with high accuracy (area under the curve: 0.86, P < 0.001) was developed. The optimized model adds CSF biomarkers to four easily measurable clinical features at baseline (mild cognitive impairment, olfactory function, motor disease severity and age). The model demonstrates a highly variable but predictable risk of dementia in Parkinson disease, e.g. a 9% risk within 10 years in a patient with normal cognition and CSF amyloid-beta(42) in the highest tertile, compared with an 85% risk in a patient with mild cognitive impairment and CSF amyloid-beta(42) in the lowest tertile. Only small or no associations with cognitive decline were found for factors that could be easily modifiable (such as thyroid dysfunction). Risk factors for cognitive decline in multiple system atrophy and progressive supranuclear palsy included signs of systemic inflammation and eye movement abnormalities. The predictive model has high accuracy in Parkinson disease and might be used for the selection of patients into clinical trials or as an aid to improve the prevention of dementia.
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| 4. |
- Bäckström, David, et al.
(författare)
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PITX3 genotype and risk of dementia in Parkinson's disease : A population-based study
- 2017
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Ingår i: Journal of the Neurological Sciences. - : ELSEVIER SCIENCE BV. - 0022-510X .- 1878-5883. ; 381, s. 278-284
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Tidskriftsartikel (refereegranskat)abstract
- Dementia is a devastating manifestation of Parkinson's disease (PD). This study investigates whether a common polymorphism in the PITX3 gene (rs2281983), which is of importance for the function of dopaminergic neurons, affects the risk of developing dementia in PD and whether it affects dopamine transporter (DAT) uptake. We PITX3 genotyped 133 patients with new-onset, idiopathic PD, participating in a population-based study in Sweden. Patients were followed prospectively during 6-11 years with extensive investigations, including neuropsychology and DAT-imaging with I-123 FP-CIT. The primary outcome was the incidence of PD dementia (PDD), diagnosed according to published criteria, studied by the Kaplan-Meier method and Cox proportional hazards. Performance in individual cognitive domains, the incidence of visual hallucinations, disease progression and striatal DAT uptake on imaging was also investigated. PD patients carrying the PITX3 C allele had an increased risk of developing PDD (hazard ratio: 2.87, 95% CI: 1.42-5.81, p = 0.003), compared to the PD patients homozygous for the T-allele. Furthermore, the PITX3 C allele carriers with PD had a poorer cognitive performance in the visuospatial domain (p < 0.001) and a higher incidence of visual hallucinations. A trend towards a lower striatal DAT uptake in the PITX3 C allele carriers was suggested, but could not be confirmed. Our results show that a common polymorphism in the PITX3 gene affects the risk of developing PDD and visuospatial dysfunction in idiopathic PD. If validated, these findings can provide new insights into the neurobiology and genetics of non-motor symptoms in PD.
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| 5. |
- Bäckström, David, et al.
(författare)
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Polymorphisms in dopamine-associated genes and cognitive decline in Parkinson's disease
- 2018
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 137:1, s. 91-98
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Tidskriftsartikel (refereegranskat)abstract
- ObjectivesCognitive decline is common in Parkinson's disease (PD), but the underlying mechanisms for this complication are incompletely understood. Genotypes affecting dopamine transmission may be of importance. This study investigates whether genotypes associated with reduced prefrontal dopaminergic tone and/or reduced dopamine D2-receptor availability (Catechol-O-methyltransferase [COMT] Val(158)Met genotype and DRD2 (CT)-T-957 genotype) affect the development of cognitive deficits in PD. Materials and methodsOne hundred and 34 patients with idiopathic PD, participating in a regional, population-based study of incident parkinsonism, underwent genotyping. After extensive baseline investigations (including imaging and biomarker analyses), the patients were followed prospectively during 6-10 years with neuropsychological evaluations, covering six cognitive domains. Cognitive decline (defined as the incidence of either Parkinson's disease mild cognitive impairment [PD-MCI] or dementia [PDD], diagnosed according to published criteria and blinded to genotype) was studied as the primary outcome. ResultsBoth genotypes affected cognition, as shown by Cox proportional hazards models. While the COMT(158)Val/Val genotype conferred an increased risk of mild cognitive impairment in patients with normal cognition at baseline (hazard ratio: 2.13, P=.023), the DRD2(957)T/T genotype conferred an overall increased risk of PD dementia (hazard ratio: 3.22, P<.001). The poorer cognitive performance in DRD2(957)T/T carriers with PD occurred mainly in episodic memory and attention. ConclusionsThe results favor the hypothesis that dopamine deficiency in PD not only relate to mild cognitive deficits in frontostriatal functions, but also to a decline in memory and attention. This could indicate that dopamine deficiency impairs a wide network of brain areas.
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| 6. |
- Domellöf, Magdalena Eriksson, 1977-
(författare)
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Cognitive and motor dysfunction in the early phase of Parkinson's disease
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disease. The diagnosis is based on a combination of the motor signs: tremor, bradykinesia, rigidity and postural abnormalities. Mild Cognitive Impairment (MCI) is common early in the disease and a large proportion of patients with PD develop dementia (PDD). Associations between motor symptoms and cognitive decline have been suggested but the results are inconclusive due to differences in the selection of participants and variables tested. Large population based studies with comprehensive neuropsychological investigation in newly diagnosed cases with PD followed prospectively are rare. The aim of this thesis was to improve characterization and understanding of cognition in PD, and to explore the relationship to motor impairment in the early phase of PD.Methods: All new patients with suspected idiopathic parkinsonism in the catchment area (142 ooo inhabitants) were examined during a period of five years and four months. Among other investigations, a comprehensive neuropsychological evaluation was carried out in 119 of 148 patients with PD together with 30 age matched healthy controls. Assessments were repeated after one three and five years.Results: Patients performed worse than healthy controls in a majority of neuropsychological tests. MCI at the time of diagnosis were found in 36% according to recently published MCI criteria. Thirty % were cognitively impaired using another definition. One fourth of the patients developed PDD within five years after diagnosis and 25 % of those with MCI at baseline reversed back to normal cognition. Age and MCI were significant predictors of dementia. Education was an independent predictor for severe cognitive dysfunction at diagnosis but did not predict PDD. Patients with MCI converting to PDD had worse performance on visuospatial function, semantic fluency, episodic memory, mental flexibility and conceptual thinking. There were no differences in cognitive performance between patients with predominant Postural and Gait Disturbances (PIGD) and the tremor dominant subtype at the baseline investigation and belonging to the PIGD subgroup at baseline did not predict PDD. Dementia converters declined more rapidly than non-converters in posture/gait function. Associations between bradykinesia and measures of executive functions and working memory were found, and between posture and gait disturbances and visuospatial function. Some of these associations were persistent after one year. Patients receiving the dopamine agonist pramipexole performed significantly worse on a measure of verbal fluency at the one year follow up.Conclusions: The differences in proportions of cognitively impaired in the different studies emphasize the value of joint criteria for PD-MCI. Even when using such criteria, a substantial proportion of patients revert back to normal function. The increase in motor disability in patients with PDD could have several different causes that need to be further investigated. Associated motor and cognitive dysfunctions could reflect common pathophysiological processes in partly shared networks. Both dopaminergic and non-dopaminergic motor and cognitive functions seems to be involved in PDD which suggests that pharmacological treatment in PD needs to go beyond the scope of dopaminergic deficiency in search for new therapies that would also be effective for non-motor symptoms.
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| 7. |
- Domellöf, Magdalena Eriksson, et al.
(författare)
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Evaluating a frontostriatal working-memory updating-training paradigm in Parkinson's disease : the iPARK trial, a double-blinded randomized controlled trial
- 2020
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Ingår i: BMC Neurology. - : BMC. - 1471-2377. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cognitive decline and dementia are common in Parkinson's disease (PD). Cognitive deficits have been linked to the depletion of dopamine in the nigrostriatal pathway, but pharmacological treatments for PD have little evidence of improving or delaying cognitive decline. Therefore, exploring non-pharmacological treatment options is important. There have been some promising results of cognitive training interventions in PD, especially for improvements in working memory and executive functions. Yet, existing studies are often underpowered, lacking appropriate control condition, long term follow-up, a thorough description of the intervention and characteristics of the participants. Working memory updating training has previously shown to increase striatal activation in healthy young and old participants as well as dopaminergic neurotransmission in healthy young participants. In the light of dopamine dysfunction in PD, with negative effects on both motor and cognitive functions it is of interest to study if an impaired striatal system can be responsive to a non-invasive, non-pharmacological intervention. Methods and design: The iPARK trial is a double-blinded, randomized controlled trial with a parallel-group design that aims to recruit 80 patients with PD (during the period 02/2017-02/2023). Included patients need to have PD, Hoehn and Yahr staging I-III, be between 45 to 75 years of age and not have a diagnosis of dementia. All patients will undergo 30 sessions (6-8 weeks) of web-based cognitive training performed from home. The target intervention is a process-based training program targeting working memory updating. The placebo program is a low dose short-term memory program. A battery of neuropsychological tests and questionnaires will be performed before training, directly after training, and 16 weeks after training. Discussion: We expect that the iPARK trial will provide novel and clinically useful information on whether updating training is an effective cognitive training paradigm in PD. Further, it will hopefully contribute to a better understanding of cognitive function in PD and provide answers regarding cognitive plasticity as well as determining critical factors for a responsive striatal system.
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| 8. |
- Ekman, Urban, et al.
(författare)
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Longitudinal changes in task-evoked brain responses in Parkinson's disease patients with and without mild cognitive impairment
- 2014
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Ingår i: Frontiers in Neuroscience. - : Frontiers. - 1662-4548 .- 1662-453X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive deficits are common in Parkinson's disease. Previous cross-sectional research has demonstrated a link between cognitive impairments and fronto-striatal dopaminergic dysmodulation. However, longitudinal studies that link disease progression with altered task-evoked brain activity are lacking. Therefore, our objective was to longitudinally evaluate working-memory related brain activity changes in Parkinson's disease patients with and without mild cognitive impairment (MCI). Patients were recruited within a longitudinal cohort study of incident patients with idiopathic parkinsonism. We longitudinally (at baseline examination and at 12-months follow-up) compared 28 patients with Parkinson's disease without MCI with 11 patients with Parkinson's disease and MCI. Functional MRI blood oxygen level dependent signal was measured during a verbal two-back working-memory task. Patients with MCI under-recruited bilateral medial prefrontal cortex at both time-points (main effect of group: p < 0.001, uncorrected). Critically, a significant group-by-time interaction effect (p < 0.001, uncorrected) was found in the right fusiform gyrus, indicating that working-memory related activity decreased for patients with Parkinson's disease and MCI between baseline and follow-up, while patients without MCI were stable across time-points. The functional connectivity between right fusiform gyrus and bilateral caudate nucleus was stronger for patients without MCI relative to patients with MCI. Our findings support the view that deficits in working-memory updating are related to persistent fronto-striatal under-recruitments in patients with early phase Parkinson's disease and MCI. The longitudinal evolution of MCI in Parkinson's disease translates into additional task-evoked posterior cortical changes.
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| 9. |
- Eriksson Domellöf, Magdalena, et al.
(författare)
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Olfactory dysfunction and dementia in newly diagnosed patients with Parkinson's disease
- 2017
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Ingår i: Parkinsonism & Related Disorders. - : Elsevier BV. - 1353-8020 .- 1873-5126. ; 38, s. 41-47
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Studies report that up to 90% of patients with idiopathic Parkinson's disease (PD) have olfactory dysfunction (hyposmia). Hyposmia has also been connected to cognitive impairment and dementia in PD, but no studies of newly diagnosed patients followed longer than three years exists. The present study investigates the prevalence of olfactory dysfunction at PD diagnosis, how it evolves over time and whether hyposmia increases the risk of dementia in Parkinson's disease.METHODS: Olfactory function was assessed with Brief Smell Identification Test (B-SIT) in 125 newly diagnosed patients with PD. They were followed for a maximum of 10 years (median six years) with extensive investigations at baseline, 12, 36, 60 and 96 months. Patients with B-SIT<9 were considered hyposmic.RESULTS: Hyposmia was found in 73% of the patients at diagnosis. During the follow up period of ten years 42 (46%) patients with hyposmia at baseline developed dementia compared to seven (21%) of the normosmic patients. Cox proportional hazards model showed that hyposmia at baseline (controlled for age, gender, UPDRS III and Mild Cognitive Impairment) increased the risk of developing dementia (hazard ratio (95%CI): 3.29 (1.44-7.52), p = 0.005). Only one of 22 patients with normal cognition and normal olfaction at baseline developed dementia.CONCLUSIONS: Olfactory dysfunction was common at the time of PD diagnosis and increased the risk of dementia up to ten years after PD diagnosis regardless of baseline cognitive function. Normal olfaction together with normal cognition at baseline predicted a benign cognitive course up to ten years after diagnosis.
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| 10. |
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