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Forsgren, Lars
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Publications (10 of 112) Show all publications
Sperens, M., Georgiev, D., Domellöf, M. E., Forsgren, L., Hamberg, K. & Hariz, G.-M. (2019). Activities of daily living in Parkinson's disease: Time/gender perspective. Acta Neurologica Scandinavica
Open this publication in new window or tab >>Activities of daily living in Parkinson's disease: Time/gender perspective
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2019 (English)In: Acta Neurologica Scandinavica, ISSN 0001-6314, E-ISSN 1600-0404Article in journal (Refereed) Epub ahead of print
Abstract [en]

Objective: The objectives of this study were to explore the changes in the activities of daily living (ADL) in persons with Parkinson's disease (pwPD) over time and to investigate possible differences in ADL performance between men and women with PD.

Materials & Methods: One hundred twenty‐nine persons (76 men) with a clinically established PD self‐assessed their ADL performance from the time of diagnosis up to 8 years follow‐up using the ADL taxonomy. Other demographic and clinical data (motor state, cognition, depression) were also collected and subjected to further analysis.

Results: Nine of 12 domains in the ADL taxonomy showed a change over time (Eating and Drinking [P = .009], Mobility [P < .001], Toilet activities [P = .031], Dressing [P < .001], Personal hygiene [P < .001], Communication [P < .001], Cooking [P = .001], Shopping [P < .001] and Cleaning [P < .001]). In addition to time, two domains, (Shopping [P = .007] and Cleaning [P = .027]) also showed an effect of gender with worse scores in women. The nine ADL domains showing effect of time, showed temporary improvement at 12 months follow‐up, most probably due to dopaminergic medication. All nine domains deteriorated at later follow‐up.

Conclusions: As expected, there was deterioration in self‐assessed performance in the majority od ADL domains over time. Women assessed their ADLs worse in two domains (Shopping and Cleaning) probably reflecting a general gender‐related activity pattern rather than being a PD‐specific finding.

Keywords
activities of daily living, gender differences, longitudinal study, Parkinson's disease
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-166577 (URN)10.1111/ane.13189 (DOI)000497350700001 ()31693751 (PubMedID)
Available from: 2019-12-19 Created: 2019-12-19 Last updated: 2019-12-19
Paslawski, W., Zareba-Paslawska, J., Zhang, X., Holzl, K., Wadensten, H., Shariatgorji, M., . . . Svenningsson, P. (2019). alpha-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients. Proceedings of the National Academy of Sciences of the United States of America, 116(30), 15226-15235
Open this publication in new window or tab >>alpha-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 30, p. 15226-15235Article in journal (Refereed) Published
Abstract [en]

The progressive accumulation, aggregation, and spread of alpha-synuclein (alpha SN) are common hallmarks of Parkinson's disease (PD) pathology. Moreover, numerous proteins interact with alpha SN species, influencing its toxicity in the brain. In the present study, we extended analyses of alpha SN-interacting proteins to cerebrospinal fluid (CSF). Using coimmunoprecipitation, followed by mass spectrometry, we found that alpha SN colocalize with apolipoproteins on lipoprotein vesicles. We confirmed these interactions using several methods, including the enrichment of lipoproteins with a recombinant alpha SN, and the subsequent uptake of prepared vesicles by human dopaminergic neuronal-like cells. Further, we report an increased level of ApoE in CSF from early PD patients compared with matched controls in 3 independent cohorts. Moreover, in contrast to controls, we observed the presence of ApoE-positive neuromelanin-containing dopaminergic neurons in substantia nigra of PD patients. In conclusion, the cooccurrence of alpha SN on lipoprotein vesicles, and their uptake by dopaminergic neurons along with an increase of ApoE in early PD, proposes a mechanism(s) for alpha SN spreading in the extracellular milieu of PD.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES, 2019
Keywords
apolipoproteins, alpha-synuclein, Parkinson's disease, cerebrospinal fluid
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:umu:diva-161992 (URN)10.1073/pnas.1821409116 (DOI)000476715500067 ()31270237 (PubMedID)
Available from: 2019-08-14 Created: 2019-08-14 Last updated: 2019-08-14Bibliographically approved
Patil, K. S., Basak, I., Dalen, I., Hoedt, E., Lange, J., Lunde, K. A., . . . Møller, S. G. (2019). Combinatory microRNA serum signatures as classifiers of Parkinson's disease. Parkinsonism & Related Disorders, 64, 202-210
Open this publication in new window or tab >>Combinatory microRNA serum signatures as classifiers of Parkinson's disease
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2019 (English)In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 64, p. 202-210Article in journal (Refereed) Published
Abstract [en]

Introduction: As current clinical diagnostic protocols for Parkinson's disease (PD) may be prone to inaccuracies there is a need to identify and validate molecular biomarkers, such as circulating microRNAs, which will complement current practices and increase diagnostic accuracy. This study identifies, verifies and validates combinatory serum microRNA signatures as diagnostic classifiers of PD across different patient cohorts. Methods: 370 PD (drug naive) and control serum samples from the Norwegian ParkWest study were used for identification and verification of differential microRNA levels in PD which were validated in a blind study using 64 NY Parkinsonism in UMea (NYPUM) study serum samples and tested for specificity in 48 Dementia Study of Western Norway (DemWest) study Alzheimer's disease (AD) serum samples using miRNA-microarrays, and quantitative (q) RT-PCR. Proteomic approaches identified potential molecular targets for these microRNAs. Results: Using Affymetrix GeneChip (R) miRNA 4.0 arrays and qRT-PCR we comprehensively analyzed serum microRNA levels and found that the microRNA (PARKmiR)-combinations, hsa-miR-335-5p/hsa-miR-3613-3p (95% CI, 0.87-0.94), hsa-miR-335-5p/hsa-miR-6865-3p (95% CI, 0.87-0.93), and miR-335-5p/miR-3613-3p/miR-6865-3p (95% CI, 0.87-0.94) show a high degree of discriminatory accuracy (AUC 0.9-1.0). The PARKmiR signatures were validated in an independent PD cohort (AUC <= 0.71) and analysis in AD serum samples showed PARKmiR signature specificity to PD. Proteomic analyses showed that the PAFtKmiRs regulate key PD-associated proteins, including alpha-synuclein and Leucine Rich Repeat Kinase 2. Conclusions: Our study has identified and validated unique miRNA serum signatures that represent PD classifiers, which may complement and increase the accuracy of current diagnostic protocols.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
microRNA, Biomarker, Parkinson's disease, Alzheimer's disease
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-164077 (URN)10.1016/j.parkreldis.2019.04.010 (DOI)000487567800030 ()31003905 (PubMedID)
Available from: 2019-10-14 Created: 2019-10-14 Last updated: 2019-11-19Bibliographically approved
Gallo, V., Vineis, P., Cancellieri, M., Chiodini, P., Barker, R. A., Brayne, C., . . . Riboli, E. (2019). Exploring causality of the association between smoking and Parkinson's disease. International Journal of Epidemiology, 48(3), 912-925
Open this publication in new window or tab >>Exploring causality of the association between smoking and Parkinson's disease
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2019 (English)In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 48, no 3, p. 912-925Article in journal (Refereed) Published
Abstract [en]

Background: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait.

Methods: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset.

Results: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding.

Conclusions: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.

Place, publisher, year, edition, pages
Oxford University Press, 2019
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-156190 (URN)10.1093/ije/dyy230 (DOI)000486642400030 ()30462234 (PubMedID)
Funder
Wellcome trustSwedish Cancer SocietySwedish Research CouncilVästerbotten County Council
Available from: 2019-02-07 Created: 2019-02-07 Last updated: 2020-01-09Bibliographically approved
Riso, L., Kaaks, R., Kuehn, T., Sookthai, D., Forsgren, L., Trupp, M., . . . Katzke, V. A. (2019). General and abdominal adiposity and the risk of Parkinson's disease: A prospective cohort study. Parkinsonism & Related Disorders, 62, 98-104
Open this publication in new window or tab >>General and abdominal adiposity and the risk of Parkinson's disease: A prospective cohort study
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2019 (English)In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 62, p. 98-104Article in journal (Refereed) Published
Abstract [en]

Introduction: Due to demographic change, an increase in the frequency of Parkinson's disease (PD) patients is expected in the future and, thus, the identification of modifiable risk factors is urgently needed. We aimed to examine the associations of body mass index (BMI) and waist circumference (WC) with incident PD. Methods: In 13 of the 23 centers of the European Prospective Investigation into Cancer and Nutrition (EPIC) study, a total of 734 incident cases of PD were identified between 1992 and 2012 with a mean follow-up of 12 years. Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (CI). We modelled anthropometric variables as continuous and categorical exposures and performed subgroup analyses by potential effect modifiers including sex and smoking. Results: We found no association between BMI, WC and incident PD, neither among men nor among women. Among never and former smokers, BMI and waist circumference were also not associated with PD risk. For male smokers, however, we observed a statistically significant inverse association between BMI and PD risk (HR 0.51, 95%CI: 0.30, 0.84) and the opposite for women, i.e. a significant direct association of BMI (HR 1.79, 95%CI: 1.04, 3.08) and waist circumference (HR 1.64, 95%CI: 1.03, 2.61) with risk of PD. Conclusion: Our data revealed no association between excess weight and PD risk but a possible interaction between anthropometry, sex and smoking.

Place, publisher, year, edition, pages
ELSEVIER SCI LTD, 2019
Keywords
Parkinson, Overweight, BMI, Smoking, Cohort, EPIC
National Category
General Practice
Identifiers
urn:nbn:se:umu:diva-162023 (URN)10.1016/j.parkreldis.2019.01.019 (DOI)000476961700016 ()30772279 (PubMedID)
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved
Håglin, L., Edström, M., Bäckman, L. & Forsgren, L. (2019). Low level of phosphate in male patients reporting swallowing disturbances in early Parkinson's disease. Clinical Nutrition Experimental
Open this publication in new window or tab >>Low level of phosphate in male patients reporting swallowing disturbances in early Parkinson's disease
2019 (English)In: Clinical Nutrition Experimental, ISSN 2352-9393Article in journal (Refereed) Epub ahead of print
Abstract [en]

Background & aim: Swallowing disturbances are associated with older age as well as with other subclinical disturbances of multifactorial origin in patients with Parkinson's disease (PD). This study assesses nutritional markers and whole-body impedance data to better understand swallowing disturbances in Parkinson's disease.

Design and patients included: This cross-sectional study includes baseline data from a cohort of newly diagnosed patients identified in the New Parkinsonism in Umeå study (NYPUM) (n = 75).

Methods: Swallowing disturbance was registered as a score of one or more on the Unified Parkinson's Disease Rating Scale (UPDRS) section II question number 7 on swallowing. The analysis used nutritional markers in plasma and anthropometry from bioimpedance.

Results: Bivariate analysis revealed that swallowing disturbances were associated with low plasma phosphate levels for males (r = −0.428; p = 0.005) and for all patients with PD (r = −0.241; p = 0.037). In males but not in females, a negative association was found between age and albumin and amount of intra-cellular water (ICW, l). Plasma albumin was associated with plasma phosphate (r = 0.315; p = 0.006; n = 75, r = 0.361; p = 0.036; n = 34, r = 0.310; p = 0.049; n = 41). Another risk pattern indicating swallowing disturbance in females was revealed by an association with visceral adiposity index (VAI), plasma triglycerides (TG), and triglyceride/high density lipoprotein (TG/HDL) ratio. The adjusted logistic regression revealed that low phosphate in males and low magnesium in females were risk factors for swallowing disturbance.

Conclusion: The age-related decline in plasma phosphate in males with PD may be an important nutritional marker for swallowing disturbances. Body composition measurements and nutritional markers provide information for the study of swallowing dysfunction as part of sarcopenia.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Anthropometry, Nutritional markers, Parkinson's disease, Sarcopenia, Swallowing disturbance, Phosphate
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-166713 (URN)10.1016/j.yclnex.2019.11.005 (DOI)2-s2.0-85076841210 (Scopus ID)
Available from: 2019-12-20 Created: 2019-12-20 Last updated: 2020-01-07
Puschmann, A., Jimenez-Ferrer, I., Lundblad-Andersson, E., Martensson, E., Hansson, O., Odin, P., . . . Swanberg, M. (2019). Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study. Parkinsonism & Related Disorders, 66, 158-165
Open this publication in new window or tab >>Low prevalence of known pathogenic mutations in dominant PD genes: A Swedish multicenter study
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2019 (English)In: Parkinsonism & Related Disorders, ISSN 1353-8020, E-ISSN 1873-5126, Vol. 66, p. 158-165Article in journal (Refereed) Published
Abstract [en]

Objective: To determine the frequency of mutations known to cause autosomal dominant Parkinson disease (PD) in a series with more than 10% of Sweden's estimated number of PD patients.

Methods: The Swedish Parkinson Disease Genetics Network was formed as a national multicenter consortium of clinical researchers who together have access to DNA from a total of 2,206 PD patients; 85.4% were from population-based studies. Samples were analyzed centrally for known pathogenic mutations in SNCA (duplications/triplications, p.Ala30Pro, p.Ala53Thr) and LRRK2 (p.Asn1437His, p.Arg1441His, p.Tyr1699Cys, p.Gly2019Ser, p.Ile2020Thr). We compared the frequency of these mutations in Swedish patients with published PD series and the gnomAD database.

Results: A family history of PD in first- and/or second-degree relatives was reported by 21.6% of participants. Twelve patients (0.54%) carried LRRK2 p.(Gly2019Ser) mutations, one patient (0.045%) an SNCA duplication. The frequency of LRRK2 p.(Gly2019Ser) carriers was 0.11% in a matched Swedish control cohort and a similar 0.098% in total gnomAD, but there was a marked difference between ethnicities in gnomAD, with 42-fold higher frequency among Ashkenazi Jews than all others combined.

Conclusions: In relative terms, the LRRK2 p.(Gly2019Ser) variant is the most frequent mutation among Swedish or international PD patients, and in gnomAD. SNCA duplications were the second.most common of the mutations examined. In absolute terms, however, these known pathogenic variants in dominant PD genes are generally very rare and can only explain a minute fraction of familial aggregation of PD. Additional genetic and environmental mechanisms may explain the frequent co-occurrence of PD in close relatives.

Place, publisher, year, edition, pages
Elsevier, 2019
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-165118 (URN)10.1016/j.parkreldis.2019.07.032 (DOI)000491684100026 ()31422003 (PubMedID)
Available from: 2019-11-11 Created: 2019-11-11 Last updated: 2019-11-11Bibliographically approved
Zhu, S., Wuolikainen, A., Wu, J., Öhman, A., Wingsle, G., Moritz, T., . . . Trupp, M. (2019). Targeted Multiple Reaction Monitoring Analysis of CSF Identifies UCHL1 and GPNMB as Candidate Biomarkers for ALS. Journal of Molecular Neuroscience, 69(4), 643-657
Open this publication in new window or tab >>Targeted Multiple Reaction Monitoring Analysis of CSF Identifies UCHL1 and GPNMB as Candidate Biomarkers for ALS
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2019 (English)In: Journal of Molecular Neuroscience, ISSN 0895-8696, E-ISSN 1559-1166, Vol. 69, no 4, p. 643-657Article in journal (Refereed) Published
Abstract [en]

The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) share some common molecular deficits including disruption of protein homeostasis leading to disease-specific protein aggregation. While insoluble protein aggregates are the defining pathological confirmation of diagnosis, patient stratification based on early molecular etiologies may identify distinct subgroups within a clinical diagnosis that would respond differently in therapeutic development programs. We are developing targeted multiple reaction monitoring (MRM) mass spectrometry methods to rigorously quantify CSF proteins from known disease genes involved in lysosomal, ubiquitin-proteasomal, and autophagy pathways. Analysis of CSF from 21 PD, 21 ALS, and 25 control patients, rigorously matched for gender, age, and age of sample, revealed significant changes in peptide levels between PD, ALS, and control. In patients with PD, levels of two peptides for chromogranin B (CHGB, secretogranin 1) were significantly reduced. In CSF of patients with ALS, levels of two peptides from ubiquitin carboxy-terminal hydrolase like protein 1 (UCHL1) and one peptide each for glycoprotein non-metastatic melanoma protein B (GPNMB) and cathepsin D (CTSD) were all increased. Analysis of patients with ALS separated into two groups based on length of survival after CSF sampling revealed that the increases in GPNMB and UCHL1 were specific for short-lived ALS patients. While analysis of additional cohorts is required to validate these candidate biomarkers, this study suggests methods for stratification of ALS patients for clinical trials and identifies targets for drug efficacy measurements during therapeutic development.

Place, publisher, year, edition, pages
Springer, 2019
Keywords
CSF biomarker, Proteomics, Parkinson's disease, ALS, Protein homeostasis
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-165738 (URN)10.1007/s12031-019-01411-y (DOI)000495982700002 ()31721001 (PubMedID)
Funder
The Kempe FoundationsSwedish Research Council
Available from: 2019-12-10 Created: 2019-12-10 Last updated: 2019-12-10Bibliographically approved
Lunde, K. A., Chung, J., Dalen, I., Pedersen, K. F., Linder, J., Domellöf, M. E., . . . Maple-Grødem, J. (2018). Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease. Alzheimer's & Dementia, 14(10), 1293-1301
Open this publication in new window or tab >>Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease
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2018 (English)In: Alzheimer's & Dementia, ISSN 1552-5260, E-ISSN 1552-5279, ISSN 1552-5260, Vol. 14, no 10, p. 1293-1301Article in journal (Refereed) Published
Abstract [en]

Introduction

Both polymorphisms and mutations in glucocerebrosidase (GBA) may influence the development of dementia in patients with Parkinson's disease.

Methods

Four hundred forty-two patients and 419 controls were followed for 7 years. Dementia was diagnosed using established criteria. Participants were analyzed for GBA genetic variants, including E326K, T369M, and L444P. Associations between GBA carrier status and dementia were assessed with Cox survival analysis.

Results

A total of 12.0% of patients with Parkinson's disease carried a GBA variant, and nearly half (22/53) of them progressed to dementia during follow-up. Carriers of deleterious GBA mutations (adjusted hazard ratio 3.81, 95% confidence interval 1.35 to 10.72; P = .011) or polymorphisms (adjusted hazard ratio 1.79; 95% confidence interval 1.07 to 3.00; P = .028) progressed to dementia more rapidly than noncarriers.

Discussion

GBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Parkinson's Disease
National Category
Neurology
Research subject
Genetics; Neurology
Identifiers
urn:nbn:se:umu:diva-148814 (URN)10.1016/j.jalz.2018.04.006 (DOI)000446086000006 ()
Projects
NYPUM projectParkWest studyPINE study
Funder
The Kempe FoundationsVästerbotten County CouncilThe Kempe FoundationsVästerbotten County Council
Available from: 2018-06-12 Created: 2018-06-12 Last updated: 2019-11-19Bibliographically approved
Johansson, C., Lindström, B., Forsgren, L. & Johansson, G. M. (2018). Balance and mobility in patients with newly diagnosed Parkinson's disease - a five-year follow-up of a cohort in northern Sweden. Disability and Rehabilitation, 1-10
Open this publication in new window or tab >>Balance and mobility in patients with newly diagnosed Parkinson's disease - a five-year follow-up of a cohort in northern Sweden
2018 (English)In: Disability and Rehabilitation, ISSN 0963-8288, E-ISSN 1464-5165, p. 1-10Article in journal (Refereed) Epub ahead of print
Abstract [en]

BACKGROUND: The presence of early balance impairment in patients with Parkinson's disease has not been fully investigated.

PURPOSE: The purpose of this study was to examine balance and mobility, self-perceived unsteadiness, self-reported falls, and effects of medication on balance among patients at their first visit to a neurological clinic and during the ensuing five years.

MATERIALS AND METHODS: The participants were collected from a prospective longitudinal study. One hundred and forty-five patients with idiopathic Parkinson's disease and 31 healthy controls were included. The outcome measures were the Berg Balance Scale, the Timed Up and Go, the Postural Stability test and a questionnaire.

RESULTS: At their first visit to the neurological clinic, the patients performed less well on the Berg Balance Scale (p < 0.001, r = 0.36), the Timed Up and Go (p < 0.001, r = 0.32), and the Postural Stability test (p < 0.001, r = 0.35) compared with the controls. In addition, a higher percentage of the patients reported self-perceived unsteadiness (p < 0.001, phi = 0.47). During the ensuing five years, balance and mobility worsened both with and without medication (p < 0.01, r = 0.24-0.37), although with small median differences.

CONCLUSIONS: Further studies are needed to confirm that minor balance impairments exist even at the time of diagnosis and worsen during the ensuing five years. IMPLICATIONS FOR REHABILITATION Impairments in balance and mobility may occur early in Parkinson's disease, especially in the elderly patients, and seem to worsen during the first five years. There is a need to use sensitive outcome measures and to ask the patients about unsteadiness and falls to detect balance impairment in this cohort. Parkinsonian medication has a limited effect on balance and may preferably be complemented with balance exercises to target balance impairment early in Parkinson's disease.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2018
Keywords
Parkinson’s disease, balance, exercise, falls, parkinsonism, postural instability
National Category
Neurology
Research subject
Neurology
Identifiers
urn:nbn:se:umu:diva-155392 (URN)10.1080/09638288.2018.1509240 (DOI)30451551 (PubMedID)
Available from: 2019-01-15 Created: 2019-01-15 Last updated: 2019-04-05
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