Structural brain MRI and cognition in newly diagnosed Parkinson’s disease
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Background: Parkinson’s disease (PD) is a common progressive neurodegenerative disorder mainly affecting the elderly. Previously regarded a pure motor disease, PD is now considered a multisystem brain disease with various nonmotor aspects, including cognitive dysfunction. Mild cognitive impairment (MCI) is currently explored as a possible pre-dementia stage in patients with PD. Little is known about the pathology underlying MCI in PD. A full characterization of the various aspects of MCI in PD would be of great value in the search for prognostic factors and potential preventive treatments for disabling dementia in patients with PD. Volumetric brain magnetic resonance imaging (MRI) is increasingly used in research aiming to find the biological basis for various neurodegenerative diseases, atrophy regarded as the end stage of neurodegeneration. In PD, studies have shown brain atrophy in patients presenting with dementia. A few studies reported loss of brain tissue of midbrain and mesocortex in advanced stage patients with PD and MCI, but no previous study has investigated possible brain atrophy in newly diagnosed patients with PD and MCI. White matter hyperintensities (WMH) are high signal changes in T2- weighted brain MRI scans as a consequence of vascular damage. WMH has been linked to cognitive dysfunction in both normal aging and neurodegenerative disease, e.g. Alzheimer’s disease. Controlling vascular risk factors resulting in WMH might thus protect against dementia and other forms of cognitive impairments. Earlier works on WMH in PD are conflicting, but a previous study indicated that WMH load is increased in demented patients with advanced PD. The role of WMH in patients with early PD and MCI is unknown. Objective: The primary aim of this thesis was to test the hypothesis that cognitive impairment in newly diagnosed PD is related to atrophy and/or WMH changes in the brain. Methods: Included subjects are all part of the Norwegian ParkWest study. The ParkWest study is a prospective multicentre cohort study of patients with incident PD from western and southern Norway, caregivers and a control group consisting of age and sex matched normal controls. An MRI examination was part of the baseline study evaluation and was conducted in 182 patients with PD and 109 controls. By widely used and validated quantitative MRI analysing methods, we performed volumetric global and regional brain segmentation and WMH quantification. WMH load was estimated by a semi-automated local threshold technique. Total volume and regional distribution of WMH in patients with newly diagnosed PD were compared with findings in age-matched controls. The impact of WMH on cognitive test performance was investigated both in the unselected PD sample and according to MCI classification. Global brain MRI atrophy measures were whole brain and total gray/white/cerebrospinal fluid volumes calculated using SIENAX software. Regional atrophy was investigated in a subgroup of patients from one centre using voxel-based morphometry (VBM) and the FreeSurfer software. Ventricular volumes were also calculated. Neuropsychological tests were chosen to minimize the impact of impaired motor skills and assessed memory, visuospatial and attention-executive domains. Nondemented patients with an observed age-and education corrected z-score deviating more than -1.5 standard deviations from the expected z-score (based on the test performance of controls) in at least one cognitive domain, were classified as having MCI. Results: Our investigations of global brain MRI atrophy parameters (whole brain, total gray and white matter volume) did not show any significant difference between newly diagnosed patients with PD and controls and were not significant predictors of cognitive performance. Furthermore, neither total WMH volume nor regional distribution of WMH was significantly different between patients and controls, irrespectively if patients were presenting MCI. Regional gray matter atrophy analyses, volume of subcortical gray matter structures and ventricular volume measures may indicate enlargement of fourth, third and left inferior lateral ventricles, but no cortical atrophy, as a sign of MCI in early PD. Conclusion: Based on these studies, WMH do not seem to play a significant role as a neurobiological factor in the cognitive dysfunctions of incident patients with PD. Volume studies could indicate a possible role of atrophy in brainstem, midbrain and temporal regions, but this needs to be explored further in future larger studies.
Paper I: Movement Disorders 24(15), Dalaker, T. O.; Larsen, J. P.; Bergsland, N.; Beyer, M. K.; Alves, G.; Dwyer, M. G.; Tysnes, O. B.; Benedict, R. H. B.; Kelemen, A.; Brønnick, K.; Zivadinov, R., Brain atrophy and white matter hyperintensities in early Parkinson’s disease, pp. 2233-2241. Copyright 2009 Movement Disorder Society. Published by Wiley. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1002/mds.22754Paper II: Movement Disorders 25(5), Dalaker, T. O.; Zivadinov, R.; Larsen, J. P.; Beyer, M. K.; Cox, J. L.; Alves, G.; Brønnick, K.; Tysnes, O. B.; Antulov, R.; Dwyer, M. G.; Aarsland, D., Gray matter correlations of cognition in incident Parkinson’s disease, pp. 629-633. Copyright 2010 Movement Disorder Society. Published by Wiley. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1002/mds.22867Paper III: Neuroimage 47(4), Dalaker, T. O.; Larsen, J. P.; Dwyer, M. G.; Aarsland, D.; Beyer, M. K.; Alves, G.; Brønnick, K.; Tysnes, O. B.; Zivadinov, R., White matter hyperintensities do not impact cognitive function in patients with newly diagnosed Parkinson’s disease, pp. 2083-2089. Copyright 2009 Elsevier. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1016/j.neuroimage.2009.06.020Paper IV: Movement Disorders 26(2), Dalaker, T. O.; Zivadinov, R.; Ramasamy, D. P.; Beyer, M. K.; Alves, G.; Brønnick, K.; Tysnes, O. B.; Aarsland, D.; Larsen, J. P., Ventricular enlargement and mild cognitive impairment in early Parkinson’s disease, pp. 297-301. Copyright 2010 Movement Disorder Society. Published by Wiley. Full text not available in BORA due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1002/mds.23443