The relation between cognition and motor dysfunction in drug-naive newly diagnosed patients with Parkinson's disease
Authors: Magdalena Eriksson Domellöf, MSc, Eva Elgh, PhD, and Lars Forsgren, MD, PhD
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Recent studies have reported cognitive decline to be common in the early phase of Parkinson's disease. Imaging data connect working memory and executive functioning to the dopamine system. It has also been suggested that bradykinesia is the clinical manifestation most closely related to the nigrostriatal lesion. Exploring the relationship between motordysfunction and cognition can help us find shared or overlapping systems serving different functions. This relationship has been sparsely investigated in population-based studies of untreated Parkinson's disease. The aim of the present study was to investigate the association between motor signs and cognitive performance in the early stages of Parkinson's disease before the intake of dopaminergic medication. Patients were identified in a population-based study of incident cases with idiopathic parkinsonism. Patients with the postural instability and gait disturbances phenotype were compared with patients with the tremor-dominant phenotype on demographics and cognitive measures. Associations between cognitive and motor scores were investigated, with age, education, and sex controlled for. Bradykinesia was associated with working memory and mental flexibility, whereas axial signs were associated with episodic memory and visuospatial functioning. No significant differences in the neuropsychological variables were found between the postural instability and gait disturbances phenotype and the tremor phenotype. Our results indicate a shared system for slow movement and inflexible thinking that may be controlled by adopaminergic network different from dopaminergic networks involved in tremor and/or rigidity. The association between axial signs and memory and visuospatial function may point to overlapping systems or pathologies related to these abilities.
© 2011 Movement Disorder Society
Summary and review by Dr. Susan H. Fox, MB, ChB, MRCP, PhD
Cognitive impairment is known to be present even at the very earliest stage of PD. Up to a third of newly diagnosed PD patients may have lower scores on cognitive function when compared to age-matched controls. This finding suggests that dopaminergic deficiency may play a role in cognitive function in PD subjects. This has been supported by imaging studies that show working memory and executive function are linked to striatal as well as mesocortical dopamine function. In addition, other non-dopaminergic neurotransmitter systems are likely involved. Thus the proposed Braak hypothesis of PD progression, suggests that pathology may start in the brainstem and thus cognitive dysfunction may relate to cholinergic and other mono-amine systems.
Certainly in advanced PD, the pathological loss of cholinergic function is well documented as well as the benefit of cholinesterase inhibitors. In advanced disease, it is increasingly apparent that certain parkinsonian phenotypes such as the postural-instability, gait disorder (PIGD) or subjects with more axial symptoms appear to more at risk of developing cognitive impairment when followed over time. However the potential relationship between motor phenotype and cognition has not been explored in early PD.This paper has examined cognitive function in a large group of drug naïve PD subjects from a relatively homogeneous genetic background (although no genetic testing was done). The lack of medication was to ensure no effect of dopaminergic drugs on measured outcomes. Subjects with dementia (MMSE < 24) at baseline were excluded.
The difficulties in accurately diagnosing idiopathic PD in such a cohort were partially overcome by using 2 independent neurologists and DAT imaging was also performed. 103 PD subjects were evaluated using the UPDRS. Subscores for tremor (item 20, 21 on the UPDRS), rigidity (item 22) , bradykinesia (items 24-26 and 31), axial impairment (items 27-30) and bulbar (items 18, 19) were used to divide the subjects into 3 subgroups, tremor -dominant, PIGD-dominant and indeterminate group, depending on their predominant presenting features. Cognition was evaluated using a standard battery of neuropsychological tests. There was no normal age-matched controls group.
The demographics of the three PD groups were similarly matched for age (68.4y), sex and disease duration (mean 22.1 months). The PIGD group had higher total UPDRS part III scores and higher bradykinesia and rigidity subscores while the tremor dominant group had, by definition, higher tremor scores and PIGD higher axial subscores. The raw neuropsychology tests did not show any significant differences between the three groups. A number of correlations were explored between demographic, motor and neuropsychological measures.
Axial impairment and bradykinesia were linked to several neuropsychological measures whereas tremor did not. Multiple linear regression with age, sex, education and motor function showed bradykinesia was significantly associated with working memory (WCST, digit span and TMT); Axial symptoms were associated with episodic memory and visuospatial orientation. No associations were found with tremor and rigidity. The authors conclude that bradykinesia and executive functions are controlled by common dopaminergic pathways, and that these are different to dopaminergic pathways that control tremor and rigidity.
The old concept of the 'Parkinsonian Personality' ie the individual with inflexibility is now being explored in more rigorous studies and suggests that a hypodopaminergic state in early PD is the cause of executive dysfunction and bradykinesia. Treatment with dopaminergics may thus improve motor as well as cognitive functioning. This study also confirms that tremor dominant individuals appear to be at lower risk of cognitive problems. The PIGD subtype tends to progress more rapidly to dementia and such individual have more posteriotemporal dysfunctions early on, such as visuospatial and episodic memory; the concept of possibly identifying and treating such a subgroup early on with cholinesterase inhibitors is an interesting proposition.
About Dr. Susan H. Fox, MB, ChB, MRCP, PhD
Dr Susan H. Fox, MB ChB, MRCP(UK), PhD, is Associate Professor Neurology, University of Toronto and Staff Neurologist in the Movement Disorders Clinic, Toronto Western Hospital, UHN, Canada. She did her medical and neurological training in Manchester and Liverpool, UK and was Consultant Neurologist, at the Walton Centre Liverpool 2001-2003. She moved to Canada in 2003 to take up her current position.
Her research interests include preclinical studies of Parkinson's disease, investigating disease mechanisms, particularly neuropsychiatric problems as well as phase II and phase III clinical trials of new treatments for movement disorders. She is a member of the MDS International Executive Committee and serves on the MDS Education Committee and Evidence Based Medicine update on treatment of motor symptoms for Parkinson's disease task force.