| | Greater motor improvement in right hemibody Parkinson's patients after dopaminergic medicationsReceived 25 July 2007; received in revised form 26 December 2007; accepted 8 February 2008. Abstract Due to motor and neuropathological asymmetries, Parkinson's disease (PD) patients with right hemibody onset (RHO) of symptoms may experience greater benefit from dopaminergic enhancing medications, relative to patients with left hemibody onset (LHO). We investigated this possibility by measuring UPDRS scores of 20 PD patients with LHO and 13 patients with RHO, both prior and subsequent to taking dopaminergic enhancing medications. Following treatment, the motor score from the UPDRS improved for both groups of patients. However, PD patients with RHO experienced greater improvement in motor functioning following administration of dopaminergic enhancing medications than those with LHO. The motor symptoms of PD typically begin laterally or asymmetrically [1], [2], [3], [4], [5]. Asymmetry has been noted in all three cardinal features of PD, including rigidity, bradykinesia, and tremor [6]. This asymmetry in motor signs and symptoms is paralleled by asymmetry in the neuropathological processes associated with PD. For example, Kempster and colleagues reported that there is a decrease in the number of dopaminergic neurons in the substantia nigra contralateral to the side of the body with the initial onset of signs and symptoms [7]. Decreased uptake of [18F]dopa in the putamen contralateral to the side of the body with greater clinical disability has also been reported [8]. Other investigators have reported a greater reduction in striatal dopamine transporter binding contralateral to the more affected side of the body [9], [10], [11]. Further, the putamen and caudate contralateral to the more affected side of the body are associated with a reduced [18F]dopa effective distribution volume and elimination rate [12]. Even when patients who had unilateral onset develop bilateral signs and symptoms these patients' motor and neuropathological asymmetries persist [13], [14], with more severe extrapyramidal signs on the side of the body initially affected [15], [16]. The asymmetrical reduction in striatal dopamine transporter binding is also more pronounced contralateral to the more affected side of the body through the course of the disease [11]. The investigation by Tatsch et al. [11] also found significant negative correlations between striatal dopamine transporter binding and disease duration. Additionally, Morrish, Sawle, and Brooks [17] found significant correlations between [18F]dopa uptake in the putamen and both the motor and total Unified Parkinson's Disease Rating Scale (UPDRS) scores, suggesting that the UPDRS accurately reflects brain pathology. Studies of patients with strokes have demonstrated that the left hemisphere of right-handed people is important for mediating skilled movements of both the right and left hands, but the right hemisphere appears to mediate movements primarily of the left hand [18], [19]. Both the loss of deftness (limb-kinetic apraxia) and a failure to implement spatial-temporal movement representations (ideomotor apraxia) have been reported to be associated with PD [20], [21]. Research has also indicated that dopamine is asymmetrically distributed in the human brain, with greater concentrations found more commonly in the left than in the right hemisphere [22], [23]. Based on these two asymmetries, when PD patients have right hemibody onset and are treated with dopaminergic medications they might demonstrate greater improvement than those patients who have primarily left sided signs and symptoms. The specific reasons for this differential improvement in right versus left hemibody onset PD are two-fold. First, since the left hemisphere is dominant for motor programming, hence up-regulation of the left hemisphere through dopaminergic enhancing medications would be more likely to improve the motor functions of both the contralateral and ipsilateral sides of the body than vice versa. An additional reason may relate to the possibility that right hemibody onset PD patients should show a greater response to dopaminergic medications because pre-morbidly they had more dopamine in their left than right hemisphere and the possibility exists that they may still have a greater number of intact nigrostriatal receptors in the left hemisphere. Some investigators have postulated an initial and predominant degeneration of the nigrostriatal cells subserving endogenous striatal dopamine production, with a sufficient number of nigrostriatal nerve terminals remaining that can convert levodopa to dopamine and store exogenously administered levodopa [8]. In addition, Rodriquez, Castellano, and Palarea [24] suggested that to compensate for a lower number of dopaminergic terminals, the right hemisphere may have a relatively higher dopamine turnover rate. Thus, with diseases that affect the dopaminergic system, such as PD, the left hemisphere may be relatively more able to compensate than the right hemisphere possibly because it might have a greater capacity to up-regulate dopamine turnover. As a result, treatment with levodopa, by improving dopamine turnover, will result in relatively more functional improvements for those patients with predominantly left hemisphere (i.e. right hemibody) onset of PD. We sought to investigate the prediction that patients with right hemibody PD would improve with dopaminergic treatment more than those with left hemibody PD by comparing scores from the UPDRS between PD patients with left versus right hemibody onset of symptoms, both prior and subsequent to taking their dopaminergic enhancing medications. 1. Methods  1.2. Apparatus The UPDRS assesses the severity of symptoms and signs in four domains, including: (1) mental abilities and mood; (2) activities of daily living; (3) motor abilities; and (4) on and off fluctuations. Only part III – motor scale of the UPDRS – was included in this investigation, with a range of scores from 0 to 108. Each of the signs and symptoms recorded in the UPDRS is rated on a five point scale, with zero representing the absence (none) of the symptoms or no evidence of this sign and four representing severe disability. 1.3. Procedures The participants were patients with PD seen at the Movement Disorders Center at the University of Florida. The project was approved by the Institutional Review Board and all subjects provided informed consent. The UPDRS was administered as part of each patient's routine neurological examination and the MMSE was administered during a neuropsychological evaluation. The UPDRS off score was obtained using standard procedures, i.e. the patients were instructed to abstain from taking their morning dose of medication the day the neurological examination was scheduled. With the exception of two patients, the UPDRS off and on scores were obtained on the same day. Regarding the two exceptions, there was a 10 day discrepancy between the off and on UPDRS scores for one LHO patient and a 146 day discrepancy for one RHO patient. 2. Results Initial analyses comparing demographic data between the LHO and RHO groups indicate that the groups did not differ in terms of age, education, or MMSE scores. However, a significant difference was found for disease duration, F(1, 31) =5.86, p=0.021, the RHO having PD longer than the LHO group. Further analyses indicated no significant differences in the dosage of levodopa/carbidopa between the LHO (levodopa: M=605.88, SD=260.94; carbidopa: M=127.35, SD=68.79) and the RHO (levodopa: M=915.91, SD=574.49; carbidopa: M=169.32, SD=92.09) groups. The results of a two (Group: LHO versus RHO) by two (State: Off versus On medication) mixed factorial ANOVA, with a repeated factor of State and a between subjects factor of Group, indicated a significant Group by State interaction, F(1, 31)=5.25, p=0.029 (see Fig. 1). Whereas the main effect of Group was not significant, the main effect for State was significant, F(1, 31)=123.04, p<0.00001. Inspection of the means indicated significantly higher UPDRS scores in the Off medication condition (M=40.32, SD=1.70) as compared to the On medication condition (M=23.81, SD=1.56). Multiple comparisons were then conducted to further analyze the significant Group by State interaction, using a Bonferroni correction to control for experiment-wise error rate (p<0.0125). The results indicated no statistically significant differences in UPDRS scores between the LHO and RHO groups when either Off or On medication, although the Off condition approached significance, t(31)=−1.98, p=0.057. Additional analyses indicated significant improvements in UPDRS scores from the Off to On medication conditions for both the LHO group, t(19)=7.65, p<0.00001 (Off: M=36.95, SD=7.72; On: M=23.85, SD=7.53), and the RHO group, t(12)=7.68, p<0.00001 (Off: M=43.69, SD=11.90; On: M=23.77, SD=10.35). Given that our primary interest was the difference in UPDRS scores from the Off to On medication conditions, we conducted a final analysis using change scores created by subtracting the UPDRS On medication score from the UPDRS Off medication score. The results of a one-way between groups ANOVA indicated a significant difference, F(1, 31)=5.25, p=0.029, in the change scores between the LHO (M=13.10, SD=0.19) and the RHO (M=19.92, SD=1.54) groups. 3. Discussion One of our initial findings, that we did not predict, was that our sample of patients with RHO of motor symptoms had the onset of their symptoms occur at a mean of about 4 years before those with LHO. However, the overall severity of the motor impairment, as assessed by the UPDRS, between the LHO and RHO patients was not significantly different. This finding has several possible interpretations. One possibility is that when PD starts in the left hemisphere, on the right side of the body, it does not progress as rapidly as it does when these symptoms start on the left side of the body. This difference might be related to a reservoir effect such that the larger the reservoir the more water that can be lost before there is a shortage. Thus, the increased amount of dopamine found in the left hemisphere in normal subjects might constitute a larger reservoir. In addition, the duration of symptoms is, in part, dependent upon when the patient recognizes their impairment. The incidence of anosognosia for hemiplegia is much higher with right than left hemisphere strokes [25] and there is some evidence that patients with PD have a form of anosognosia. It has been found that when the symptoms of PD start on the left side people are less likely to recognize these signs than when they start on the right side [26]. The possibility also exists that individuals with RHO become aware of their dysfunction earlier due to using their right hemibody for more actions that require fine motor control. Our findings also indicated that, although both LHO and RHO PD patients experienced significant improvement as a result of receiving dopaminergic enhancing medications, the patients with RHO experienced significantly greater improvement than those with LHO. There are several potential explanations for this treatment asymmetry. The possibility exists that pre-morbidly there are more dopaminergic neurons in the left versus right hemisphere. Thus, patients with RHO might still have a greater number of intact nigrostriatal receptors in their left hemisphere, as compared to the number of intact receptors in the right hemisphere of patients with LHO. Additionally, since in right-handed people the left hemisphere plays a dominant role in the motor programming of both hands, up-regulation of the left hemisphere would be more likely to improve the motor function of both the contralateral and ipsilateral sides of the body. Future research might attempt to replicate this treatment asymmetry, perhaps by using a suprathreshold dose of levodopa. If the findings are replicated then these two possible mechanisms might be able to be dissociated. However, these two possible mechanisms are not mutually exclusive and might be linked. Based on the dopamine receptor hypothesis we would expect that with levodopa treatment of the patients with RHO would demonstrate a greater improvement of the right side of their body than those with LHO would show of their left body. In contrast, if the motor dominance hypothesis was correct, we would expect that with levodopa treatment of the patients with RHO we would see a greater improvement of their left side, than we would see on the right side in those patients with LHO. Another possible explanation of our findings is that a more dramatic response to treatment might be related to the duration of the disease as well as to the duration of treatment. Research has indicated that the short duration response curve following a single dose of levodopa becomes more prominent than the long duration response over the time course of the disease. Furthermore, over the course of the disease the short duration response curve becomes steeper, shorter in duration, and the magnitude of the response increases. The increase in magnitude of the short duration response is related to not only disease duration and severity but also duration of treatment [10], [27], [28], [29]. Given these findings, the possibility exists that our findings are due to the significant difference in disease duration between our groups. Further research should be conducted to examine the veracity of the possible explanation, possibly using another test to assess disease severity in addition to the UPDRS, such as the finger tapping test. Our hypothesis of greater improvement in PD patients with RHO was partially based on the proposition that the left hemisphere may be relatively more able to compensate than the right hemisphere due to a potentially greater capacity to up-regulate dopamine turnover. Parkinson's disease usually does not become symptomatic until about 70–80% of dopaminergic neurons are lost in the substantia nigra. Further, as mentioned previously, the left hemisphere has greater dopaminergic enervation than the right hemisphere [22], [23]. 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a University of Florida, Gainesville, FL, USA b Malcom Randall VAMC, Gainesville, FL, USA c Psychology Department, Middle Tennessee State University, 1500 Greenland Drive, Murfreesboro, TN 37132, USA d Oasi Institute for Research on Mental Retardation and Brain Aging, Troina, EN, Italy e University of Canterbury, Christchurch, New Zealand f Brain Injury Rehabilitation Service, Burwood Hospital, Christchurch, New Zealand g Hunter Holmes McGuire VAMC, Richmond, VA, USA  Corresponding author. Psychology Department, Middle Tennessee State University, 1500 Greenland Drive, Murfreesboro, TN 37132, USA. Tel.: +1 615 898 2007; fax: +1 615 898 5027.
PII: S1353-8020(08)00054-0 doi:10.1016/j.parkreldis.2008.02.006 © 2008 Elsevier Ltd. All rights reserved. | |
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