PII: S0022-510X(00)00491-3


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PII: S0022-510X(00)00491-3

  1. 1. Journal of the Neurological Sciences 184 (2001) 123–130 www.elsevier.com / locate / jns Dopamine supports sentence comprehension in Parkinson’s Disease Murray Grossman*, Guila Glosser, Julia Kalmanson, Jennifer Morris, Matthew B. Stern, Howard I. Hurtig Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA, USA Received 8 May 2000; received in revised form 10 October 2000; accepted 28 November 2000 Abstract Objective: To determine the role of dopamine in the executive resource component of sentence comprehension. Methods: We studied sentence–picture matching in 20 right-handed, non-demented, native English speakers with mild Parkinson’s disease (PD) when ‘on’ and ‘off’ their levodopa, taking into account disease duration to control for endogenous dopamine metabolism. We also administered a verbal working memory measure that does not involve specific grammatical manipulations. Results: PD patients ‘off’ levodopa demonstrated a significant discrepancy in their comprehension of grammatically complex sentences compared to grammatically simpler sentences that was not evident when PD patients were ‘on’ levodopa. An error analysis demonstrated that impaired comprehension of grammatically complex sentences when ‘off’ levodopa was associated with poorer performance on foils requiring working memory resources. Performance on an independent measure of verbal working memory correlated only with comprehension of grammatically complex sentences during levodopa supplementation, but working memory according to this measure did not differ during ‘on’ and ‘off’ states. Conclusion: Dopamine supports the executive resources contributing to sentence comprehension in PD. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Parkinson‘s disease; Dopamine; Sentence comprehension 1. Introduction of DA in the cognitive difficulties of PD patients. For example, investigators have compared neuropsychological Several studies have demonstrated that non-demented performance in two groups of PD patients taking different patients with Parkinson’s disease (PD) have difficulty amounts of dopaminergic medication. The findings of during complex cognitive tasks that we use daily, such as these studies have been inconsistent. Some assessments sentence processing [1–3]. The clinical manifestations of have found that dopaminergic medication benefits execu- PD have been attributed largely to the degeneration of tive functioning and speed of mental information process- dopamine (DA)-containing neurons in the pars compacta of ing [4], but other studies have observed little difference or the substantia nigra, but the precise role of DA in these frank impairment on executive measures and short-term sorts of cognitive functions has not been elucidated. In the memory assessments in association with dopaminergic study reported below, we have evaluated the role of DA in treatment [5–7]. sentence comprehension by examining PD patients while Another strategy for establishing the role of DA in ‘on’ or ‘off’ levodopa. cognitive functioning has been to examine the same PD Several approaches have been used to examine the role patients when they are ‘on’ or ‘off’ a DA-supplementing medication like levodopa. A within-patient design such as this has the advantage that it can control for factors such as *Corresponding author. Department of Neurology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104- differences in disease duration that reflect the extent of 4283, USA. Tel.: 11-215-662-3361; fax: 11-215-349-8464. endogenous DA depletion and can confound results in a E-mail address: mgrossman@mail.med.upenn.edu (M. Grossman). between-patient design. Exogenous DA administration may 0022-510X / 01 / $ – see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 00 )00491-3
  2. 2. 124 M. Grossman et al. / Journal of the Neurological Sciences 184 (2001) 123 – 130 have a greater impact in patients with longer disease 2. Methods duration, for example, because of the associated long-term changes in endogenous DA metabolism [8–10]. Research- 2.1. Subjects ers have taken advantage of the predictably brief availabili- ty of levodopa [11] to study cognitive functioning under We assessed 20 non-demented (Mini Mental State conditions of full DA supplementation compared to rela- Examination [39] mean529.1, S.D.51.19, range526–30), tive DA depletion in the same patient. This has involved right-handed, native English speakers with idiopathic PD. withholding a patient’s medication in some studies, while The patients were mildly impaired (Hoehn and Yahr Stage other studies have examined patients at mid-dose and 1 or Stage 2), and signs included mild resting tremor and during an end-of-dose wearing-off period. Several studies rigidity, according to the Unified Parkinson’s Disease have demonstrated improvements in cognitive measures of Rating Scale [40]. Demographic characteristics and medi- memory and attention when PD patients are relatively ‘on’ cations at the time of the study are provided in Table 1. their levodopa [12–16], but other studies have reported Exclusionary criteria for participation in this study in- mixed results [17–19]. Discrepancies across these studies cluded the presence of a primary psychiatric disorder such may be due to differences in the extent of DA loss in PD as psychosis, another akinetic–rigid disorder such as patients participating in different studies. The impact of progressive supranuclear palsy, another neurologic con- endogenous DA metabolism on cognitive functioning thus dition such as head trauma or hydrocephalus, a dementing has been demonstrated in the evaluation of PD patients condition such as Alzheimer’s disease or dementia with ‘on’ and ‘off’ levodopa: memory and executive func- lewy bodies, another movement disorder such as parkin- tioning were generally better in the subgroup of patients sonism due to small vessel ischemic disease or neuroleptic with a stable response to levodopa who had a shorter drug use, or a metabolic or systemic disorder that could disease duration than the PD patient subgroup with end-of- interfere with intellectual functioning. dose wearing-off associated with longer disease duration, The patients were examined under two conditions, i.e., despite equivalent serum DA levels [20]. when they were fully supplemented by levodopa at an Sentence comprehension is a complex cognitive process optimal clinical dosage, and when they had been without that we use daily. A crucial component of sentence levodopa for at least 12 h. The two sessions occurred at the comprehension is grammatical processing. Some have same time of day (in the early morning), were typically argued that sentence comprehension impairments in PD are separated by less than a week (mean52.85 days, S.D.5 due directly to an impairment in grammatical processing, 2.45 days between sessions), and the order of ‘on’ and such as difficulty with the long-distance syntactic depen- ‘off’ assessments was randomized. We did not find an dencies among words in a sentence [21–23]. Recent work effect for the order in which patients were tested has indicated that sentence comprehension also is depen- [F(1,38)50.66; ns]. dent in part on executive resources [24–26]. For example, information retained in short-term memory from the 2.2. Materials beginning of a sentence must be retrieved instantaneously as it becomes needed later in a sentence [27]. In this PD patients performed a 24-item sentence–picture context, sentence comprehension difficulty in PD has been matching task using orally presented sentences. Sentence related to their limited executive resources [28–34]. Given stimuli were equally divided into simpler items containing the important contribution of working memory to sentence terminal subordinate clauses (e.g. ‘The hawk chased the comprehension and the apparent sensitivity of executive eagle that was fast’) and more complex items containing functioning to DA, we hypothesized that the accuracy of center-embedded subordinate clauses (e.g. ‘The eagle that sentence processing in PD patients would vary depending the hawk chased was fast’). All sentences were semantical- on the level of levodopa supplementation. ly unconstrained in that the action could be performed with Despite a consensus that executive resources contribute equal plausibility by either the agent or the recipient. to sentence processing, there is considerable debate about Patients responded in an untimed fashion by selecting one the nature of these resources. While some studies are most of four color pictures. One choice was an accurate consistent with the claim that executive resources are representation of the stimulus sentence. Picture foils material-neutral and equally applicable to the processing of included: a different verb depicting the action (in the any domain of knowledge [35–37], other work is more above example, the picture might illustrate ‘pecking’ consistent with a model of comprehension wherein the instead of ‘chasing’); a different agent performing the cognitive resources are dedicated to sentence processing action (e.g. a picture showing an owl chasing an eagle); [24,38]. To explore the nature of executive resources in the and a reversal of the agent role and the theme role DA-mediated sentence comprehension difficulties of PD involved in the action (e.g. an eagle chasing a hawk instead patients, we also obtained an independent measure of of a hawk chasing an eagle). The two former foils involve verbal working memory capacity that does not involve a comprehension of a single word, are less resource-demand- specific syntactic manipulation during the different states ing, and appear to depend in large part on left temporal of DA supplementation. brain regions that are sparsely innervated by DA projec-
  3. 3. M. Grossman et al. / Journal of the Neurological Sciences 184 (2001) 123 – 130 125 Table 1 Mean (6S.D.) clinical and demographic characteristics and medication regimens of patients with Parkinson’s disease All PD PD patient subgroups patients Greater Limited executive executive resources resources Group size 20 9 11 Age (years) 66.5 (11.2) 65.4 (12.1) 67.4 (10.8) Education (years) 16.1 (2.4) 16.9 (2.1) 15.4 (2.5) Duration (years) 9.6 (5.7) 8.8 (4.5) 10.6 (6.6) Disease severity Stage 1 ([ pts)† left54; right55 left53; right51 left51; right54 Stage 2 ([ pts) 11 5 6 Motor exam tremor — right 0.13 (0.24) 0.14 (0.22) 0.11 (0.26) — left 0.24 (0.41) 0.33 (0.63) 0.13 (0.32) rigidity — right 0.22 (0.41) 0.14 (0.33) 0.27 (0.45) — left 0.25 (0.46) 0.25 (0.53) 0.23 (0.41) Medications a levodopa 678 (436) 794 (464) 582 (408) selegiline 5.5 (5.1) 6.7 (5.0) 4.5 (5.2) bromocriptine 3.6 (4.4) 4.0 (5.5) 3.2 (3.4) a The medications are tabulated as the total mg dosage / day. All patients were taking levodopa in combination with carbidopa as Sinemet, ten patients were taking selegiline, four patients were taking bromocriptine, and five patients were taking pergolide (pergolide daily dosage was multiplied by ten to be roughly equated with bromocriptine). In addition to the medications listed in the table, three patients were taking amantadine (at 200 mg qd or 300 mg qd), one patient was taking amitryptiline (50–75 mg qhs), one patient was taking doxepin (100 mg qhs), one patient was taking trihexyphenidyl (1 mg qid), one patient was taking benztropine (1.5 mg tid), one patient was taking alprazolam (0.25 mg qhs), and one patient was taking triazolam (0.125 mg qhs) (qd5daily, qhs5nightly, tid5three times each day, qid5four times each day). † With lateralized tremor. tions; the latter foil involves mapping thematic roles (who a repeated-measures analysis of variance (ANCOVA) with is doing what to whom) on to grammatical roles (sentence a DA status (on vs. off) 3 type of sentence (terminal subject and object), a process that requires considerable subordinate vs. center-embedded subordinate) design to working memory resources and appears to be dependent on assess differences in sentence comprehension. To control left frontal brain regions that are mediated in part by DA. These choices were equally distributed across trials in each of four possible positions that were arrayed in a 232 configuration. None of the patients had visual–perceptual difficulty that could have interfered with picture interpreta- tion. To explore the nature of the executive resources that contribute to sentence processing difficulty in PD, we examined these patients on a measure of verbal working memory — the reading span procedure [41]. The reading span procedure requires a subject to read a list of complex sentences orally, and to recall the final words of the list of sentences when finished reading them. The list of sent- ences presented in a block becomes progressively longer, analogous to a digit span procedure. A subject’s reading span is equal to the number of sentences whose final words are correctly reproduced after reading these lists. 3. Results Fig. 1. Mean (6S.E.) sentence comprehension accuracy of terminal Fig. 1 summarizes PD patients’ sentence comprehension subordinate and center-embedded subordinate sentences in Parkinson’s accuracy during ‘on’ and ‘off’ assessment phases. We used disease when ‘off’ and ‘on’ levodopa medication.
  4. 4. 126 M. Grossman et al. / Journal of the Neurological Sciences 184 (2001) 123 – 130 for the effects of endogenous DA metabolism, we covaried with more errors only for the resource-demanding reversal for disease duration on the assumption that longer disease foil. duration is associated with greater DA depletion. We did We found that the reading span of PD patients ‘off’ not find any significant main effects, but the DA status 3 levodopa (mean reading span score ‘off’ levodopa533.05; type of sentence interaction effect was highly significant S.D.5610.32) did not differ substantially from their [F(1,18)57.82; P,0.01]. We did not observe a similar reading span performance when ‘on’ levodopa (mean interaction effect when we covaried for other clinical reading span score ‘on’ levodopa528.45; S.D.5610.17). factors such as age [F(1,18)51.94; P50.18] and education We related PD patients’ executive resources ‘off’ levodopa [F(1,18)50.17; P50.68]. t-Tests demonstrated that com- to their comprehension of sentences during levodopa prehension of center-embedded subordinate sentences was supplementation. Individual patient’s performance profiles significantly worse than terminal subordinate sentences are summarized in Table 2. We found that reading span only during the ‘off’ phase of testing [t(19)52.17; P, ‘off’ levodopa is significantly correlated with the com- 0.05], but comprehension of center-embedded subordinate prehension of center-embedded subordinate sentences ‘on’ sentences did not differ from comprehension of terminal levodopa [r(18)50.647; P,0.002], but is not correlated subordinate sentences during the ‘on’ phase of testing. with the comprehension of terminal subordinate sentences To learn more about the basis for the effect of DA on ‘on’ levodopa [r(18)50.425; ns]. Reading span ‘off’ sentence comprehension, we examined the errors that levodopa was not correlated with sentence comprehension patients made when they chose an incorrect picture. The ‘off’ levodopa, and reading span ‘on’ levodopa was not results are summarized in Fig. 2. Separate ANCOVAs were correlated with sentence comprehension under ‘on’ or ‘off’ performed for verb, agent, and reversal foils, comparing conditions. the frequency of selecting a foil during the comprehension We also used a ‘median split’ to divide the patients into of terminal subordinate and center-embedded subordinate two subgroups according to their cognitive resources ‘off’ sentences while ‘on’ and ‘off’ levodopa, covarying for levodopa, i.e., into those with ‘greater executive resources’ disease duration. This revealed a significant drug effect (n59; mean reading span score537.56; S.D.566.23) and only for the reversal error [F(1,18)512.69; P,0.002]. The those with ‘limited executive resources’ (n511; mean impairment in PD patients’ performance on center-embed- reading span score522.72; S.D.566.10) (because of ties, ded sentences while ‘off’ levodopa thus was associated the median split could not be used to divide the PD Fig. 2. Mean (6S.E.) proportion of foils selected when patients with Parkinson’s disease erred in their sentence–picture matching. * indicates a statistically significant difference.
  5. 5. M. Grossman et al. / Journal of the Neurological Sciences 184 (2001) 123 – 130 127 Table 2 Individual patient’s executive resource and sentence comprehension profiles ‘off’ and ‘on’ levodopa medication a Patient Reading Terminal subordinate Center-embedded subordinate ID span Off On Off On a Greater executive resources 205 49 88 100 100 100 217 48 75 100 88 88 237 43 88 75 100 88 241 42 88 88 75 88 075 41 88 63 75 88 171 41 88 63 75 88 257 40 100 88 75 88 246 35 75 75 88 75 248 34 100 88 63 88 Limited executive resources a 133 31 100 75 88 75 194 31 88 75 100 63 227 31 88 75 88 75 236 30 88 88 75 75 216 29 75 88 100 88 253 29 75 75 75 50 013 27 75 88 38 75 266 21 100 100 100 100 269 21 88 63 38 63 258 16 75 100 63 100 260 4 75 63 50 63 a Executive resources were established by performance on a reading span task. Reading span is scored as the total number of sentences with correctly recalled terminal words, and subjects with larger reading spans have greater executive resources. See text for additional details. Comprehension of terminal subordinate and center-embedded sentences is reported as percent correct. patients into two equal subgroups). These subgroups thematic relations in a sentence, i.e., who is doing what to differed significantly in their reading span scores (t(18)5 whom. This aspect of sentence comprehension is depen- 5.35; P,0.001), but they did not differ statistically in their dent on executive resources. The results of an independent age, education, disease duration, forward digit span, or measure of verbal working memory suggest that cognitive medication regimen, as summarized in Table 1. Consistent resources dedicated to sentence processing and material- with the correlation analysis, inspection of non-zero differ- neutral executive resources both contribute to the com- ences revealed that 72% of PD patients with greater prehension of complex sentences. executive resources were superior during ‘on’ compared to Previous studies have attempted to assess whether or not ‘off’ conditions in their comprehension of center-embed- DA levels influence cognitive performance in PD [4–7]. ded subordinate sentences. Only 44% of PD patients with The results of studies using a between-patient design have limited executive resources showed this advantage during been difficult to interpret since they have not been able to ‘on’ compared to ‘off’ conditions for center-embedded control for differences in disease severity and CNS DA subordinate sentences. These subgroups did not differ in levels across the groups of PD patients being compared the relative ‘on’ vs. ‘off’ advantage for their comprehen- [18,20]. Studies using a within-patient design have demon- sion of terminal subordinate sentences (greater executive strated some levodopa-associated improvement in mea- resource subgroup528%; limited executive resource sures of attention, memory, and executive functioning. For subgroup538%). example, several reports have described improved verbal memory when patients receive their dopaminergic medica- tion compared to performance during an unmedicated 4. Discussion period [13,15]. Brown et al. [12] observed improvement in measures of intelligence and general reasoning during the Our observations suggest that sentence comprehension is ‘on’ phase of medication response compared to the ‘off’ influenced by levodopa levels in PD. In particular, we phase. A report of uncued and cued choice reaction time found that differences in understanding grammatically found that DA supplementation helps patients take advan- simple and grammatically complex sentences when ‘off’ tage of the predictability of a stimulus [14]. Owen et al. levodopa are diminished by DA supplementation in PD [16] found reduced planning accuracy in unmedicated patients. An error analysis revealed that this effect is patients that improved with levodopa treatment, although specifically associated with more accurate grasp of the the patients’ response latencies did not change. Improved
  6. 6. 128 M. Grossman et al. / Journal of the Neurological Sciences 184 (2001) 123 – 130 cognitive functioning while ‘on’ levodopa, however, has specific grammatical manipulations. Several aspects of our not been a universal finding in assessments using a within- study are consistent with the hypothesis that the DA- patient design. Several studies have reported mixed results, mediated effects impact on a specific, resource-dependent associating some measures of executive functioning and component of sentence comprehension. An error analysis learning with relatively impaired performance during DA thus associated impaired sentence comprehension during supplementation but other measures with improved per- limited DA supplementation with difficulty mapping gram- formance [18,19]. Another study failed to find any DA- matical roles on to thematic roles in sentences. Grammati- associated differences in measures of verbal memory, cal–thematic mapping requires intensive working memory visuospatial orientation, attention, and executive function- support, and this aspect of sentence comprehension has ing [17]. proven quite difficult for PD patients [28–30,33]. More- Several factors may have contributed to discrepant over, unlike the comprehension of grammatically demand- results across these studies, such as differences in disease ing sentences, we found comparatively little change in duration and severity. We covaried for disease duration, reading span during ‘on’ and ‘off’ conditions. These reasoning that patients with a longer disease duration observations are more consistent with the hypothesis that should have relatively limited endogenous DA metabolism. the executive resource component of sentence comprehen- This analysis revealed a significant effect of DA on sion is different from the material-neutral form of execu- sentence comprehension: there was a significant dis- tive resources that may support other cognitive tasks [24]. crepancy in the ability to understand grammatically simple However, this cannot entirely explain the DA-dependent and grammatically complex sentences when patients were change in sentence comprehension since we also found ‘off’ levodopa due to the relatively poor comprehension of that an independent measure of verbal working memory complex grammatical sentences during limited DA supple- correlated with the comprehension of the most complex mentation. This discrepancy in understanding simple and sentences during the ‘on’ condition, but did not correlate complex grammatical sentences was not evident when the with the comprehension of simpler sentences. This ob- patients were ‘on’ levodopa. Other observations have also servation is more consistent with the hypothesis that demonstrated a relationship between the performance of material-neutral resources contribute to sentence com- complex cognitive tasks and DA metabolism in PD, prehension as well. Taken together, these findings suggest consistent with the hypothesis that improvement in cogni- that the DA-mediated cognitive resources contributing to tive functioning during levodopa supplementation in PD is sentence comprehension in PD are multifaceted in nature. mediated in part by disease duration [20]. The mechanism by which DA supplementation impacts Another factor that may explain some of the discrepan- working memory and executive resources during sentence cies across previous studies of DA-dependent cognitive comprehension in PD remains to be elucidated. One functioning has to do with the model of executive re- possibility is that specific brain regions have different sources under examination. The results described above sensitivities to DA [18,44], and that the network of brain thus are discrepant only if one assumes that there is a regions responsible for working memory resources in single, material-neutral executive resource underlying all language is particularly sensitive to DA because of its aspects of cognitive functioning. For example, slowed neuroanatomic distribution. Recent work has shown that an information processing speed [42] or a limitation in total interaction of grammatically complex sentence structure processing space [43] have each been cited as a unified and increased working memory demands is crucial to the source of limited cognitive resources in the healthy elderly. recruitment of left inferior frontal regions during an fMRI An alternative account is that executive resources support a activation study of sentence comprehension in healthy relatively narrow range of cognitive functions, and that adults [45]. This frontal area is part of a dopamine- there may be cognitive resources that are specifically modulated frontal-striatal network that is thought to play a dedicated to sentence processing [24]. Studies of sentence role in the cognitive deficits of PD patients [46], and this processing in PD, beyond confirming the contribution of area also appears to receive mesocortical projections from cognitive resources, raise the possibility that limitations of the substantia nigra that contribute to cognitive functioning several different types of resource are associated with in PD [47]. The regional specificity of DA-mediated neural comprehension difficulty. For example, information pro- systems may also explain the non-significant decline in cessing speed [32], working memory [30], and planning performance on terminal-subordinate sentences and in- [31] each appear to be related to comprehension difficulty creased selection of a different agent and a different verb in PD, and it has been hypothesized that each of these when ‘on’ DA, since these less-demanding grammatical resources supports a specific aspect of sentence processing and lexical semantic features of sentences are reliant on that may be compromised in PD [25]. non-frontal regions [45,48] where DA projections are We investigated the nature of the executive resource relatively sparse. limitation during sentence comprehension in PD by ex- Another possible mechanism for the DA-mediated ef- amining the errors seen during the patients’ comprehension fects in PD patients’ sentence comprehension and execu- performance and by assessing performance on a working tive functioning is related to the amount of DA [49]. From memory measure that is verbal but does not involve this perspective, the resource component of sentence
  7. 7. M. Grossman et al. / Journal of the Neurological Sciences 184 (2001) 123 – 130 129 comprehension may have been more sensitive to DA [2] Lieberman P, Friedman J, Feldman LS. Syntax comprehension in dosage than reading span. Similarly, the substrate for Parkinson’s disease. Journal of Nervous and Mental Disease 1990;178:360–6. cognitive resources in sentence comprehension may have [3] Natsopoulos D, Katsarou Z, Bostantzopoulos S, Grouios G, Men- been so compromised in the subgroup of PD patients with tenopoulos G, Logothetis J. Strategies in comprehension of relative limited cognitive resources that they would have required clauses in Parkinsonian patients. Cortex 1991;27:255–68. more levodopa supplementation to derive any benefit. If [4] Zimmermann P, Sprengelmeyer R, Fimm B, Wallesch C-W. Cogni- DA supplementation has an inverted-U-shaped effect on tive slowing in decision tasks in early and advanced Parkinson’s cognitive functioning [44], the PD patients may have been disease. Brain and Cognition 1992;18:60–9. [5] Cooper JA, Sagar HJ, Sullivan EV. Short-term memory and temporal receiving a relative excess of DA supplementation in the ordering in early Parkinson’s disease: Effects of disease chronicity ‘on’ state for aspects of sentence comprehension with few and medication. Neuropsychologia 1993;31:933–49. resource demands such as grammatically simpler sentences [6] Downes JJ, Roberts AC, Sahakian BJ, Evenden JL, Morris RG, and single word meaning. Additional research is necessary Robbins TW. Impaired extra-dimensional shift performance in to establish the specific basis for the DA-mediated impact medicated and unmedicated Parkinson’s disease: Evidence for a of working memory resources during sentence comprehen- specific attentional dysfunction. Neuropsychologia 1989;27:1329– 43. sion. [7] Owen AM, James M, Leigh PN, Summers BA, Marsden CD, Quinn Several caveats should be kept in mind when interpret- NP, Lange KW, Robbins TW. Fronto-striatal cognitive deficits at ing the results of this report. We studied mildly impaired, different stages of Parkinson’s disease. Brain 1992;115:1727–51. high-school-educated PD patients and caution should be [8] Melamed E, Hefti F, Pettibone DJ, Liebman J, Wurtman RJ. used in generalizing our results to other groups of PD Aromatic L-amino acid decarboxylase in rat corpus striatum: Impli- patients. PD patients were assessed with a limited variety cations for action of L-dopa in parkinsonism. Neurology 1981;31:651–5. of sentences using only one kind of comprehension [9] Zhang W, Tilson HA, Nanry KP, Hudson PM, Hong JS, Stachowiak measure, and our observations must be replicated with MK. Increased dopamine release from striata of rats after unilateral other linguistic techniques in a larger group of patients. We nigrostriatal bundle damage. Brain Res 1988;461:335–42. focused on levodopa supplementation in a relatively small [10] Fabbrini G, Juncos JL, Mouradian MM, Serrati C, Chase TN. group of PD patients with a limited range of disease Levodopa pharmacokinetic mechanisms and motor fluctuations in duration, and additional work is necessary to establish the Parkinson’s disease. Ann Neurol 1987;21:370–6. [11] Wooten GF, Marsden CD, Fahn S, editors, Movement Disorders 2, contribution of disease duration to cognitive difficulty in 1st ed, Pharmacokinetics of levodopa, Vol. 11, London: Butter- PD. The effect of withholding levodopa was limited, given worths, 1987, pp. 231–48. the relatively brief period that this medication was with- [12] Brown RG, Marsden CD, Quinn N, Wyke MA. 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