Lack of efficacy of a nicotine transdermal treatment on motor and cognitive deficits in Parkinson's disease

Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 31 – 39 www.elsevier.com/locate/pnpbp

Lack of efficacy of a nicotine transdermal treatment on motor and cognitive deficits in Parkinson’s disease Simon Lemaya,b, Sylvain Chouinardb, Pierre Blanchetb, He´le`ne Massonb, Vale´rie Solandb, Anne Beutera, Marc-Andre´ Be´darda,b,* a Cognitive Neuroscience Centre (CNC), Universite´ du Que´bec a` Montre´al (UQAM), Montreal, Que´bec, Canada Unite´ des troubles du mouvement Andre´ Barbeau, Centre Hospitalier de l’Universite´ de Montre´al (CHUM) (Hoˆtel-Dieu), 3840 St-Urbain, 5e e´tage, Pavillon Jeanne Mance, Montreal, Que´bec, Canada H2W 1T8

b

Accepted 11 July 2003

Abstract Studies assessing the efficacy of nicotine in Parkinson’s disease (PD) have generated contradictory results. The controversy seems to stem from uncontrolled factors including the lack of objective measures, the practice effect in a test – retest design, and the absence of plasmatic dosage. This study aimed at further controlling these factors using transdermal nicotine in PD. Methods: Twenty-two nonsmoking PD patients received a transdermal nicotine treatment over 25 days in increasing titrated doses. Motor and cognitive assessments were carried out on days 11 and 25 (low-dose and high-dose assessments, respectively) and after a 14-day washout period. Results: Patients tolerated nicotine poorly. Thirteen (59%) withdrew, mostly because of acute side effects. In the remaining nine patients, nicotine neither improved nor worsened motor or cognitive functioning in comparison with 10 age, gender and education matched controls. Conclusions: Transdermal nicotine is not effective in treating motor and cognitive deficits in PD. The results obtained with our objective measures confirm a recent double-blind, placebo-controlled study that used clinical measures. It is possible that nicotine lacks specificity in targeting critical nicotinic receptors that might be involved in PD pathophysiology. The low tolerability may be related to such a lack of specificity of nicotine, which would directly stimulate the autonomic nervous system. D 2003 Elsevier Inc. All rights reserved. Keywords: Cognition; Movement; Neuropsychology; Nicotine; Parkinson’s disease

1. Introduction Over the last decade, many authors have suggested that nicotine may have a role as a therapeutic agent (Baron, 1996; Benowitz, 1996; LeHouezec, 1998). In addition to improving cognitive functioning in normal individuals (Wesnes and Warburton, 1983), nicotine has been suggested to have beneficial effects on various diseases, including Abbreviations: CRT, choice reaction time; Diado, Diadochokinesimeter; DRS, Dementia Rating Scale; EKM, Eurythmokinesimeter; GDS, Geriatric Depression Scale; LNseq, Letter-Number Sequencing; NC, normal elderly controls; PD, Parkinson’s disease; RAVLT, Rey Auditory Verbal Learning Test; Reteff, retrieval efficiency; S  G, Session  Group interaction; SAT, speed – accuracy tradeoff; SeqRT, sequential reaction time; UPDRS, Unified Parkinson’s Disease Rating Scale. * Corresponding author. Unite´ des troubles du mouvement Andre´ Barbeau, Centre Hospitalier de l’Universite´ de Montre´al (CHUM) (HoˆtelDieu), 3840 St-Urbain, 5e e´tage, Pavillon Jeanne Mance, Montreal, Que´bec, Canada H2W 1T8. Tel.: +1-514-890-8000x15587; fax: +1-514-412-7139. E-mail address: [email protected] (M.-A. Be´dard). 0278-5846/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0278-5846(03)00172-6

Parkinson’s disease (PD). The rationale for using nicotine in PD first came from epidemiological studies demonstrating an inverse relationship between smoking and PD prevalence (Baron, 1986; Grandinetti et al., 1994; Fratiglioni and Wang, 2000). In animals, pretreatment with nicotine significantly decreased the dopaminergic cell mortality associated with MPTP, a neurotoxin of the dopaminergic cells (Quik and Jeyarasasingam, 2000; Parain et al., 2001). Moreover, chronic nicotine administration in rats slowed age-associated dopaminergic receptor loss (Prasad et al., 1994). Neurochemical rationales have been advanced for the administration of nicotine in PD. More specifically, the dopaminergic nigrostriatal pathway that is affected in PD is rich in nicotinic receptors. In vivo and in vitro studies have shown that local application of nicotine at the nigrostriatal terminals increased the exocytosis of dopamine (Wonnacott et al., 2000; see Levin et al., 1990a for a review of earlier studies). Nicotinic receptors are also found on the terminals of some cholinergic systems that are thought to be

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involved in the PD pathophysiology. Cholinergic cell loss has been described in the basal forebrain as well as in the pedunculopontine and laterodorsal tegmental nuclei of PD patients (Jellinger, 1999). Nicotinic receptor loss has also been documented in PD in the parietal cortex (Perry et al., 1990), frontal and temporal cortices, hippocampus, thalamus, striatum (Lange et al., 1991; Rinne et al., 1991; Aubert et al., 1992), substantia nigra pars compacta, and laterodorsal tegmental nucleus (Perry et al., 1995). It has been suggested that this cortical cholinergic depletion could be associated with the dementia that is frequently observed in this disease (Hirsch et al., 1987; Zweig et al., 1989; Shinotoh et al., 2001). However, because cholinergic systems were also found to be affected in nondemented PD patients (Aubert et al., 1992; Shinotoh et al., 1999; Mattila et al., 2001), they could be involved in other aspects of the disease, including sleep and gait disorders (Pahapill and Lozano, 2000), and the mild cognitive deficits or dysexecutive syndrome of PD (Dubois et al., 1990; Be´dard et al., 1998). Some case reports have suggested that nicotine may improve motor and cognitive symptoms in PD. Moll (1926) administered nicotine subcutaneously to postencephalitic parkinsonian patients and documented a decrease in rigidity. Unfortunately, severe side effects were also observed, including nausea, vomiting, spasm, and tremor, but repetition of the treatment reduced these side effects. Other case studies suggested that parkinsonian symptoms were relieved after cigarette smoking (Ishikawa and Miyatake, 1993) or nicotine patch application (Fagerstrom et al., 1994; Villafane et al., 2000). On the other hand, another case report (Nishimura et al., 1997) documented a worsening of symptoms after cigarette smoking and no significant motor improvement was seen after using nicotine chewing gum (Clemens et al., 1995). This variation in the therapeutic efficacy could be related to the method for administering nicotine (better efficacy with patches than with cigarette and gum) and to the duration of the treatment (better efficacy with chronic treatment than with acute administration). Three controlled studies assessed the therapeutic efficacy of transdermal nicotine in PD (Ebersbach et al., 1999; Kelton et al., 2000; Vieregge et al., 2001). Again, the results were contradictory: one study reported a worsening of motor symptoms (Ebersbach et al., 1999), another revealed an improvement (Kelton et al., 2000), and the third concluded that there was no effect (Vieregge et al., 2001). These studies mainly evaluated the efficacy of nicotine on movement. Only one study assessed the effect of nicotine on cognition (Kelton et al., 2000). The conclusion was that nicotine improved attention and processing speed in PD. However, it was not clear if this improvement resulted from a practice effect. For this reason, we used a methodological design that allows to study the effect of nicotine while controlling for the practice effect that usually occurs with the repetition of cognitive measures.

2. Methods 2.1. Subjects Twenty-two nondemented PD patients (age 65.23 F 9.55 years, M/F 19:3) were enrolled in the study. The diagnosis of idiopathic PD was confirmed by an experienced neurologist from the Andre´ Barbeau Movement Disorders Unit of the Centre Hospitalier de l’Universite´ de Montre´al. The disease severity was mild to moderate according to the Hoehn and Yahr (1967) scale (Stages 1– 3). Patients maintained their usual dopaminergic treatment throughout the study. Those treated with anticholinergic medication or hblockers were excluded. Depression was ruled out by using a cutoff score of 11 on the Geriatric Depression Scale (GDS) (Yesavage et al., 1982). Dementia was ruled out by using DSM-IV criteria (APA, 1994) and a cutoff score of 123 on the Dementia Rating Scale (DRS) (Mattis, 1976). Other exclusion criteria were a history of psychiatric symptoms or brain surgery or any medical condition not suitable for a nicotine treatment, such as cardiac, renal or hepatic disease, and uncontrolled hypertension. Written informed consent was obtained before their inclusion in the study. Only 9 of the 22 patients completed the study. Ten normal elderly controls (NC) were selected from the general population to match patients for age, gender and education. PD patients and controls were all nonsmokers; either they had never smoked or they had quit at least 2 years ago. 2.2. Procedure Nicotine was supplied to patients by adhesive transdermal patches (Nicoderm) containing 36, 78 or 114 mg. Over a 24-h period, nicotine absorption with these three kinds of patch was 7, 14 and 21 mg, respectively. Given that it is currently no longer possible to obtain placebo patches from the industry, the present study was structured following an open-label design. Patients started the study by applying daily a 7-mg patch for 11 days. On the 11th day, they came to the Movement Disorders Unit for the first assessment session (low-dose assessment), which included measures of both movement and cognition (see description of assessment). The nicotine dose was then increased to 14 mg for another 11 days followed by a 3-day period with 21 mg/day. Three days was long enough for the 21-mg period to assure maximal stability in nicotine blood concentration given that the nicotine blood concentration reaches steady state by the second patch application of a given dosage (Gupta et al., 1993). On the 25th day, patients returned to the unit for the second assessment session (high-dose assessment). Then, they entered a 14-day washout period after which they were seen for the third assessment session (39th day). This baseline measure (39th day) was performed after the nicotinic treatment to control for a possible practice effect. If nicotine improves cognition or movement, performance should be better at the second than at the third session,

S. Lemay et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 31–39

while if there is a learning effect, performance should be better at the third than at the first session. Control subjects were assessed three times, at the same intervals as PD patients (14 days), although they did not receive any pharmacological treatment. On the days of dose increments, patients were kept under observation at the Movement Disorders Unit for a 2-h period. Following application of the nicotine patch, vital signs were periodically monitored. Patches were worn for 24 h and changed each morning at home by the patients themselves at the same time that they took their usual antiparkinsonian medication (always before 9 a.m.). Blood concentration of nicotine with these patches reaches peak level in 2 – 4 h following the application and remains fairly stable for the next 24 h. The assessment sessions occurred in the afternoon and the same investigator administered the tests to all participants. A blood sample was taken at each assessment session for nicotine dosage. Throughout the duration of the study, patients had to complete daily a personal diary in which they recorded the time when the patch was applied and the occurrence of side effects. 2.3. Assessment Motor and cognitive tests were always administered in a fixed order, and alternate forms were used when available (see tests descriptions). Each assessment session included the following motor and cognitive tests: (a) The Eurythmokinesimeter (EKM) (Beuter et al., 1999a) allows the quantification of alternating pointing movements. Using a stylus, subjects have to point to a target on a proximal and a distal metal plate, alternating continuously between one and the other. Each metal plate was divided into four areas including three concentric circles (diameter 1.4, 2.2 and 11.5 mm) and one external area. The distance between the two center targets was 30 cm, and the apparatus was oriented at 30j from the vertical axis. Subjects were instructed to be as fast and as accurate as possible. The test consisted of two 30-s trials completed with the dominant hand. Scores were expressed by a speed – accuracy tradeoff (SAT) computed from the following formula: SAT = t/log(2A/W), where t is the transit time between targets, A is the distance between the two center targets, and W is the distance between the point of the contact and the center target. The lower the SAT score, the better the performance. This test may be considered as an objective and sensitive measure of hand-eye coordination quantifying speed and accuracy of proximodistal arm movements (Beuter et al., 1999a). (b) The Diadochokinesimeter (Diado). This task (Beuter et al., 1999b) allows the quantification of rapid pronation – supination movements of the forearm. Subjects held a ball in each hand and were told to rotate both hands in coordination, as fast as possible and without moving their elbows. The balls were connected to a computerized device, which digitized the signal at 200 Hz. A velocity score was

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computed and expressed in degrees per second. Two trials each 5 s long were averaged. This task has been shown to be sensitive to the bradykinesia in PD (Beuter et al., 1999b). (c) The Unified Parkinson’s Disease Rating Scale (UPDRS) (Fahn and Elton, 1987). The third section (motor examination) of this scale was administered by an experienced neurologist. A given patient was always evaluated by the same neurologist at all three assessment sessions. The neurologists were blind to the experimental design and were not informed of the use of nicotine. We report the global score (total of 108) as well as subscores for tremor (Items 20 – 21, total of 28), rigidity (Item 22, total of 20), bradykinesia (Items 23 – 26 and 31, total of 36) and axial impairment (Items 27– 30, total of 16) (Levy et al., 2000). The UPDRS is frequently used in a test – retest design, although its test – retest reliability has never been formally assessed. However, the UPDRS is known for its good interrater agreement and internal consistency reliability (Martı`nez-Martin et al., 1994; Richard et al., 1994). (d) The Rey Auditory Verbal Learning Test (RAVLT) was the first of a series of six cognitive measures. The test was administered following the procedure described by Lezak (1995). A first 15-word list was orally presented to the subject who had to recall as many words as possible in any order. This procedure was repeated for five consecutive trials (Trials 1 –5). Then, an interference list was presented and recalled by the subject followed immediately by a recall of the first list. A delayed recall of the first list was performed after a 30-min delay (Delayed recall). The test ended with a yes/no recognition in which the subject had to identify only the words from the first list among distractors. Parallel forms of the test (Rey, 1970; Crawford et al., 1989) were used at each of the three assessment sessions. Scores included the total recall (sum of words in Trials 1 – 5), which is known to be sensitive in PD (Taylor et al., 1986). A retrieval efficiency score (Reteff) (Spreen and Strauss, 1998) was also computed as follows: (Delayed recall/15)/ (0.5[1 + HR FP]), where HR (hit rate) was the proportion of words correctly recognized (Recog/15) and FP (false positive) was the error proportion in the recognition trial (distracters not rejected/35). The total recall and Reteff scores are known to possess good test – retest reliability (Lemay et al., 2002). (e) The Stroop Color-Word Test. This attentional task is sensitive to difficulties in inhibiting interfering stimuli (Lezak, 1995). The task includes three conditions. First, subjects had to read as fast as possible a list of four different colors (red, green, blue and yellow) printed in black ink (Reading condition). Second, they had to name the colors of rectangles (red, green, blue and yellow) (Naming condition). Finally, subjects had to name the ink color of words written in a color that conflicted with the word’s verbal content (e.g., blue written in red ink) (Interference condition). Completion time for the Interference condition is reported and expressed in seconds. To remove the verbomotor component, the completion time for the Naming condition

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was subtracted from the completion time for the Interference condition. Completion time scores had previously shown a good test –retest reliability (Lemay et al., 2002). (f) The Alternate Verbal Fluency Test. This test is a useful measure for detecting initiation and shifting deficits. Subjects had to generate as many words as possible in 60 s. Three different types of alternation were required: (a) Phonological alternation, in which the subject had to alternate between words beginning with given letters (C and D); (b) Semantic alternation, where subjects had to alternate between semantic categories (Colors and Occupations); (c) Mixed alternation included two trials in which the subject had to alternate between a semantic category and words beginning with a given letter (Animals and P, Fruit and L). Scores corresponded to the total number of words generated in the four trials. Recent studies have suggested that the alternate fluency test is more sensitive than the more classical verbal fluency test (either phonological or semantic) to the mild cognitive deficits found in PD (Zec et al., 1999). (g) The Letter-Number Sequencing Test (LNseq). This working memory task was administered and corrected in conformity with the instructions in the WAIS-III manual (Wechsler, 1997). Various series of mixed letters and numbers were presented orally to subjects, who had to recall all the items, first naming the numbers in ascending order and then the letters in alphabetical order. To ensure that subjects understood the task, a three-item example was performed by the examiner before beginning the task. The score corresponded to the sum of correct items. Such tests were previously found sensitive to cognitive deficits in PD (Cooper et al., 1991). (h) The 2 and 7 Test. In this attentional test (Ruff et al., 1992), subjects had to mark on a sheet the target digits (2 and 7) interspersed among letters or other digits distracters in horizontal lines. Speed and processing scores were computed and corrected for age and education (see Ruff et al., 1992). The speed score corresponds to the sum of all 2s and 7s detected. The processing score is a ratio score corresponding to the discrepancy between searching for digits among letters and searching for digits among other digits. The higher the ratio, the more the subject benefits from searching in a low-conflict condition (among letters). Both scores have previously been found to be impaired in PD (Paquet et al., 2001). (i) Reaction Time Tests. These tasks (Lepage and Richer, 1996) included a choice reaction time (CRT) and a sequential reaction time test (SeqRT). In the CRT, subjects had to press one of two keys in response to the presentation of the letter A or B on a computer screen. Each stimulus required a response. A fixation cross appeared on the screen followed by one of the two letters, which remained on the screen until the subject pressed the button. Subjects always used the left index finger to press the ‘‘A’’ key and the right index to press the ‘‘B’’ key. In the SeqRT, subjects had to reproduce, on the keypad, a sequence of three letters made up of the

letters A and B (e.g., ABA and BAA). Presentation and response procedures were identical to the CRT condition. The sequence on the screen only disappeared after the third key press and no feedback was provided about the accuracy of the response. Errors were excluded from the analysis. Median RT is reported for the 60 trials of both CRT and SeqRT. For the SeqRT task, only the RT for the first response is reported. This score reflects the planning time for the entire response sequence. 2.4. Statistical analysis Distribution of data was first observed visually to verify if data met the normality requirement for statistical analysis. If a score exceeded three standard deviations from the mean, data were winsorized symmetrically (Wilcox, 2001). For the variables showing a distribution that did not fit into the normal curve, an appropriate transformation was applied. The latter transformation was done for the statistical analyses, and the nontransformed data are reported in Tables 2– 4. Results on motor and cognitive tests were compared between PD patients and controls and across assessment sessions using an analysis of variance (ANOVA) for repeated measures with one within factor (Session) and one between factor (Group). The nicotine effect was analyzed with the Session  Group interaction (S  G), with the exception of the UPDRS scores, for which nicotine effect was revealed by a Session main effect, given that this scale was not administered to control subjects. Significant results ( P < .05) were further processed by post hoc comparisons using a Bonferroni correction for multiple comparisons.

3. Results 3.1. Sample description Thirteen of the 22 patients (59%) did not complete the study. Ten of these patients dropped the study because of side effects including dizziness, nausea, vomiting, increased blood pressure and intestinal cramps (see Lemay et al., 2003 for a detailed description). The other three patients withdrew from the study for reasons unrelated to the nicotine treatment (medical or personal reasons). These 13 patients included the only three females enrolled in the study, so that the nine patients who completed the study were male. Table 1 presents the characteristics of the control subjects and PD patients who completed the study. There was no difference between PD patients and controls in terms of age and education. However, PD patients scored higher than controls on the GDS [t(17) = 2.43, P=.027] and lower on the DRS scale [t(17) = 2.25, P=.038], although scores in PD patients did not reach the cutoff value for depression and dementia, respectively. For one patient, UPDRS, Diado, CRT and SeqRT scores were

S. Lemay et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 31–39 Table 1 Sociodemographic and clinical characteristics of the sample

Age Education GDS score DRS score Hoehn and Yahr stage Disease duration (years)

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Table 3 UPDRS ratings for PD patients at each assessment session

PD patients (n = 9), mean (S.D.)

Controls (n = 10), mean (S.D.)

64.00 (8.00) 12.65 (4.67) 5.67 (2.40) 136.11 (5.67) 2.11 (0.22) 6.00 (3.08)

63.40 13.30 2.44 140.50

(6.74) (5.52) (2.92) (2.37)

not computed because of missing data. The detection of one outlier required the winsorization of data obtained on the Stroop and the SeqRT tasks. EKM data were log transformed to normalize distribution. 3.2. Blood sample According to the patients’ diaries, compliance with the nicotine treatment was excellent. Patches were changed daily by all the patients throughout the study. Mean nicotine blood concentration for the PD patients was 11.74 F 1.66 ng/ml at the low-dose assessment, 33.57 F 10.22 ng/ml at the high-dose assessment and 1.36 F 0.53 ng/ml following the washout period (third assessment session). These results were statistically different between each pair of assessment sessions [ F(2,16) = 53.15, P < .001]. Following the washout, no significant concentration of nicotine could be detected. Indeed, nicotine blood concentration below 2 ng/ ml can be attributable to measurement error, given that quality control analysis can reach up to 2 ng/ml by using blank bovine serum. 3.3. Motor tasks Results on the Diado and EKM showed a similar profile (see Table 2). PD patients obtained significantly lower performance than controls on these two motor tasks at each assessment sessions. However, the tasks were not sensitive to a practice effect given that session main effect did not reached statistical significance. S  G interactions were not significant either for these two motor measures, suggesting that nicotine had no effect. In the UPDRS, the total motor score and the rigidity subscore were found to differ across

UPDRS

Motor scores Total motor Bradykinesia Rigidity Tremor Axial

Mean (S.D.) Low dose

High dose

Baseline

23.75 10.81 5.19 2.94 1.75

20.69 9.13 4.00 3.44 1.44

18.88 8.06 3.56 2.88 1.31

(9.66) (4.37) (3.05) (2.60) (1.39)

(9.94) (3.53) (3.39) (3.35) (0.90)

(11.70) (5.88) (3.11) (2.55) (1.16)

F values, F(2,14)

5.38 * 2.55 5.58 * 0.38 1.21

All significant results appear in bold. Given that control subjects were not evaluated on the UPDRS, the effect of nicotine was revealed by a Session main effect. * P < .05.

the assessment sessions (Table 3). Post hoc analyses revealed that these two scores were higher (movement more affected) during low-dose session than following the washout period. However, during high-dose session, these scores did not differ from those obtained during the low-dose session or from those observed following the washout period. A trend analysis on these two scores revealed a significant linear trend [ F(1,7) = 8.30, P=.024 and F(1,7) = 11.06, P=.013 for total and rigidity scores, respectively] without a quadratic trend [ F(1,7) = 0.32, P=.592 and F(1,7) = 0.70, P=.430, respectively]. For all other UPDRS scores including bradykinesia, tremor and axial impairment, results were not significant. 3.4. Cognitive tasks Table 4 presents the cognitive results for each group in the three assessment sessions. PD patients showed significant deficits compared with normal controls in all cognitive tasks, given that the group main effects were all significant. A practice effect was also observed in many cognitive tasks including the Stroop and Alternate Fluency and the speed score for the 2 and 7 Test and SeqRT scores. Practice effects were observed between first and second assessment sessions as well as between first and third assessment sessions but never between second and third assessment sessions. There was no effect of nicotine given that almost all S  G interactions were nonsignificant. The only exception was the significant interaction found for the Interference

Table 2 Motor performance for PD patients and controls at each assessment session Motor scores

EKM SAT Diado Velocity

Mean (S.D.)

F values

Low dose

High dose

Baseline

PD NC

0.188 (0.040) 0.156 (0.031)

0.184 (0.035) 0.156 (0.028)

0.176 (0.030) 0.148 (0.026)

PD NC

44.12 (12.09) 57.61 (20.90)

41.29 (14.24) 61.98 (18.76)

46.21 (21.58) 64.21 (20.54)

All significant results appear in bold. * P < .05.

Session

Group

SG

F(2,34) 1.73

F(1,17) 5.13 *

F(2,34) 0.04

F(2,32) 0.94

F(1,16) 4.84 *

F(2,32) 0.58

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Table 4 Cognitive performance of PD patients and controls at each assessment session Cognitive scores

Mean (S.D.) Low dose

RAVLT Total

High dose

Session, F(2,34)

42.11 (9.78) 54.00 (7.54) 0.54 (0.22) 0.75 (0.13)

40.78 52.20 0.53 0.82

0.60

8.64**

0.11

0.62

8.99**

0.94

41.78 52.30 0.54 0.77

PD NC

62.70 (18.67) 64.92 (19.13)

59.30 (13.54) 43.54 (13.86)

56.89 (15.01) 40.57 (9.35)

16.81***

2.55

7.23**

PD NC

37.33 (14.10) 52.30 (9.24)

42.22 (15.16) 56.30 (12.32)

44.89 (14.60) 58.30 (9.32)

14.64***

6.43 *

0.19

PD NC

9.22 (3.87) 12.00 (2.49)

9.22 (3.80) 12.30 (2.31)

9.89 (2.76) 12.70 (2.95)

4.59 *

0.11

PD NC PD NC

213.67 (29.84) 305.70 (32.51) 1.094 (0.103) 1.211 (0.091)

229.33 329.80 1.127 1.222

55.96***

1.61

2.01

6.82 *

0.15

CRT a Median reaction time (ms)

PD NC

534.13 (67.98) 459.05 (68.62)

558.13 (85.39) 447.15 (58.55)

541.63 (111.95) 447.10 (70.19)

0.23

7.68**

1.01

SeqRT a Median reaction time (ms)

PD NC

865.19 (181.27) 690.10 (104.93)

816.00 (104.64) 670.60 (83.90)

788.44 (130.49) 663.40 (115.80)

5.64**

7.36 *

1.28

Stroop Interference

(11.16) (7.98) (0.20) (0.16)

Group, F(1,17)

S  G, F(2,34)

Baseline

PD NC PD NC

Reteff

(10.95) (6.91) (0.22) (0.16)

F values

Alternate fluency

LNseq Total score

2 and 7 Speed Processing

(38.33) (21.06) (0.087) (0.138)

224.33 336.80 1.081 1.185

(43.16) (29.66) (0.048) (0.116)

2.14

8.45**

All significant results appear in bold. a For CRT and SeqRT, degrees of freedom were as follows: F(2,32) for the Session effect and the S  G interaction and F(1,16) for the Group effect. * P < .05. ** P < .01. *** P < .001.

subtask of the Stroop. Separate t tests revealed that the two groups did not differ at the lowest nicotine dose [t(17) = 0.26, P=.801], but patients became impaired in comparison with controls at the high-dose assessment [t(17) = 2.50, P=.023] as well as after the washout period [t(17) = 2.88, P=.010].

4. Discussion 4.1. Nicotine on PD movement and cognition The results of the present study confirm those of Vieregge et al. (2001) showing that nicotine neither improves nor worsens motor performance in PD. Motor and cognitive deficits remain unchanged during nicotine treatment. These results contradict those of Ebersbach et al. (1999), which showed poorer motor performance following a 12-h exposure to transdermal nicotine. Methodological factors may

account for these differences. As in the Vieregge et al. (2001) study and contrary to that of Ebersbach et al. (1999), nicotine treatment in the present study extended over a longer period (3 weeks). Moreover, in our study and in that of Vieregge et al. (2001), patients remained on stable dopaminergic medication, whereas in the Ebersbach et al. (1999) study, patients went off their usual antiparkinsonian medication during the nicotine treatment. Preliminary results published by Kelton et al. (2000) suggested that both acute and chronic administration of nicotine might improve cognitive and motor functioning in PD. However, very few cognitive tests in the chronic phase of this study were reported as being statistically significant, and some trends identified by the authors were far from significant. Moreover, they had no control group, and the improvement reported may be explained by a practice effect. The persistence of the improvement following the washout period reinforces the idea of a practice effect. In the present study, performance improvements were

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clearly attributable to a test – retest learning effect and not to any beneficial effect of nicotine, given that no S  G interaction could be observed for most measures. Among the motor measures, only the total motor score and the rigidity subscore of the UPDRS were found to differ across the three assessment sessions. This effect was not in proportion of the administered dose of nicotine, so that it could more likely be a progressive improvement related to the repetition of the assessments. This hypothesis is supported by the significant linear trend on these measures. Such a progressive improvement across the sessions may be related to the UPDRS poor test – retest stability. Interrater agreement and internal consistency have been well documented for this scale, but there still is a need to evaluate the temporal stability and test – retest reliability in PD patients. In contrast, the other motor measures used in this study (Diado and EKM) showed good test –retest reliability and temporal stability across assessment sessions. These objective measures were found sensitive in distinguishing PD patients from normal controls, but they did not reveal any effect of nicotine on bradykinesia and motor coordination. Results obtained with the cognitive tasks revealed only one S  G interaction, and this was observed with the Stroop test. There are two possible explanations for this result. First, given that Stroop performance in PD patients was constant across sessions, while it improved in normal controls, it is possible that the disease itself will prevent patients from showing a practice effect on this task. Alternatively, one might suggest that nicotine significantly worsens performance and that the treatment itself may have prevented the practice effect on the Stroop task. If so, patients’ performance should have improved after the cessation of treatment. However, patients’ performance following the washout period revealed that this was not the case. 4.2. Alternative hypotheses One possible explanation for the absence of differences between any of the three assessment sessions could be that nicotine exerts a significant effect at the very first session (low dose) and that this effect does not vary as a function of dose. However, this hypothesis is unlikely, given that patients still remained impaired at each assessment session compared with controls. Moreover, this would also imply that nicotine has a persistent effect even after a 14-day washout period. However, the pharmacokinetic data argue against this explanation, given that the half-life of a 21-mg patch is 4.2 h and that nicotine blood concentration falls below detectable levels in 10 –12 h (Gorsline et al., 1993). Moreover, the absence of nicotine following the washout period was confirmed by the blood sample analysis. On the other hand, previous studies have suggested that a nicotine (or nicotinic agonist) effect on cognition or motor functioning may persist even when nicotine is no longer detectable in blood. In animals, such an effect has been described to last 24 h (Terry et al., 1993) after cessation of an acute

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treatment and up to 2 weeks after a chronic treatment (Levin et al., 1990b). The evidence suggests that this persistent effect is related to the direct action of nicotine and not to the behavioral experience that may occur during the influence of nicotine (and that may influence performance even after a withdrawal). Indeed, nicotine-treated rats learned a radial maze faster than controls when training began 1 week after nicotine withdrawal (Levin et al., 1992). The possible persistent effect of nicotine could be mediated by a nicotine induction of neurotrophic factors (Belluardo et al., 2000). Prolonged fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) elevation after withdrawal of an acute nicotine exposure has been observed in rats, with effects on various brain structures including the hippocampus (Kenny et al., 2000) and the striatum (Terry and Clarke, 1994; Maggio et al., 1998; Roceri et al., 2001). However, all studies showed that this increase in neurotrophic factors returned to baseline values 24– 48 h after nicotine withdrawal. It is not known whether a long-term nicotinic treatment over several weeks will produce elevated neurotrophic factors for a longer period after withdrawal. Another possible mechanism for the persistent effect of nicotine is an up-regulation of nicotinic receptors in the brain. Chronic nicotine infusion in animals revealed that binding to nicotinic receptors was increased up to 8 days after withdrawal (Collins et al., 1990; Pietila¨ et al., 1998; Kassiou et al., 2001). One study showed a direct correspondence between elevated cortical nicotinic binding and enhanced locomotor activity (Ksir et al., 1985). These studies suggest that binding returns to control levels between 1 and 5 weeks after withdrawal, although the methodological design of the studies did not allow one to determine exactly when the nicotinic receptor up-regulation returned to baseline level. It should be stressed that the presumed persistent effect of nicotine remains a controversial issue. Contrary to their previous results, Levin et al. (1996) have more recently demonstrated no persistent effect of nicotine on working and reference memory or response latency in rats. Moreover, a 7-week nicotine treatment that improved locomotor activity in mice has no effect 24 h after the nicotine withdrawal (Ga¨ddna¨s et al., 2000). Another evidence against a persistent effect of nicotine comes from a case study evaluating the effect of nicotine patches in PD, which suggested that there was no residual effect after a 2-week washout period (Fagerstrom et al., 1994).

5. Conclusion This study suggests that a long-term nicotinic treatment has no real benefit against the motor and cognitive deficits of PD. This should not, however, be considered as a sufficient reason to give up any effort to investigate nicotinic agents in PD. Interesting results were obtained recently in MPTP-treated monkeys using Altinicline (SIB-1508Y), a

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compound that is selective for the a4h2 nicotinic receptors (Schneider et al., 1999). This nicotinic agonist has been shown effective against motor and cognitive deficits in the animal MPTP model of PD. The efficacy and tolerability of such nicotinic agonists should be further investigated in humans.

Acknowledgements This work was supported by the Fonds de la Recherche en Sante´ du Que´bec (FRSQ) and by the Fonds pour la formation de Chercheurs et l’Aide a` la Recherche (FCAR). The authors are grateful to Avantis Pharma for providing the nicotine patches (Nicoderm). The authors thank Chantale Beauvais, Francßoise Be´nard and Hubert Poiffaut for their help with blood samples, pressure monitoring and patient appointment scheduling. Special thanks also to Francß ois Richer for reviewing the manuscript.

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