Transdermal Rivastigmine Treatment Does Not Worsen Impaired Performance of Complex Motions in Patients with Alzheimer’s Disease

• Introduction
• Subjects and Methods
• Subjects
• Comparison Between AD Patients, MCI Patients, and Controls
• Rivastigmine Study
• Methods
• Peg Insertion
• CRT
• Statistics
• Ethics
• Results
• Comparison Between AD Patients, MCI Patients, and Controls
• Rivastigmine Study
• Correlation Analysis
• Discussion
• Acknowledgments
• References

Background: There is a debate about the deterioration of fine motor behavior during treatment with cholinesterase inhibitors. Methods: We used an instrumental motor test, which demands a complex motion series. Thereby we assessed motor function in patients with Alzheimer’s disease (AD), in patients with mild cognitive impairment (MCI), and in controls. We also performed this task and a complex reaction time paradigm (CRT) during a six-week open-label safety study using transdermal delivery of the cholinesterase inhibitor rivastigmine. Objectives: To investigate (1) the performance of complex movements during deterioration of cognitive function and (2) the impact of rivastigmine on fine motor behavior and CRT outcomes in AD patients. Results: There were significant differences in the motor test outcomes, particularly when performed with the left non-dominant hand, between controls and patients with AD and MCI. Rivastigmine did not deteriorate assessed fine motor skills and CRT results. Conclusion: Our study shows an impaired carrying out of complex motion series during neurodegeneration associated with cognitive dysfunction. Rivastigmine selectively inhibits the predominant cortical and hippocampal G1 cholinesterase isoform; therefore, hypothetically no deterioration of fine motor behavior appeared during transdermal rivastigmine treatment. We assume that a putative drug-induced increase in speed and attention did not offset a deterioration of motion performance because we found no significant changes in the CRT results.

Introduction

There are reports on the deterioration of fine motor behavior during treatment with cholinesterase inhibitors, but concomitant application of typical and atypical neuroleptics has confounded study outcomes or case reports in patients with Alzheimer’s (AD) or Parkinson’s disease (PD) with dementia [1] [7] [22] [32]. A further drawback of these reports may be a missing compliance control of AD individuals due to oral administration of cholinesterase inhibitors with their sometimes nausea-inducing effects. One placebo-controlled trial showed a discrete, non-significant improvement in the smoothness of hand movements following oral intake of donepezil during a 12-week interval with the use of a standardized handwriting paradigm [6]. This positive effect was independent of changes in cognitive function and confirmed outcomes of a study suggesting normalization of disturbances in the motor cortex of patients with AD treated with donepezil [14]. Because writing with the non-dominant hand is rather complex and demands a certain cognitive load and because hand dominance may influence the outcome when motor activity is assessed [29], we suggest additional use of simpler instrumental motor tests to address the issue of the impact of cholinesterase inhibition on motion. A standardized peg-insertion procedure is such a tool. It requires conduction of a complex motion series. This simpler instrumental motor test reflects motor impairment in PD patients and their response to various antiparkinsonian drugs [17] [19]. It resembles pegboard testing. This instrumental tool showed no significant change in outcome during an open-label treatment with donepezil during an interval of 12 weeks, whereas a non-significant trend for improvement of simple motions appeared within a finger-tapping paradigm [1]. We used the peg-insertion task for evaluation of motor function in patients with AD, in patients with wild mild cognitive impairment (MCI), and in controls. Moreover, we performed this test during an open-label safety study with transdermal delivery of the cholinesterase inhibitor rivastigmine [27] in order to investigate the impact of rivastigmine on fine motor skills. Because cholinergic agents may increase cognitive speed and attention and thus may influence the results of the instrumental motor test, we also simultaneously performed a complex reaction time paradigm (CRT) in series. Our aim was to examine whether a drug-induced increase in speed and attention could offset a putative deterioration of motor performance by transdermal rivastigmine treatment [23] [28].

Subjects and Methods

Subjects

Participants included 12 AD patients (7 men, 5 women, age 78.67 ± 6.11; 64-86 [mean ± SD, minimum-maximum], MMSE: 18.58 ± 5.96; 9-27), 12 MCI patients (9 men, 3 women; age 72.00 ± 6.27; 63-82, MMSE: 28.83 ± 1.19; 26-30), and 12 healthy controls (6 men, 6 women, age 71.33 ± 4.64; 64-80, MMSE: 29.92 ± 0.29; 29-30), who mostly were the spouses of the AD and MCI patients. All participants were right-handed. Handedness was determined by interview [9]. Age did not significantly differ between groups, but the Mini Mental Score Examination (MMSE) score was significantly lower in the AD patients (results not shown). The MMSE was employed as an easy-to-perform descriptive tool for dementia severity [13]. All patients fulfilled the clinical diagnostic DSM IV and NINCDS-ADRDA criteria for AD and the ICD 10 (F.06.7) criteria for MCI. We excluded patients with depression and previous exposure to drugs affecting the dopaminergic system. All participants were also examined by a movement disorders specialist to exclude concomitant Lewy body disease.

Comparison Between AD Patients, MCI Patients, and Controls

We compared the baseline motor test results of the AD patients before rivastigmine application with the outcomes of the MCI patients and the controls.

Rivastigmine Study

AD patients were titrated after their initial performance of both instrumental tests with daily application of patches, which delivered rivastigmine in various dosages (18 mg, 27 mg, 36 mg; mean treatment dosage of all participants: 21.66 ± 3.98; 18-27 mg). We increased rivastigmine dosages only with the patients’ consent at their weekly visits during the 42-day study. We asked AD patients to repeat the motor test and then the CRT at the end of the trial under the same conditions.

Methods

Peg Insertion

We instructed subjects to transfer 25 pegs (diameter 2.5 mm, length 5 cm) from a rack into one of 25 holes (diameter 2.8 mm) in a computer-based contact board individually and as quickly as possible. The distance between the rack and the appropriate holes was exactly 32 cm. The board was positioned in the middle and the task was carried out on each side. When transferring each peg from rack to hole, elbows were allowed to be in contact with the table. We measured the time interval between inserting of the first and the last peg initially with the right and then the left hand. We assessed the time period for this task by using a computer with an accuracy < 100 ms [17] [19]. We added the outcomes of test performance with the right hand (RPGS) and the left hand (LPGS) to the total peg-insertion score (TPGS).

CRT

We assessed motor response with computed measurement of a choice reaction time task. The paradigm presented optical and acoustic stimuli alone or in combination following a standardized pattern. The apparatus consisted of a 31 × 42-cm rectangular surface with two stimulus lights (red and yellow), each coupled to the reaction button electrode, which was 1 cm in diameter and 15 cm equidistant from a central start button electrode. The acoustic signal was provided by a small loud speaker fixed between the two stimulus lights. The subject pressed the central start button with the index finger of his right dominant hand. After the appearance of the yellow stimulus light, the subject had to switch off the light as quickly as possible by moving his finger from the central start button to the reaction button. Thus, this task may also be classified as a discrimination reaction time paradigm, which employs a number of stimuli but requires only one type of response all the time. Reaction time (RT) was considered the elapsed interval between onset of the yellow stimulus light and release of the start button. Movement time (MT) was the time between release of the start button and the pressing of the reaction button [15].

We allowed all participants to familiarize themselves with both instrumental tests for an interval of 60 seconds to reduce or avoid learning and training effects on test performance [20].

Statistics

Data showed a normal distribution according to the Kolmogorow-Smirnow test. As a result, we performed only parametric tests. We used ANCOVA with repeated measures design and included sex, age, MMSE score, and mean rivastigmine dosage as covariates for comparison within the rivastigmine-treated AD patients and ANCOVA with covariates age, MMSE, and sex for comparisons between patients with AD, patients with MCI, and controls. Then we performed a post hoc analysis with planned comparisons. We regarded P-values below 0.05 as significant. In addition, we employed linear regression for correlation analysis.

Ethics

Each subject gave written informed consent. The local ethics committee approved this study.

Results

Comparison Between AD Patients, MCI Patients, and Controls

TPGS and RPGS did not significantly differ between patients with AD or MCI and controls (TPGS: ANCOVA F _{(dF 2, dF 31)} = 1.6, P = 0.22; RPGS: ANCOVA F _{(dF 2, dF 31)} = 0.87, P = 0.43). There were significant differences in LPGS between patients with AD or MCI and controls (ANCOVA F _{(dF 2, dF 31)} = 3.39, P = 0.04). Only the comparisons between MCI patients and controls (P = 0.009) and AD patients and controls (P = 0.005) were significant according to the post hoc analysis. We found no significant impact of the set covariates in the whole analysis.

Rivastigmine Study

There were no significant changes in the instrumental motor test results (TPGS [P = 0.21], RPGS [P = 0.17], LPGS [P = 0.37]) or in the CRT outcomes (RT [P = 0.10], MT [P = 0.42]) during rivastigmine application via the skin. No significant impact of the covariates appeared.

Correlation Analysis

There were significant relations between MT and RPGS before (r = 0.74; P = 0.006) and at the end (r = 0.73; P = 0.01) of rivastigmine treatment. Inverse significant associations between age and RT (start: r = -0.87; P = 0.003; end: r = -0.84; P = 0.001) occurred at both assessment points of the rivastigmine study. We found no clinically relevant side effects or safety problems in our study cohort during rivastigmine application.

Discussion

We show that patients with cognitive disturbances need longer to perform the peg-insertion paradigm in comparison to controls. Our preliminary study confirms a deterioration in the carrying out of complex motion series in chronic neurodegeneration, which predominantly affects cognitive function [2] [3]. This was also shown in disorders with preponderant functional basal ganglia disturbances, i. e., Huntington’s disease or Parkinson’s disease [19] [24] [25]. We confirm that assessment of coordinated movements with the non-dominant hand better reflects disturbances of fine motor behavior during neurodegeneration, probably because of regular training and use of the right hand, both of which contribute to overcoming the motor deficit [18] [19] [21] [24] [25] [30]. Additionally, we suggest that an improved brain plasticity of the dominant brain hemisphere, with secondary compensation of motor deficits, is responsible for the inferior sensitivity of the applied instrumental paradigm to reflect motor disturbances of the upper limbs during a neurodegenerative process [10] [18] [19] [25] [29] [30]. Our outcomes with impaired motor function support the concept of subclinical motor cortex disinhibition during chronic neurodegeneration. This results in functional motor disturbances in AD and may be aggravated by the cholinergic dysfunction and the resulting frontal dysbalance of dopaminergic and cholinergic neurotransmission [4] [11] [14]. Further trials with enrollment of more participants, serial evaluation, and better clinical characterization of the cognitive deficit are needed to address the value of this instrumental tool in dementia-related processes.

There were significant relations between MT, but not RT, and the RPGS scores. This suggests a certain relationship between both instrumental tools in the determination of movement performance. We confirm the known age dependence of RT in AD patients [8] [16] .

We found no deterioration of complex motion performance during transdermal rivastigmine application in our AD patients [26]. There were no significant changes in the outcomes of the CRT, which represents an instrumental tool for assessment of aspects of cognitive speed and attention. Therefore, we suggest that rivastigmine application via patches has no negative effect on fine motor skills. This finding is of interest because there is a controversial debate about the onset of extrapyramidal symptoms during cholinesterase inhibition in AD patients or in patients with parkinsonism in dementia with Lewy bodies [4] [6] [7] [22]. Our outcomes suggest that rivastigmine does not cause an impairment of complex movement performance with its demand for additional various forms of complex information processing with visual, cognitive, and sensory inputs [17] [18] [21]. We suggest that the pharmacological profile of rivastigmine with its selective inhibition of the G1 cholinesterase isoform, which is predominantly located in the cortical and hippocampal regions, contributes to this effect [31].

Limitations of this trial include the low number of participants; the missing comparison to placebo administration, with its putative confounding dopamine-releasing and thus cognition- and motion-improving effect; and the insufficient serial detailed clinical evaluation of cognitive and motor impairment with rating procedures [5] [11] [12].

In conclusion, we show a certain deterioration of complex movement performance in patients with preponderant cognitive dysfunction. This disturbance of fine motor skills does not worsen during treatment with transdermal delivery of rivastigmine.

Acknowledgments

Novartis Pharma, Basel, Switzerland, funded the open-label rivastigmine trial.

References

• 1 Bohnen N, Kaufer D, Hendrickson R, Ivanco L, Moore R, DeKosky S. Effects of donepezil on motor function in patients with Alzheimer disease.  J Clin Psychopharmacol. 2004;  24 354-356
  PubMedSearch in Google Scholar
• 2 Davis K L, Mohs R C, Marin D, Purohit D P, Perl D P, Lantz M. et al . Cholinergic markers in elderly patients with early signs of Alzheimer disease.  JAMA. 1999;  281 1401-1406
  CrossrefPubMedSearch in Google Scholar
• 3 DeKosky S T, Ikonomovic M D, Styren S D, Beckett L, Wisniewski S, Bennett D A. et al . Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment.  Ann Neurol. 2002;  51 145-155
  CrossrefPubMedSearch in Google Scholar
• 4 Di L V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C. et al . Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease.  J Neurol Neurosurg Psychiatry. 2004;  75 555-559
  CrossrefPubMedSearch in Google Scholar
• 5 Fuente-Fernandez R, Stoessl A J. The biochemical bases of the placebo effect.  Sci Eng Ethics. 2004;  10 143-150
  PubMedSearch in Google Scholar
• 6 Hegerl U, Mergl R, Henkel V, Gallinat J, Kotter G, Muller-Siecheneder F. et al . Kinematic analysis of the effects of donepezil hydrochloride on hand motor function in patients with Alzheimer dementia.  J Clin Psychopharmacol. 2003;  23 214-216
  CrossrefPubMedSearch in Google Scholar
• 7 Heinze M, Andreae D, Grohmann R. Rivastigmin and impaired motor function.  Pharmacopsychiatry. 2002;  35 79-80
  Thieme ConnectPubMedSearch in Google Scholar
• 8 Houx P J, Jolles J. Age-related decline of psychomotor speed: effects of age, brain health, sex, and education.  Percept Mot Skills. 1993;  76 195-211
  PubMedSearch in Google Scholar
• 9 Inskip P D, Tarone R E, Brenner A V, Fine H A, Black P M, Shapiro W R. et al . Handedness and risk of brain tumors in adults.  Cancer Epidemiol Biomarkers Prev. 2003;  12 223-225
  PubMedSearch in Google Scholar
• 10 Ioffe M E. Brain mechanisms for the formation of new movements during learning: the evolution of classical concepts.  Neurosci Behav Physiol. 2004;  34 5-18
  CrossrefPubMedSearch in Google Scholar
• 11 Jefferson A L, Cosentino S A, Ball S K, Bogdanoff B, Leopold N, Kaplan E. et al . Errors produced on the mini-mental state examination and neuropsychological test performance in Alzheimer's disease, ischemic vascular dementia, and Parkinson's disease.  J Neuropsychiatry Clin Neurosci. 2002;  14 311-320
  PubMedSearch in Google Scholar
• 12 Knecht S, Breitenstein C, Bushuven S, Wailke S, Kamping S, Floel A. et al . Levodopa: faster and better word learning in normal humans.  Ann Neurol. 2004;  56 20-26
  CrossrefPubMedSearch in Google Scholar
• 13 Koch H J, Gurtler K, Szecsey A. Correlation of Mini-Mental-State-Examination (MMSE), Syndrom-Kurztest (SKT) and Clock test (CT) scores in patients with cognitive impairment assessed by means of multiple regression and response surface analysis.  Arch Gerontol Geriatr. 2005;  40 7-14
  CrossrefPubMedSearch in Google Scholar
• 14 Liepert J, Bar K J, Meske U, Weiller C. Motor cortex disinhibition in Alzheimer's disease.  Clin Neurophysiol. 2001;  112 1436-1441
  CrossrefPubMedSearch in Google Scholar
• 15 Müller T, Benz S, Przuntek H. Choice reaction time after levodopa challenge in parkinsonian patients.  J Neurol Sci. 2000;  181 98-103
  CrossrefPubMedSearch in Google Scholar
• 16 Müller T, Kuhn W, Buttner T, Przuntek H. Colour vision abnormalities and movement time in Parkinson's disease.  Eur J Neurol. 1999;  6 711-715
  CrossrefPubMedSearch in Google Scholar
• 17 Müller T, Kuhn W, Schulte T, Przuntek H. Intravenous amantadine sulphate application improves the performance of complex but not simple motor tasks in patients with Parkinson's disease.  Neurosci Lett. 2003;  339 25-28
  CrossrefPubMedSearch in Google Scholar
• 18 Müller T, Meisel M, Russ H, Przuntek H. Motor impairment influences Farnsworth-Munsell 100 Hue test error scores in Parkinson's disease patients.  J Neurol Sci. 2003;  213 61-65
  CrossrefPubMedSearch in Google Scholar
• 19 Müller T, Schafer S, Kuhn W, Przuntek H. Correlation between tapping and inserting of pegs in Parkinson's disease.  Can J Neurol Sci. 2000;  27 311-315
  PubMedSearch in Google Scholar
• 20 Nutt J G, Lea E S, Van Houten L, Schuff R A, Sexton G J. Determinants of tapping speed in normal control subjects and subjects with Parkinson's disease: differing effects of brief and continued practice.  Mov Disord. 2000;  15 843-849
  CrossrefPubMedSearch in Google Scholar
• 21 Pal P K, Lee C S, Samii A, Schulzer M, Stoessl A J, Mak E K. et al . Alternating two finger tapping with contralateral activation is an objective measure of clinical severity in Parkinson's disease and correlates with PET.  Parkinsonism Relat Disord. 2001;  7 305-309
  CrossrefPubMedSearch in Google Scholar
• 22 Richard I H, Justus A W, Greig N H, Marshall F, Kurlan R. Worsening of motor function and mood in a patient with Parkinson's disease after pharmacologic challenge with oral rivastigmine.  Clin Neuropharmacol. 2002;  25 296-299
  PubMedSearch in Google Scholar
• 23 Robbins T W. The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry.  Psychopharmacology (Berl). 2002;  163 362-380
  CrossrefPubMedSearch in Google Scholar
• 24 Saft C, Andrich J, Meisel N M, Przuntek H, Müller T. Assessment of complex movements reflects dysfunction in Huntington's disease.  J Neurol. 2003;  250 1469-1474
  CrossrefPubMedSearch in Google Scholar
• 25 Saft C, Andrich J, Meisel N M, Przuntek H, Müller T. Congruent deterioration of complex and simple movements in patients with Huntington's disease. J Neural Transm Suppl 2004: 97-104
  Search in Google Scholar
• 26 Siepmann M, Handel J, Mueck-Weymann M, Kirch W. The effects of moclobemide on autonomic and cognitive functions in healthy volunteers.  Pharmacopsychiatry. 2004;  37 81-87
  Thieme ConnectPubMedSearch in Google Scholar
• 27 Tse F L, Laplanche R. Absorption, metabolism, and disposition of [14C]SDZ ENA 713, an acetylcholinesterase inhibitor, in minipigs following oral, intravenous, and dermal administration.  Pharm Res. 1998;  15 1614-1620
  CrossrefPubMedSearch in Google Scholar
• 28 Turchi J, Sarter M. Cortical acetylcholine and processing capacity: effects of cortical cholinergic deafferentation on crossmodal divided attention in rats.  Brain Res Cogn Brain Res. 1997;  6 147-158
  PubMedSearch in Google Scholar
• 29 Van Hilten J J, Middelkoop H A, Kuiper S I, Kramer C G, Roos R A. Where to record motor activity: an evaluation of commonly used sites of placement for activity monitors.  Electroencephalogr Clin Neurophysiol. 1993;  89 359-362
  PubMedSearch in Google Scholar
• 30 van Vugt J P, Siesling S, Piet K K, Zwinderman A H, Middelkoop H A, Van Hilten J J. et al . Quantitative assessment of daytime motor activity provides a responsive measure of functional decline in patients with Huntington's disease.  Mov Disord. 2001;  16 481-488
  CrossrefPubMedSearch in Google Scholar
• 31 Weinstock M. Selectivity of cholinesterase inhibition - Clinical implications for the treatment of Alzheimer's disease.  CNS Drugs. 1999;  12 307-323
  CrossrefPubMedSearch in Google Scholar
• 32 Werber E A, Rabey J M. The beneficial effect of cholinesterase inhibitors on patients suffering from Parkinson's disease and dementia.  J Neural Transm. 2001;  108 1319-1325
  CrossrefPubMedSearch in Google Scholar

Thomas Müller, MD

Department of Neurology

St. Josef Hospital

Ruhr University Bochum

Gudrunstrasse 56

44791 Bochum

Germany

Phone: ++49-234-509-2426

Fax: ++49-234-509-2414

Email: thomas.mueller@ruhr-uni-bochum.de

References

• 1 Bohnen N, Kaufer D, Hendrickson R, Ivanco L, Moore R, DeKosky S. Effects of donepezil on motor function in patients with Alzheimer disease.  J Clin Psychopharmacol. 2004;  24 354-356
  PubMedSearch in Google Scholar
• 2 Davis K L, Mohs R C, Marin D, Purohit D P, Perl D P, Lantz M. et al . Cholinergic markers in elderly patients with early signs of Alzheimer disease.  JAMA. 1999;  281 1401-1406
  CrossrefPubMedSearch in Google Scholar
• 3 DeKosky S T, Ikonomovic M D, Styren S D, Beckett L, Wisniewski S, Bennett D A. et al . Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment.  Ann Neurol. 2002;  51 145-155
  CrossrefPubMedSearch in Google Scholar
• 4 Di L V, Oliviero A, Pilato F, Saturno E, Dileone M, Marra C. et al . Motor cortex hyperexcitability to transcranial magnetic stimulation in Alzheimer's disease.  J Neurol Neurosurg Psychiatry. 2004;  75 555-559
  CrossrefPubMedSearch in Google Scholar
• 5 Fuente-Fernandez R, Stoessl A J. The biochemical bases of the placebo effect.  Sci Eng Ethics. 2004;  10 143-150
  PubMedSearch in Google Scholar
• 6 Hegerl U, Mergl R, Henkel V, Gallinat J, Kotter G, Muller-Siecheneder F. et al . Kinematic analysis of the effects of donepezil hydrochloride on hand motor function in patients with Alzheimer dementia.  J Clin Psychopharmacol. 2003;  23 214-216
  CrossrefPubMedSearch in Google Scholar
• 7 Heinze M, Andreae D, Grohmann R. Rivastigmin and impaired motor function.  Pharmacopsychiatry. 2002;  35 79-80
  Thieme ConnectPubMedSearch in Google Scholar
• 8 Houx P J, Jolles J. Age-related decline of psychomotor speed: effects of age, brain health, sex, and education.  Percept Mot Skills. 1993;  76 195-211
  PubMedSearch in Google Scholar
• 9 Inskip P D, Tarone R E, Brenner A V, Fine H A, Black P M, Shapiro W R. et al . Handedness and risk of brain tumors in adults.  Cancer Epidemiol Biomarkers Prev. 2003;  12 223-225
  PubMedSearch in Google Scholar
• 10 Ioffe M E. Brain mechanisms for the formation of new movements during learning: the evolution of classical concepts.  Neurosci Behav Physiol. 2004;  34 5-18
  CrossrefPubMedSearch in Google Scholar
• 11 Jefferson A L, Cosentino S A, Ball S K, Bogdanoff B, Leopold N, Kaplan E. et al . Errors produced on the mini-mental state examination and neuropsychological test performance in Alzheimer's disease, ischemic vascular dementia, and Parkinson's disease.  J Neuropsychiatry Clin Neurosci. 2002;  14 311-320
  PubMedSearch in Google Scholar
• 12 Knecht S, Breitenstein C, Bushuven S, Wailke S, Kamping S, Floel A. et al . Levodopa: faster and better word learning in normal humans.  Ann Neurol. 2004;  56 20-26
  CrossrefPubMedSearch in Google Scholar
• 13 Koch H J, Gurtler K, Szecsey A. Correlation of Mini-Mental-State-Examination (MMSE), Syndrom-Kurztest (SKT) and Clock test (CT) scores in patients with cognitive impairment assessed by means of multiple regression and response surface analysis.  Arch Gerontol Geriatr. 2005;  40 7-14
  CrossrefPubMedSearch in Google Scholar
• 14 Liepert J, Bar K J, Meske U, Weiller C. Motor cortex disinhibition in Alzheimer's disease.  Clin Neurophysiol. 2001;  112 1436-1441
  CrossrefPubMedSearch in Google Scholar
• 15 Müller T, Benz S, Przuntek H. Choice reaction time after levodopa challenge in parkinsonian patients.  J Neurol Sci. 2000;  181 98-103
  CrossrefPubMedSearch in Google Scholar
• 16 Müller T, Kuhn W, Buttner T, Przuntek H. Colour vision abnormalities and movement time in Parkinson's disease.  Eur J Neurol. 1999;  6 711-715
  CrossrefPubMedSearch in Google Scholar
• 17 Müller T, Kuhn W, Schulte T, Przuntek H. Intravenous amantadine sulphate application improves the performance of complex but not simple motor tasks in patients with Parkinson's disease.  Neurosci Lett. 2003;  339 25-28
  CrossrefPubMedSearch in Google Scholar
• 18 Müller T, Meisel M, Russ H, Przuntek H. Motor impairment influences Farnsworth-Munsell 100 Hue test error scores in Parkinson's disease patients.  J Neurol Sci. 2003;  213 61-65
  CrossrefPubMedSearch in Google Scholar
• 19 Müller T, Schafer S, Kuhn W, Przuntek H. Correlation between tapping and inserting of pegs in Parkinson's disease.  Can J Neurol Sci. 2000;  27 311-315
  PubMedSearch in Google Scholar
• 20 Nutt J G, Lea E S, Van Houten L, Schuff R A, Sexton G J. Determinants of tapping speed in normal control subjects and subjects with Parkinson's disease: differing effects of brief and continued practice.  Mov Disord. 2000;  15 843-849
  CrossrefPubMedSearch in Google Scholar
• 21 Pal P K, Lee C S, Samii A, Schulzer M, Stoessl A J, Mak E K. et al . Alternating two finger tapping with contralateral activation is an objective measure of clinical severity in Parkinson's disease and correlates with PET.  Parkinsonism Relat Disord. 2001;  7 305-309
  CrossrefPubMedSearch in Google Scholar
• 22 Richard I H, Justus A W, Greig N H, Marshall F, Kurlan R. Worsening of motor function and mood in a patient with Parkinson's disease after pharmacologic challenge with oral rivastigmine.  Clin Neuropharmacol. 2002;  25 296-299
  PubMedSearch in Google Scholar
• 23 Robbins T W. The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry.  Psychopharmacology (Berl). 2002;  163 362-380
  CrossrefPubMedSearch in Google Scholar
• 24 Saft C, Andrich J, Meisel N M, Przuntek H, Müller T. Assessment of complex movements reflects dysfunction in Huntington's disease.  J Neurol. 2003;  250 1469-1474
  CrossrefPubMedSearch in Google Scholar
• 25 Saft C, Andrich J, Meisel N M, Przuntek H, Müller T. Congruent deterioration of complex and simple movements in patients with Huntington's disease. J Neural Transm Suppl 2004: 97-104
  Search in Google Scholar
• 26 Siepmann M, Handel J, Mueck-Weymann M, Kirch W. The effects of moclobemide on autonomic and cognitive functions in healthy volunteers.  Pharmacopsychiatry. 2004;  37 81-87
  Thieme ConnectPubMedSearch in Google Scholar
• 27 Tse F L, Laplanche R. Absorption, metabolism, and disposition of [14C]SDZ ENA 713, an acetylcholinesterase inhibitor, in minipigs following oral, intravenous, and dermal administration.  Pharm Res. 1998;  15 1614-1620
  CrossrefPubMedSearch in Google Scholar
• 28 Turchi J, Sarter M. Cortical acetylcholine and processing capacity: effects of cortical cholinergic deafferentation on crossmodal divided attention in rats.  Brain Res Cogn Brain Res. 1997;  6 147-158
  PubMedSearch in Google Scholar
• 29 Van Hilten J J, Middelkoop H A, Kuiper S I, Kramer C G, Roos R A. Where to record motor activity: an evaluation of commonly used sites of placement for activity monitors.  Electroencephalogr Clin Neurophysiol. 1993;  89 359-362
  PubMedSearch in Google Scholar
• 30 van Vugt J P, Siesling S, Piet K K, Zwinderman A H, Middelkoop H A, Van Hilten J J. et al . Quantitative assessment of daytime motor activity provides a responsive measure of functional decline in patients with Huntington's disease.  Mov Disord. 2001;  16 481-488
  CrossrefPubMedSearch in Google Scholar
• 31 Weinstock M. Selectivity of cholinesterase inhibition - Clinical implications for the treatment of Alzheimer's disease.  CNS Drugs. 1999;  12 307-323
  CrossrefPubMedSearch in Google Scholar
• 32 Werber E A, Rabey J M. The beneficial effect of cholinesterase inhibitors on patients suffering from Parkinson's disease and dementia.  J Neural Transm. 2001;  108 1319-1325
  CrossrefPubMedSearch in Google Scholar

Thomas Müller, MD

Department of Neurology

St. Josef Hospital

Ruhr University Bochum

Gudrunstrasse 56

44791 Bochum

Germany

Phone: ++49-234-509-2426

Fax: ++49-234-509-2414

Email: thomas.mueller@ruhr-uni-bochum.de