Material and Method: Ten idiopathic Parkinson’s disease (PD) patients and 9 PDD patients were included to the study. Patients were assessed by neuropsychological test battery and also neurophysiological tests (P300, MRCP and RT) before rivastigmine treatment and after the sixth month of treatment.

Results: PDD patients showed statistically significant improvement in neuropsychological tests related memory and shortening of P300 latency. However, we didn’t found any statistically significant changes in the measurements of MRCP and RT tests after therapy.

Conclusion: Our study has suggested that while rivastigmine therapy improve cognitive functions in PDD, it doesn’t cause any side effects on motor function of patients.

1- A diagnosis of PD,
2- PD diagnosis must have preceded diagnosis of dementia by at least 2 years,
3- MMSE score <26,
4- The activities of daily life were compromised by dementia,
5- At least two of the cognitive functions listed below must have been compromised:
a) Naming months backwards or counting backwards from 100 in increments of 7 (at least two mistakes),
b) Verbal fluency or ability to draw a clock,
c) MMSE pentagon drawing,
d) Recalling three words.
6- Absence of major depression, as shown using the Geriatric Depression Scale [GDS],
7- Absence of delirium,
8- Absence of any disease with an uncertain diagnosis.

Control group (PD with no dementia): This group contained idiopathic PD patients. PD was diagnosed by clinical examination (resting tremor, cogwheel rigidity, bradykinesia/akinesis, postural instability, and flexor posture) using the UK PD society Brain Bank clinical diagnostic criteria. Dementia was excluded using the tests described above. We excluded patients diagnosed with secondary parkinsonism (caused by infection, drugs, toxins, vascular disease, trauma, or an intracranial mass), Parkinson-plus syndromes, any inherited degenerative disease, major depression, or delirium; These latter conditions were excluded by historytaking, clinical examination, and brain magneticresonance imaging and any patient for whom rivastigmine was contraindicated. Patients who met the inclusion criteria completed forms giving demographic details. We recorded the findings of clinical examinations, and drugs used. In addition, the “Unified Parkinson’s disease Rating Scale” (the UPDRS) and the Hoehn and Yahr Staging (HYS) module were administered to all patients of both groups at months 0 and 6. To evaluate cognitive functioning, a neuropsychiatric test battery was administered to all patients, and P300 recordings were obtained. As acetylcholinesterase inhibitors used to treat PDD can exacerbate PD symptoms, Movement-Related Cortical Potential (MRCP) and Reaction Time (RT) tests were performed to evaluate such effects. In the test group, rivastigmine was slowly titrated upward after initial testing. The initial dose was 1.5 mg twice daily and was increased by 3 mg monthly. The maximum active best-tolerated dose was maintained. The average dose was 7.8 mg/day (range, 6-12 mg/day). Some patients who could not tolerate the side-effects of the drug were provided with drug-containing transdermal patches. All neuropsychological and neurophysiological tests were performed with patients in “drug-on” periods.

Neuropsychological testing was performed using a test battery administered over ~40–50 min that yielded information on various cognitive fields. Testing was conducted in a silent room and patients were not distracted. Daily life activities were evaluated using the Mini-Mental test (the MMSE) and the Instrumental Activities of Daily Living (IADL) Scale; the tests evaluated various cognitive fields. Patients deteriorated clinically as IADL scores increased. Accompanying psychiatric symptoms were evaluated using the neuropsychiatric inventory (NPI). All patients were administered the Rey Auditory Verbal Learning Test (Rey AVLT) to test verbal memory, the Wechsler Memory Scale Edition III (WMS-III) visual memory subtest to evaluate visual memory, and the trail-making test (parts A and B) and Luria’s drawing test to assess executive functioning. The ‘forward and backward digit span’ test was used to evaluate attention; the Similarities Test to evaluate abstract reasoning; and the F-A-S Test to explore verbal fluency.

P300 recordings were obtained using the Nihon Kohden Neuropack 8 device. The electrode placement points were first specified, and the head cleaned using alcohol followed by rubbing with a gel that abraded the skin. Ag/AgCl disk electrodes were used during recording; active electrodes were placed on the Fz and Cz locations and the reference electrode on the earlobe. All patients wore headphones. The stimulation method was the standard auditory “oddball paradigm”, which required patients to distinguish and count treble tones (2 kHz) that were presented at a frequency of 20% of bass tones (1 kHz). Patients were asked to count the numbers of sounds with a treble tone. Each screen, analyzed at 1-s intervals, consisted of 10 small squares presented 0.1 s apart. Thirty potentials developing when targets (stimulants) were distinguished and counted were averaged, and the traces evaluated. The P300 latency and the peak-to-peak P300 amplitude were measured in each trace obtained from the Fz, Cz, and Pz electrodes.

Movement-Related Cortical Potential test recordings were obtained using the Nihon Kohden Neuropack 8 device. The electrode placement points were first specified, and the head cleaned using alcohol followed by rubbing with a gel that abraded the skin. Ag/AgCl disk electrodes were used during recording; active electrodes were placed at the C3, Cz, and C4 locations, and the reference electrode on the earlobe. To trigger the MRCP wave complex, patients were instructed to perform intermittent wrist extensions, and EMG activities were measured via surface electrodes placed on the musculus extensor digitorum communis. The frequency limits were maintained at 0.1-50 Hz. The total analysis time was 5 s, including “back averaging” commencing 3,500 ms before EMG activity. An average of 20 MRCP responses was collected. The test was performed twice and traces from the C3, Cz, and C4 electrodes were analyzed for: (a) Latency of the readiness potential, (b) amplitude of the readiness potential, (c) amplitude of the early readiness potential, (d) amplitude of the late readiness potential, (e) latency of skilled performance positivity, and (f) amplitude of skilled performance positivity. Two measurements were used to estimate the latency of the readiness potential; these were: (a) Time from when pre-motion negativity commenced to when EMG activity commenced, and (b) time from when pre-motion negativity commenced to when the negativity peaked.

To measure reaction time (RT), each patient, with both eyes open, was seated (twice) in front of a monitor, at a distance of at least 1 m. The monitor was used to record visually stimulated potentials. Black-andwhite squares were used as stimuli. Induction of a stimulus ensured triggering of the device. Each stimulus was induced by the technician administering the test, without prior notice to the patient, and the patient was asked to make a quick extension of the wrist as soon as the color of the squares on the screen changed. Simultaneously, EMG activities were measured via surface electrodes placed on the musculus extensor digitorum communis. The analysis time was 1 s. The latency to the time of commencement of EMG activity was taken to be the reaction time latency.

The SPSS software was used to perform statistical analyses. Wilcoxon’s rank-sum test was used to analyze descriptive data, and a paired samples t-test to compare data from the test and control groups obtained at months 0 and 6.

Initially, when data from the two groups were compared, no significant differences were found in the UPDRS and HYS scores (p=0.19). When IADL scores were compared, the PDD (test) group scored significantly higher than the control group (13.3 vs. 5.9; p=0.01). The total NPI score did not differ significantly between the two groups (6.7 vs. 2.7; p=0.39). Also, no significant difference was identified in NPI sub-group analyses. Demographic data of all patients are shown in (Table 1).

Click Here to Zoom

Table 1: Socio-demographic and clinical aspects

After rivastigmine treatment, the MMSE score was significantly higher in the test (PDD) group at month 6 compared to the baseline value (p=0.04), but this was not true of the control group. The AVLT-5 (assessing the influence of AVLT on learning) and AVLT-7 (measuring long-term memory) sub-parameters increased significantly in the test group by month 6 compared to the baseline values (p=0.04, p=0.01, respectively). In the control group, the value of the AVLT-5 sub-parameter did not change over time, but a significant increase in the AVLT-7 value was evident at month 6 compared to baseline (p=0.007). The K-A-S Test value increased significantly in the test group by month 6 (p=0.01), but not in the control group. No significant 6-month change in WMS III Visual Memory sub-test data measuring early and late recall (subtests 1 and 2) was found in either group (p=0.1 vs. p=0.3; test vs. control). In terms of the WMS III similarity sub-test scores, a slight (but not significant) difference was evident between the two groups at month 6 (p=0.2). The results of the trail-making test (parts A and B) and the forward and backward digit span test did not differ between groups at the end of month 6.

In terms of P300 latency (at the Cz, Pz, and Fz electrodes), the dementia (test) group exhibited significant shortening at month 6 (p=0.05, p=0.03, and p=0.03, respectively). In the control group, however, the increase was not significant. The P300 amplitude did not differ between groups at the end of month 6. All data are summarized in (Table 2). Pre- and posttreatment P300 traces from a dementia patient are shown in Figures 1 and 2 respectively.

Click Here to Zoom

Table 2: P300 results

Click Here to Zoom

Figure 1: .

Click Here to Zoom

Figure 2: .

At the end of treatment, a slight increase was evident in the UPDRS tremor subscale score of the dementia group, but this was not significant (p<0.08). No significant change was evident between pre-and posttreatment MRCP measurements of dementia patients following rivastigmine treatment. A significant decrease was evident only in the amplitude of the readiness potential of control patients. No significant change was evident when any other between-group pair of parameters was compared. No significant betweengroup difference was observed, at either month 0 or 6, in RT measurements. Changes in MRCP C3 electrode data and RT results are shown in Table 3. The MRCP trace of a dementia patient and the RT trace are shown in Figures 3 and 4.

Click Here to Zoom

Table 3: Changes in MRCP C3 electrode data and RT results

Click Here to Zoom

Figure 3: .

Click Here to Zoom

Figure 4: .

Previous epidemiological studies assessing the risk of PDD found that the risk of dementia increased with advanced age (regardless of age at disease onset)¹⁰; a low level of education⁹; long duration of disease; and the severity of disease symptoms¹¹. The average ages of the patients in our two groups were similar, as were their educational levels. However, the PD duration of the dementia group was longer than that of the control group. It must be remembered, however, that our reason for inclusion of PD patients without dementia was, first, to assess whether their motor functions would deteriorate by the end of month 6 in the absence of rivastigmine therapy. Our other purposes were to assess whether regression in cognitive functioning would occur over the 6-month period, attributable to the degenerative nature of PD; and to observe whether the P300 latency would become extended. We did not wish to compare between-group differences in the effects of the drug, but rather to neurophysiologically evaluate the natural 6-month disease course of each control patient. We are thus of the view that the difference in PD duration between the two groups did not influence our results.

No significant difference in IADL scores before or after treatment was evident in the dementia group. Although the absence of any influence of such improvement on functional capacity may be attributable to the short follow-up duration. The IADL is relatively less effective than other tests evaluating daily life activities and may have failed to reveal the effectiveness of treatment. We consider that such effectiveness could be rendered more visible by employing scales that evaluate daily life activities in more detail.

The prevalence of depression was 9% in PD and 13% in PDD patients¹². In our control group, depression was considerably more prevalent than in PDD patients. This may be attributable to our study design, because the Geriatric Depression Scale (GDS) was used. Using a GDS scale, patients who scored 15 points or over were excluded from the study. This might explain why fewer patients with depression were evident in the dementia group.

The prevalence of hallucinations in PD patients ranges from 25% to 40% and from 45% to 65% in PDD patients¹³. It has been suggested that visual hallucinations are precursors of dementia^14,15. One of the nine patients in our dementia group reported visual hallucinations, but no hallucinations were reported in the control group. The frequency of hallucinations in the single dementia patient mentioned was reduced following rivastigmine treatment.

In PDD patients, attention and executive functions are primarily affected¹⁶. PDD patients exhibited significant impairment (compared to controls) in the digit span test and also in the trail-making test. Although slight improvements were evident after rivastigmine therapy, these were not significant. It may be that our sample size was too small to allow improvements to be detected; this is a limitation of our study.

When executive functioning was evaluated, the test group was significantly more impaired than the control group. Although a slight improvement was evident after rivastigmine therapy, this was not significant. In the control group, however, such functioning deteriorated over the 6 months. This may be attributable to the degenerative process of PD. Thus, when the two groups were compared, it appeared that rivastigmine stopped such deterioration. Previous studies on rivastigmine also showed that the drug improved executive functioning^7,17.

A general overview of neuropsychological test results revealed significant differences between the dementia and control groups in all of memory, attention, and executive functioning, and that improvement in the dementia group following treatment was limited to memory features only. It might be argued that rivastigmine significantly improves memory by exerting a cholinergic influence but fails to markedly improve executive functioning, considering that deficits in the mesocortical and nigrostriatal pathways are more prominent than are cholinergic deficits in terms of the pathogenesis of executive functioning.

The P300 latency is extended in patients with AD and those with mild forms of cognitive disease, compared to normal controls^3-6. The test has also been used to evaluate the effectiveness of AD treatment, because impairment in cognitive functioning has been correlated with impairment evident in the P300 test, and the P300 latency decreased with improvement in cognitive functioning evident by week 24 of drug treatment^6,18. In many previous studies, comparisons of PD and normal control patients have shown that P300 latency was greater in PD patients¹⁹. Although the presence and type of dementia in PDD patients can be determined using clinical and neuropsychological tests, the presence and (to an extent) the severity of dementia may also be assessed using the P300 test, which is an electrophysiological method of evaluation⁴. Studies comparing P300 latencies in PDD and PD patients have shown that the PDD groups exhibited extensions of latency^20,21. The P300 test has been used to evaluate the effectiveness of AD treatment, but has not been previously employed to evaluate the effectiveness of PDD treatment. In (control) PD patients without dementia, a slight increase in P300 latency was evident at 6 months, but PDD patients who underwent 6 months of rivastigmine therapy exhibited a statistically significant shortening of latency compared to the baseline value. Our findings are important both because, as shown previously, the P300 latency was extended in PDD patients; because this parameter may be objectively used during follow-up and to monitor drug effectiveness; and because latency was decreased by treatment.

The principal side-effect of rivastigmine was an increase in tremor in most PD patients, but the drug did not significantly aggravate bradykinesia or rigidity^7,8,22. In the present study, the MRCP and RT tests were used to this end. MRCP variations in PD patients parallel clinical exacerbation of the disease²³. In our present study, no significant change at 6 months, in either the latency or amplitude of the readiness potential, was evident in either the control or dementia group, suggesting that motor functions (especially, bradykinesia) were not aggravated after rivastigmine therapy.

The RT test has been used to monitor motor slowdown in untreated compared to treated groups²⁴. In the dementia group, a non-significant improvement was observed, suggesting that attention was mildly improved by rivastigmine therapy. Attention is of greater concern in PDD than AD patients. We also showed that no side-effect of motor slowdown was attributable to the drug.

This study had limitation. It examined a relatively small number of subjects. It is necessary increasing the number of patients to expand the study of.

Our study supports the notion that rivastigmine improves cognitive functioning in PDD patients, as assessed both clinically and electrophysiologically, and the drug did not adversely affect motor functioning.

1) Cummings JL. Intellectual impairment in Parkinson’s disease: clinical, pathologic, and biochemical correlates. J Geriatr Psychiatry Neurol 1988; 1: 24-36.

2) Aarsland D, Andersen K, Larsen JP, Lolk A, Nielsen H, Kragh-Sorensen P. Risk of dementia in Parkinson’s disease: a community based, prospective study. Neurology 2001; 56: 730-6.

3) Katada E, Sato K, Ojika K, Ueda R. Cognitive event-related potentials: useful clinical information in Alzheimer’s disease. Curr Alzheimer Res 2004; 1: 63-9.

4) Polich J, Ehlers CL, Otis S, Mandell AJ, Bloom FE. P300 latency reflects the degree of cognitive decline in dementing illness. Electroenceph Clin Neurophysiol 1986; 63: 138-44.

5) Ball SS, Marsh J, Schubarth G, Brown WS, Standburg R. Longitudinal P300 latency changes in Alzheimer’s disease. J Gerontol Med Sci 1989; 44: 195-200.

6) Werber EA, Gandelman-Marton R, Klein C, Rabey JM. The clinical use of P300 event related potentials for the evaluation of cholinesterase inhibitors treatment in demented patients. J Neural Transm 2003; 110: 659-69.

7) Emre M. Aarsland D, Albanese A, et al. Rivastigmine for dementia associated with Parkinson’s disease. N Engl J Med 2004; 351: 2509-18.

8) Poewe W, Wolters E, Emre M, et al. Long-term benefits of rivastigmine in dementia associated with Parkinson’s disease: an active treatment extension study. Mov Disord 2006; 21: 456-61.

9) Emre M, Aarsland D, Brown R. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 2007; 22: 1689-707.

10) Levy G, Schupf N, Tang MX, et al. Combined effect of age and severity on the risk of dementia in Parkinson's disease. Ann Neurol 2002; 51: 722-9.

11) Alves G, Larsen JP, Emre M, Wentzel-Larsen T, Aarsland D. Changes in motor subtype and risk for incident dementia in Parkinson's disease. Mov Disord 2006; 21: 1123-30.

12) Aarsland D, Ballard C, Larsen JP, McKeith I. A comparative study of psychiatric symptoms in dementia with Lewy bodies and Parkinson’s disease with and without dementia. Int J Geriatr Psychiatry 2001; 16: 528-36.

13) Aarsland D, Litvan I, Larsen JP. Neuropsychiatric symptoms of patients with progressive supranuclear palsy and Parkinson’s disease. J Neuropsychiatry Clin Neurosci 2001; 13: 42-9.

14) Aarsland D, Andersen K, Larsen JP, et al. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 2003; 60: 387-92.

15) Krige D, Carroll MT, Cooper JM, et al. Platelet mitochondrial function in Parkinson’s disease. Ann Neurol 1992; 32: 782-8.

16) Emre M. What causes mental dysfunction in Parkinson’s disease. Mov Disord 2003; 18: 63-71.

17) Wesnes KA, Mckeith I, Edgar C, et al. Benefits of rivastigmine on attention in dementia associated with Parkinson disease. Neurology 2005; 65: 1654-6.

18) Katada E, Sato K, Sawaki A. Long-term effects of donepezil on p300 auditory event-related potentials in patients with Alzheimer’s disease. J Geriatr Psychiatry Neurol 2003; 16: 39-43.

19) Prabhakar S, Syal P, Srivastava T. P300 in newly diagnosed non-dementing Parkinson’s disease: effect of dopaminergic drugs. Neurol India 2000; 48: 239-42.

20) Tanakaa H, Roberto D, Pascual-Marquia RD. Event related potential and EEG measures in Parkinson’s disease without and with dementia. Dement Geriatr Cogn Disord 2000; 11: 39-45.

21) Matsui H, Nishinaka K, Oda M, Kubori T, Udaka F. Auditory event-related potentials in Parkinson's disease: prominent correlation with attention. Parkinsonism Relat Disord 2007; 13: 394-8.

22) Emre M. Treatment of dementia associated with Parkinson's disease. Parkinsonism Relat Disord 2007; 13: 457-61.

23) Colebatch JG. Bereitschafts potential and movement- related potentials: origin, significance, and application in disorders of human movement. Clin Neurophysiol 2007; 118: 381-90.

24) Camicioli R, Wieler M, Frias C, Martin W. Early, untreated Parkinson’s disease patients show reaction time variability. Neuroscience Letters 2008; 441: 77-80.