ORIGINAL RESEARCH
Parallel Improvement of Cognitive Functions and P300 Latency Following Donepezil Treatment in Patients With Alzheimer’s Disease: A Case–Control Study Yu-San Chang,* Hsiang-Lan Chen,† Chung-Yao Hsu,†† Shu-Hui Tang,† and Ching-Kuan Liu††
Purpose: To evaluate the effect of donepezil, one of the cholinesterase inhibitors, on P300 measurements in patients with Alzheimer’s disease (AD) and investigate the relationship between the subfactors of cognitive performance and P300 components. Methods: One hundred outpatients with AD were evaluated for cognitive function (cognitive ability screening instrument) and event-related potentials before and after 22 to 23 weeks of treatment with donepezil (5 mg/day). Twenty age-matched normal control subjects were recruited. Results: The patients with AD showed prolonged P300 and N200 latency, no significant differences in N100 and P200 components, and poor performance in neuropsychological assessments compared with control subjects at baseline. After donepezil treatment, the patients with AD had reduction in P300 latency at Pz lead, which was associated with a parallel improvement in cognitive function in terms of remote memory, recent memory, visual instruction, and orientation. The pre–post treatment difference of P300 latency significantly correlated with the cognitive ability screening instrument score difference and recent memory score difference, respectively. Conclusions: The patients with AD still had intact early sensory processing but impaired higher-level cognitive processes that could influence behavior deviation. The donepezil treatment, which enhances higher-level cognitive processing time, revealed that P300 latency decreases as cognitive capability increases, especially improved in recent memory. Key Words: Alzheimer’s disease, P300, Donepezil, Cognitive function. (J Clin Neurophysiol 2014;31: 81–85)
P
300 is a positive component of event-related potentials (ERPs), which occurs approximately 300 milliseconds after a target stimulus (usually auditory) is given (Picton, 1992). It is considered to be a cognition-related brain potential and thought to reflect the mental processes associated with short-term memory and attention. Because limbic system is involved in these processes and in the generation of P300 (Dierks et al., 1994; Halgren et al., 1998), it is reasonable to use P300 as an indicator when assessing the influences of pharmaceutics on memory function and cognitive process (Dierks et al., 1994). Concerning the neurochemical substrates, GABAergic, cholinergic, noradrenergic, dopaminergic, and serotonergic substrates are known to influence P300 (Frodl-Bauch et al., 1999). However, a relationship between P300 and the cholinergic system has been From the *Department of Neuropsychiatry, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan; Faculty of Nursing Department, Meiho University, Pingtung, Taiwan; †Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan; and ††Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, China. Address correspondence and reprint requests to Chung-Yao Hsu, MD, PhD, Department of Neurology, Kaohsiung, Medical University Hospital, No. 100, Tzyou 1st Road Kaohsiung 807, Taiwan; e-mail: [email protected]. Copyright Ó 2014 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/14/3101-0081
proposed (Hammond et al., 1987). The anticholinergic scopolamine prolonged P300 latency and decreased P300 amplitude, while physostigmine [a cholinesterase inhibitor (ChEI)] reduced P300 latency in the short term. These findings suggest that generation of P300 potentials is modulated by cholinergic input, although acetylcholine may either produce some modulating effect alone or together with serotonin (Frodl-Bauch et al., 1999; Meador et al., 1995). Cholinergic hypothesis has been advanced as an etiology of Alzheimer’s disease (AD) on the basis of the presynaptic deficit found in the diseased brains. Current approach for the evaluation of treatment efficacy in AD patients is mainly based on neuropsychological tests, which are heavily influenced by culture background and educational level (Prince et al., 2004). Polich and Herbst (2000) suggested that P300 could be an effective parameter for evaluating the medications effect on central nervous system. Furthermore, P300 are free from culture and educational influence and can provide useful, noninvasive insights into cognitive process (Katada et al., 2004; Polich and Corey-Bloom, 2005). Donepezil (DPZ) is one of the ChEIs with a long duration of inhibitory action and a greater specificity for brain tissue (Bryson and Benfield, 1997). Many studies have demonstrated the efficacy of DPZ in patients with AD (Homma et al., 2000; Rogers and Friedhoff, 1998). The study aimed to evaluate the effect of DPZ on P300 measurements in patients with AD and investigate the relationship between the subfactors of cognitive performance and P300 components.
METHODS This was a prospective, case–control, 22- to 23-week follow-up study. One hundred outpatients (42 men and 58 women; mean age, 76.47 6 6.49 years; mean years of education, 5.97 6 4.36 years) with mild AD according to the Clinical Dementia Rating scale (Hughes et al., 1982) were enrolled into the study. All patients underwent a neurologic examination, and a neuroimaging and laboratory workup to rule out other treatable causes of dementia. The diagnosis criteria were based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (American Psychiatric Association, 1994) and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (McKhann et al., 1984) for probable AD. None had a history of stroke, epilepsy, other significant psychiatric disease, or any central nervous system–active drug treatment. According to the procedure of the Bureau of National Health Insurance in Taiwan, it is necessary to evaluate cognitive function every 24 weeks at least after the initial administration DPZ for applying continuing prescription, so we decided 22 to 23 weeks as the study period. All patients were treated with 5 mg/day of DPZ during the study period and were submitted to neuropsychological and electrophysiologic assessments at baseline and at 22 to 23 weeks. Twenty age-matched normal control subjects
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(9 men and 11 women; mean age, 74.60 6 6.95 years; mean years of education: 7.50 6 4.51 years) were recruited from the hospital and the general community. They were carefully screened to ensure that they had no neurologic or psychiatric disease and were arranged neuropsychological and electrophysiologic assessments. Written informed consent was obtained from all subjects before participation in the study, which was conducted with the approval of the Ethics Committee of the Kaohsiung Municipal Kai-Syuan Psychiatric Hospital.
Neuropsychological Assessment Cognitive function of the subjects was assessed using the cognitive ability screening instrument (CASI) (Liu et al., 2002b; Teng et al., 1994) conducted by a clinical psychologist. The CASI consist of nine component scores including remote memory, recent memory, attention, concentration, language, abstract thinking/judgment, orientation, visual instruction, and verbal fluency. The sum of the nine component scores yields one global score of cognitive function (maximum, 100), with higher scores representing better cognitive function. Some of CASI items were comparable with items used in the mini–mental state examination (MMSE). Thus, a CASI-estimated MMSE scores or MMSE-CE scores (Liu et al., 2002a) was also obtained.
Electrophysiologic Assessments
An “odd-ball” stimulus paradigm (Brain Atlas III Computer Biologic System Company, USA) was used to elicit auditory ERPs, and an electroencephalograph was recorded using Ag/AgCl electrodes placed at 19 scalp locations (FP1, FP2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, O2) based on the 10–20 system. All were referenced to linked earlobes. The electrode impedance was kept below 3 kU. The amplifier had a high-frequency filter (37 Hz), a low-frequency filter (0.1 Hz), and gain 20,000. The sampling rate was 256 Hz. The averaging epoch was 612 milliseconds, including 100 milliseconds of prestimulus baseline. The subjects were tested while sitting in a comfortable chair with a neck support in a sound-attenuated room with dim lighting. First, the binaural audiometric thresholds were determined at 1,000 Hz for each subject. All stimuli were presented over headphones at 80 dB (each 50 milliseconds in duration). The auditory stimuli consisted of 1,000 Hz pure tone bursts as standard stimuli and 2,000 Hz pure tone bursts as target stimuli. The interstimulus intervals were 1.3 seconds. The probability of each sound category was 84.62% for standard and 15.38% for target. Thus, there were 50 target trials in each block. The two sound types were presented randomly in a stimulus sequence. Subjects were asked to press a button using the right thumb as quickly as possible when they detected the target sound. The experiment consisted of two blocks, with 325 trials in each block. Reaction time was measured relative to target onset for correct trials, whereas accuracy was measured as the percentage of correct responses out of all responses to the target tones. The artifact of vertical eyeball movement was detected using electrodes placed above and below the right eye, and horizontal movement from electrodes placed at the left outer canthus. Individual trials with eye blink artifacts more than 250 mV of peak-to-peak amplitude, reaction time more than 1.4 seconds, and nontarget trials with a response were excluded from the averaging. Separate ERP averages were made for each trial type. Peak amplitudes were measured relative to a 100 milliseconds baseline preceding the stimulus onset. For the highest amplitude distribution, the N100, P200, and N200 were assessed at Cz lead; P300 components at Fz, Cz, and Pz leads for detailed analysis. The latency windows were N100 component as the maximum negativity
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between 75 and 150 milliseconds, P200 component as the maximum positivity between 150 and 260 milliseconds, N200 component as the maximum negativity between 190 and 360 milliseconds, and P300 component as the maximum positivity between 250 and 500 milliseconds.
Statistical Analysis
Sex distribution between the groups was compared by the x2 test. Group differences in age, years of education, and neuropsychological and neurophysiologic assessments were evaluated by the Student’s t-test. Repeat measures analysis of variance with age as covariant were used to compare the follow-up measurements with baseline data in terms of neurophysiologic assessments. Paired t-tests were used to compare the follow-up measurements with baseline data in terms of neuropsychological assessments. The score difference of the pre- and posttreatment cognitive factors correlated with the difference of the pre- and posttreatment statistically significant factors of neurophysiologic components by Pearson’s correlation. Statistical significant was defined as P , 0.05.
RESULTS There was no difference in demographic characteristics, including age, sex, and years of education between the AD patients and the control subjects (Table 1). The statistics of the baseline neuropsychological and neurophysiologic assessments for the patient group and control subjects are summarized in Table 1. Compared with the control subjects, the AD patients performed poorly in the CASI and MMSE-CE. Latency of N200 at Cz lead and latency of P300 at Fz, Cz, and Pz leads in patients group also revealed more prolongation than that in control subjects. There was no significant difference of the mean amplitude of N100, P200, N200, and P300 components among the patient groups and control subjects at baseline. Statistics of the baseline and 22 to 23 weeks of follow-up neuropsychological and neurophysiologic assessments for the patients are summarized in Tables 1 and 2. The patients group showed significant improvement in P300 latency at the Pz lead, MMSE-CE scores, CASI scores, and the subfactors of remote memory, orientation, recent memory, and visual instruction. The N100, P200, and N200 components (both latency and amplitude) and the mean P300 amplitude at Fz, Cz, and Pz leads did not show statistical differences among the patient groups after 22 to 23 weeks of follow-up assessment with 5 mg/day of DPZ. Figure 1 shows the grand average ERP waveforms of the P300 at Fz, Cz, and Pz leads from patients on baseline and follow-up. Because of the reduction in P300 latency at Pz lead and the improvement in cognitive scores, the correlation values changed on the completion of the study (Table 2). The P300 latency at Pz lead difference significantly correlated with the CASI score difference, recent memory score difference, and MMSE-CE score difference, respectively.
DISCUSSION In the study, the mean latencies and amplitudes of N100 and P200 components did not show statistical differences between the patients and control subjects at baseline or between the patients after 22 to 23 weeks with 5 mg/day of DPZ. These findings were similar to those reported in previous researches (Caravaglios et al., 2008; Golob et al., 2002). N100 and P200 reflect early stage of sensory processing (Katada et al., 2004) related to filter mechanisms involved in triggering attention and allocation of attention, Copyright Ó 2014 by the American Clinical Neurophysiology Society
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TABLE 1. Demographic, Neuropsychological, and P300 Variables in Control Subjects and Patients at Baseline and After 22 to 23 weeks of Follow-up
Age (years) Sex (M/F) Education (years) CASI (score)* MMSE-CE (score)* N1 Cz-L (ms)† Cz-A (mV)† P2 Cz-L (milliseconds)† Cz-A (mV) † N2 Cz-L (milliseconds)† Cz-A (mV)† P3 Fz-L (milliseconds)† Fz-A (mV)† P3 Cz-L (milliseconds)† Cz-A (mV)† P3 Pz-L (milliseconds)† Pz-A (mV)†
Control Subjects (n ¼ 20)
AD (n ¼ 100) Baseline
t or x2
df
P
74.60 6 6.95 9/11 7.50 6 4.51 86.05 6 7.27 26.05 6 2.76 98.55 6 9.45 25.52 6 2.72 198.10 6 14.33 3.20 6 2.84 266.60 6 29.14 22.75 6 2.40 367.50 6 24.18 2.88 6 2.40 366.80 6 24.97 2.62 6 1.83 367.90 6 23.81 3.00 6 2.63
76.47 6 6.49 42/58 5.97 6 4.36 52.75 6 13.28 14.94 6 3.79 99.40 6 13.36 25.24 6 3.07 204.87 6 21.41 4.09 6 2.20 315.52 6 21.65 22.45 6 1.77 400.74 6 14.62 2.11 6 1.85 402.97 6 15.77 2.13 6 1.47 403.60 6 16.05 2.32 6 2.02
21.16 0.06 1.42 10.86 12.44 20.27 0.39 21.35 21.57 28.68 0.66 28.16 1.61 28.41 1.30 28.30 1.30
118 1 118 118 118 118 118 118 118 118 118 118 118 118 118 118 118
0.248 0.804 0.157 ,0.001 ,0.001 0.787 0.699 0.179 0.120 ,0.001 0.511 ,0.001 0.110 ,0.001 0.197 ,0.001 0.198
AD (n ¼ 100) Follow-Up d d d 54.88 6 15.80 6 99.42 6 25.19 6 201.81 6 3.89 6 305.01 6 22.38 6 397.18 6 2.41 6 398.66 6 2.27 6 398.05 6 2.54 6
13.53 4.21 15.22 2.85 19.50 2.15 36.95 1.61 12.53 2.32 15.95 1.95 12.68 1.74
F(1, 98) or Pair t-Test
P
d d d 0.008 0.009 0.28 0.14 0.69 ,0.01 0.95 1.40 1.06 0.11 1.08 1.16 5.72 0.56
d d d 0.032 0.018 0.600 0.708 0.410 0.975 0.332 0.241 0.307 0.744 0.301 0.285 0.019 0.458
*Analysis by paired t-test. †Analysis by repeat measures analysis of variance with age as covariant. df ¼ 99; F, female; M, male; L, latency; A, amplitude.
FIG. 1. The grand average mean P300 wave from baseline and at 22 to 23 weeks after the treatment with donepezil (5 mg/day). Copyright Ó 2014 by the American Clinical Neurophysiology Society
respectively (Lijffijt et al., 2009). This suggested that mild AD patients in our study still had intact early stage of sensory processing and the processing was not modulated by ChEIs. The auditory ERP and neuropsychological assessments demonstrated significantly more prolonged P300 (all measured at Pz, Cz, and Fz) and N200 latencies (measures at Cz) and poorer cognitive performance in patients of AD than that in control subjects in the study. However, only P300 latency measured at Pz improved in patients after 22 to 23 weeks of treatment with DPZ. Parallel improvements in CASI and MMSE-CE were also apparent. We replicated the finding that mild AD patients have prolonged N200 and P300 latencies (Caravaglios et al., 2008; Pfefferbaum et al., 1990). Prolongation of N200 and P300 latencies may reflect a pathologic delay in the processes of stimulus evaluation (Kutas et al., 1977) or timing of attentional resources when working memory is update (Polich and Criado, 2006). In our results, the patients showed delayed N200 and P300 latencies and increased behavior errors compared with control subjects, indicating that patients with mild AD compromise the higher-level processes that could influence behavior deviation. The N200 component represents an early alternation of cognitive ability, such as target discrimination (Ritter et al., 1982), while the P300 component reflects information processing, such as target evaluation, judgment, and decision making (Gironell et al., 2005; Katada et al., 2004). Our finding that the patients after 22 to 23 weeks with DPZ showed P300 latency measured at Pz improved but not in N200 latency. This suggested that once the target is identified, ChEIs could modulate alone or together with other neurotransmitters to enhance the speed of information processing. The reduction of P300 latency at Pz place in this study correlated with improvements in cognitive function. The Cohen’s d values were approximately 0.4 for P300 latency and 0.2 for CASI and MMSE-CE scores. The effect size was modest. Table 3 summarized our study and others. Changes in P300 latency and improvement 83
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TABLE 2. Cognitive Function in Patients at Baseline and After 22 to 23 Weeks of Follow-up and the Correlation Values of the Difference of Pre- and Posttreatment Cognitive Function and P300 Latency at Pz on Completion of the Study (n ¼ 100) Baseline CSAI scores Remote memory Orientation Concentration Attention Recent memory Verbal fluency Language Abstract thinking/judgment Visual instruction MMSE-CE scores
52.75 8.05 7.47 4.34 5.62 1.84 3.97 8.14 6.15 6.13 14.94
6 6 6 6 6 6 6 6 6 6 6
13.28 2.00 3.77 3.21 1.45 1.68 2.18 1.71 2.28 3.63 3.79
Follow-up
Paired t-Test
P
r
P
6 6 6 6 6 6 6 6 6 6 6
22.70 22.73 23.74 20.80 21.02 23.59 21.76 20.74 20.97 22.31 22.66
0.008 0.007 0.000 0.424 0.311 0.001 0.082 0.464 0.334 0.023 0.009
20.22 20.03 20.02 0.08 20.18 20.23 20.04 20.06 20.19 20.09 20.24
0.032 0.799 0.867 0.410 0.081 0.023 0.722 0.582 0.060 0.385 0.018
54.88 8.52 8.50 4.30 5.77 2.28 4.31 8.24 6.35 6.73 15.80
13.53 1.82 3.83 3.18 1.42 1.96 2.08 1.64 2.19 3.20 4.21
r, the coefficient of Pearson’s correlation.
in cognitive function after DPZ treatment in this study were similar to those reported by Thomas et al. (2001) and Werber et al. (2003). However, our effect sizes in P300 and neuropsychological tests were smaller than other studies. Because the mean age of our patients was higher and mean MMSE-CE scores was lower compared with other studies, this difference might be derived from the characteristics of the patients and the dosage of ChEIs used. The effect size of the effect of ChEIs on P300 latency was larger than that on psychometric scales, either in our study or that of Thomas et al. (2001) and Werber et al. (2003). Because neurophysiologic change does not necessarily correspond with clinical or behavior changes, the results of neuropsychological tests sometimes remain abnormal or clinical improvement may not be significant despite improvement of P300 latency (Katada et al., 2004). The pretreatment P300 latency in our study were similar to those reported by Katada et al. (2003) who found that P300 latency was significantly
TABLE 3.
improved at 3 months but had a tendency toward being delayed at 6 months. In our study, P300 latency remained improved after 22 to 23 weeks of treatment with DPZ (5 mg/day). Further study is warranted to evaluate P300 latency changes on a monthly basis in response to DPZ (5 mg/day) treatment. Donepezil has no discernible effect on auditory P300 amplitude in our study or others. Previous investigators have advocated that the P300 latency reflects the speed of mental processing, and the amplitude can reflect probability and evaluation of the stimulus (Donchin et al., 1984; Polich and Corey-Bloom, 2005). In general, P300 latency is a measure of mental processing speed and is unrelated to the response selection process (Katada et al., 2004). Because P300 latency is an index of processing time required before response generation, it is more sensitive than P300 amplitude in temporal measure of neural activity underlying the mental process in AD patients after DPZ treatment.
Summarized Demographical, Neuropsychological, and P300 Variables in the Our Study and Other Studies P300 Variables P300 Latency at Pz (Milliseconds) Age (Years)
Present study (n ¼ 100) Katada et al., 2003 (n ¼ 13) Thomas et al., 2001 (n ¼ 20)
76.5 6 6.5 78.6 6 6.1 66.5 6 9.2
Werber et al., 2003 (n ¼ 32)
75 (62–82)
Dose of Medication DPZ 5 mg/day DPZ 5 mg/day DPZ 5 mg/day for 15 days and 10 mg/day thereafter Tacrine 100 mg/day, DPZ 6.5 mg/day or rivastigmine 9.5 mg/day
Follow-up Period
Baseline/Follow-up
Cohen’s d
22–23 weeks 6 months 6 months
403.60 6 16.05/398.05 6 12.68 404.3 6 49.4/405.4 6 51.7 382.7 6 3.4/367.4 6 3.1
0.38 d 4.70
26 weeks
383 6 7.9/359 6 7
3.22
Neuropsychological Variables ADAS-cog or CASI (Score) Baseline/Follow-up 52.75 6 13.28/54.88 6 13.53 23.6 6 12.6/19.9 6 12.2 33.3 6 2.7/31.8 6 2.7 29.4 6 3.0/27.4 6 3.1
MMSE (Score) Cohen’s d
Baseline/Follow-up
Cohen’s d
0.16 0.30 0.56 0.66
14.94 6 3.79/15.80 6 4.21 18.5 6 4.3/20.5 6 4.9 16 6 0.5/16 6 0.5 19.8 6 1.4/20.1 6 1.3
0.21 0.43 d 0.22
ADAS-cog, Alzheimer’s disease assessment scale.
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Journal of Clinical Neurophysiology Volume 31, Number 1, February 2014 P300 Latency in Alzheimer’s Disease With Donepezil
The remote memory, recent memory, visual instruction, and orientation in our AD patients significantly improved after DPZ treatment. The improvement of recent memory significantly correlated with shorter P300 latency. Little research has been conducted examining the impact of ChEIs on the subfactors of cognitive function. However, the results presented herein are consistent with those described in an earlier report published by our group (Chang et al., 2005). The recent memory improvement described in this study is also similar to that reported by López-Pousa et al. (2001), in which recent memory and language function improved in patients with AD following 12 months of treatment with DPZ (5–10 mg/day). Cholinergic blockade by scopolamine (inducing significant memory impairment) was found to be associated with an increased latency or abolition of the auditory P300, thus supporting hypothesized links between P300 and memory (Schneider and Shiffrin, 1977). P300 probably reflects the encoding of information into short-term memory and the limbic system is involved in this process (Dierks et al., 1994; Juckel et al., 2008). However, auditory event-related P300 is mainly generated in temporoparietal regions (Juckel et al., 2008). It seems that drugs that modulate the cholinergic system revealed that P300 latency decreases as cognitive capability increases, especially improves in recent memory. There were a few limitations in our study. First, we cannot rule out the possibility of practice effects resulting in some of the improvements observed in the following assessment. Second, there was no elderly normal control subjects treated with DPZ; therefore, the specificity of these observations for AD is unknown. Third, in the procedure of electrophysiologic assessments, we used the fixed interstimulus interval and did not record the data of the performance measures in ERPs recordings for comparing any performance differences before and after the treatment. That would be a bias for ERP grand average recording. Fourth, the CASI instrument is a preferred research tool for epidemiologic research; however, it does not fulfill a need for psychological assessments in clinical practice. Fifth, this was not a double-blind, placebo-controlled study. In conclusion, mild AD patients had delayed N200 and P300 latencies, no significant differences in N100 and P200 components, and impaired cognitive function compared with control subjects, indicating that patients with mild AD still had intact early sensory processing but impaired higher-level cognitive processes that could influence behavior deviation. The ChEI DPZ that enhances higher-level cognitive processing time revealed that P300 latency decreased as cognitive capability increased, especially improved in recent memory. REFERENCES American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth ed (DSM-IV). Washington: American Psychiatric Press, 1994. Bryson HM, Benfield P. Donepezil. Drugs Aging 1997;10:234–239. Caravaglios G, Costanzo E, Palermo F, Muscoso EG. Decreased amplitude of auditory event-related delta responses in Alzheimer’s disease. Int J Psychophysiol 2008;70:23–32. Chang YS, Tang SH, Chen MC, Chen WJ. Effects of donepezil on the cognitive function in patients with Alzheimer’s disease. Taiwanese J Psychiatry 2005;19:161–163. Dierks T, Frölich L, Ihl R, Maurer K. Event-related potentials and psychopharmacology. Cholinergic modulations of P300. Pharmacopsychiatry 1994;27:72–74. Donchin E, Heffley E, Hillyard SA, et al. Cognition and event-related potentials II. The orientation reflex and P300. Ann N Y Acad Sci 1984;425:39–57. Frodl-Bauch T, Bottlender R, Hegerl U. Neurochemical substrates and neuroanatomical generators of the event-related P300. Neuropsychobiology 1999;40: 86–97.
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Gironell A, Garcia-Sanchez C, Estevez-Gonzalea, et al. Usefulness of P300 in subjective memory complaints: a prospective study. J Clin Neurophysiol 2005;22:279–284. Golob EJ, Johnson JK, Starr A. Auditory event-related potentials during target detection are abnormal in mild cognitive impairment. Clin Neurophysiol 2002;113:151–161. Halgren E, Marinkovic K, Chauvel P. Generators of the late cognitive potentials in auditory and visual oddball tasks. Electroencephalogr Clin Neurophysiol 1998;106:156–164. Hammond EJ, Meador KJ, Aung-Din R, Wilder BJ. Cholinergic modulation of human P3 event-related potentials. Neurology 1987;37:346–350. Homma A, Takeda M, Imai Y, et al. Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer’s disease. A 24week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group. Dement Geriatr Cogn Disord 2000;11:299–313. Hughes CP, Berg L, Danziger WL, et al. A new clinical scale for the staging of dementia. Br J Psychiatry 1982;140:566–572. Juckel G, Clotz F, Frodl T, et al. Diagnostic usefulness of cognitive auditory event-related P300 subcomponents in patients with Alzheimer’s disease? J Clin Neurophysiol 2008;25:147–152. Katada E, Sato K, Sawaki A, et al. 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. Katada E, Sato K, Ojika K, Ueda R. Cognitive event-related potentials: useful clinical information in Alzheimer’s disease. Curr Alzheimer Res 2004;1:63–69. Kutas M, McCarthy G, Donchin E. Augmenting mental chronometry: the P300 as a measure of stimulus evaluation. Science 1977;197:792–795. Lijffijt M, Lane SD, Meier SL, et al. P50, N100, and P200 sensory gating: relationships with behavioral inhibition, attention, and working memory. Psychophysiology 2009;46:1059–1068. Liu HC, Teng EL, Chuang YY, et al. The Alzheimer’s Disease Assessment Scale: findings from a low-education population. Dement Geriatr Cogn Disord 2002a;13:21–26. Liu HC, Teng EL, Lin KN, et al. Performance on the cognitive abilities screening instrument at different stages of Alzheimer’s disease. Dement Geriatr Cogn Disord 2002b;13:244–248. López-Pousa S, Vilalta-Franch J, Garre-Olmo J, et al. Effectiveness of donepezil on several cognitive functions in patients with Alzheimer’s disease over 12 months [in Spanish]. Neurologia 2001;16:342–347. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984;34:939–944. Meador KJ, Loring DW, Hendrix N, et al. Synergistic anticholinergic and antiserotonergic effects in humans. J Clin Exp Neuropsychol 1995;17:611–621. Pfefferbaum A, Ford JM, Kraemer HC. Clinical utility of long latency cognitive event- related potentials (P3): the cons. Electroencephalogr Clin Neurophysiol 1990;76:6–12. Picton PW. The P300 wave of the human event-related potential. J Clin Neurophysiol 1992;9:456–479. Polich J, Corey-Bloom J. Alzheimer’s disease and P300: review and evaluation of task and modality. Curr Alzheimer Res 2005;2:515–525. Polich J, Criado JR. Neuropsychology and neuropharmachology of P3a and P3b. Int J Psychophysiol 2006;60:172–185. Polich J, Herbst KL. P300 as a clinical assay: rationale, evaluation, and findings. Int J Psychophysiol 2000;38:3–19. Prince M, Acosta D, Chiu H, et al. Effects of education and culture on the validity of the Geriatric Mental State and its AGECAT algorithm. Br J Psychiatry 2004;185:429–436. Ritter W, Simon R, Vaughan HG Jr, Macht M. Manipulation of event-related potential manifestations of information processing stages. Science 1982;218: 909–911. Rogers SL, Friedhoff LT. Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: an interim analysis of the results of a US multicentre open label extension study. Eur Neuropsychopharmacol 1998; 8:67–75. Schneider W, Shiffrin RM. Controlled and automatic human information processing I: detection, search and attention. Psychol Rev 1977;84:1–66. Teng EL, Hasegawa K, Homma A, et al. The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia. Int Psychogeriatr 1994;6:45–58. Thomas A, Iacono D, Bonanni L, et al. Donepezil, rivastigmine, and vitamin E in Alzheimer’s disease: a combined P300 event-related potentials/neuropsychologic evaluation over 6 months. Clin Neurpharmacol 2001;24:31–42. Werber EA, Gandelan-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;110:659–669.
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Parallel Improvement of Cognitive Functions and P300 Latency Following Donepezil Treatment in Patients With Alzheimer’s Disease: A Case–Control Study Yu-San Chang,* Hsiang-Lan Chen,† Chung-Yao Hsu,†† Shu-Hui Tang,† and Ching-Kuan Liu††
Purpose: To evaluate the effect of donepezil, one of the cholinesterase inhibitors, on P300 measurements in patients with Alzheimer’s disease (AD) and investigate the relationship between the subfactors of cognitive performance and P300 components. Methods: One hundred outpatients with AD were evaluated for cognitive function (cognitive ability screening instrument) and event-related potentials before and after 22 to 23 weeks of treatment with donepezil (5 mg/day). Twenty age-matched normal control subjects were recruited. Results: The patients with AD showed prolonged P300 and N200 latency, no significant differences in N100 and P200 components, and poor performance in neuropsychological assessments compared with control subjects at baseline. After donepezil treatment, the patients with AD had reduction in P300 latency at Pz lead, which was associated with a parallel improvement in cognitive function in terms of remote memory, recent memory, visual instruction, and orientation. The pre–post treatment difference of P300 latency significantly correlated with the cognitive ability screening instrument score difference and recent memory score difference, respectively. Conclusions: The patients with AD still had intact early sensory processing but impaired higher-level cognitive processes that could influence behavior deviation. The donepezil treatment, which enhances higher-level cognitive processing time, revealed that P300 latency decreases as cognitive capability increases, especially improved in recent memory. Key Words: Alzheimer’s disease, P300, Donepezil, Cognitive function. (J Clin Neurophysiol 2014;31: 81–85)
P
300 is a positive component of event-related potentials (ERPs), which occurs approximately 300 milliseconds after a target stimulus (usually auditory) is given (Picton, 1992). It is considered to be a cognition-related brain potential and thought to reflect the mental processes associated with short-term memory and attention. Because limbic system is involved in these processes and in the generation of P300 (Dierks et al., 1994; Halgren et al., 1998), it is reasonable to use P300 as an indicator when assessing the influences of pharmaceutics on memory function and cognitive process (Dierks et al., 1994). Concerning the neurochemical substrates, GABAergic, cholinergic, noradrenergic, dopaminergic, and serotonergic substrates are known to influence P300 (Frodl-Bauch et al., 1999). However, a relationship between P300 and the cholinergic system has been From the *Department of Neuropsychiatry, Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan; Faculty of Nursing Department, Meiho University, Pingtung, Taiwan; †Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan; and ††Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, China. Address correspondence and reprint requests to Chung-Yao Hsu, MD, PhD, Department of Neurology, Kaohsiung, Medical University Hospital, No. 100, Tzyou 1st Road Kaohsiung 807, Taiwan; e-mail: [email protected]. Copyright Ó 2014 by the American Clinical Neurophysiology Society
ISSN: 0736-0258/14/3101-0081
proposed (Hammond et al., 1987). The anticholinergic scopolamine prolonged P300 latency and decreased P300 amplitude, while physostigmine [a cholinesterase inhibitor (ChEI)] reduced P300 latency in the short term. These findings suggest that generation of P300 potentials is modulated by cholinergic input, although acetylcholine may either produce some modulating effect alone or together with serotonin (Frodl-Bauch et al., 1999; Meador et al., 1995). Cholinergic hypothesis has been advanced as an etiology of Alzheimer’s disease (AD) on the basis of the presynaptic deficit found in the diseased brains. Current approach for the evaluation of treatment efficacy in AD patients is mainly based on neuropsychological tests, which are heavily influenced by culture background and educational level (Prince et al., 2004). Polich and Herbst (2000) suggested that P300 could be an effective parameter for evaluating the medications effect on central nervous system. Furthermore, P300 are free from culture and educational influence and can provide useful, noninvasive insights into cognitive process (Katada et al., 2004; Polich and Corey-Bloom, 2005). Donepezil (DPZ) is one of the ChEIs with a long duration of inhibitory action and a greater specificity for brain tissue (Bryson and Benfield, 1997). Many studies have demonstrated the efficacy of DPZ in patients with AD (Homma et al., 2000; Rogers and Friedhoff, 1998). The study aimed to evaluate the effect of DPZ on P300 measurements in patients with AD and investigate the relationship between the subfactors of cognitive performance and P300 components.
METHODS This was a prospective, case–control, 22- to 23-week follow-up study. One hundred outpatients (42 men and 58 women; mean age, 76.47 6 6.49 years; mean years of education, 5.97 6 4.36 years) with mild AD according to the Clinical Dementia Rating scale (Hughes et al., 1982) were enrolled into the study. All patients underwent a neurologic examination, and a neuroimaging and laboratory workup to rule out other treatable causes of dementia. The diagnosis criteria were based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (American Psychiatric Association, 1994) and the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (McKhann et al., 1984) for probable AD. None had a history of stroke, epilepsy, other significant psychiatric disease, or any central nervous system–active drug treatment. According to the procedure of the Bureau of National Health Insurance in Taiwan, it is necessary to evaluate cognitive function every 24 weeks at least after the initial administration DPZ for applying continuing prescription, so we decided 22 to 23 weeks as the study period. All patients were treated with 5 mg/day of DPZ during the study period and were submitted to neuropsychological and electrophysiologic assessments at baseline and at 22 to 23 weeks. Twenty age-matched normal control subjects
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(9 men and 11 women; mean age, 74.60 6 6.95 years; mean years of education: 7.50 6 4.51 years) were recruited from the hospital and the general community. They were carefully screened to ensure that they had no neurologic or psychiatric disease and were arranged neuropsychological and electrophysiologic assessments. Written informed consent was obtained from all subjects before participation in the study, which was conducted with the approval of the Ethics Committee of the Kaohsiung Municipal Kai-Syuan Psychiatric Hospital.
Neuropsychological Assessment Cognitive function of the subjects was assessed using the cognitive ability screening instrument (CASI) (Liu et al., 2002b; Teng et al., 1994) conducted by a clinical psychologist. The CASI consist of nine component scores including remote memory, recent memory, attention, concentration, language, abstract thinking/judgment, orientation, visual instruction, and verbal fluency. The sum of the nine component scores yields one global score of cognitive function (maximum, 100), with higher scores representing better cognitive function. Some of CASI items were comparable with items used in the mini–mental state examination (MMSE). Thus, a CASI-estimated MMSE scores or MMSE-CE scores (Liu et al., 2002a) was also obtained.
Electrophysiologic Assessments
An “odd-ball” stimulus paradigm (Brain Atlas III Computer Biologic System Company, USA) was used to elicit auditory ERPs, and an electroencephalograph was recorded using Ag/AgCl electrodes placed at 19 scalp locations (FP1, FP2, F7, F3, Fz, F4, F8, T3, C3, Cz, C4, T4, T5, P3, Pz, P4, T6, O1, O2) based on the 10–20 system. All were referenced to linked earlobes. The electrode impedance was kept below 3 kU. The amplifier had a high-frequency filter (37 Hz), a low-frequency filter (0.1 Hz), and gain 20,000. The sampling rate was 256 Hz. The averaging epoch was 612 milliseconds, including 100 milliseconds of prestimulus baseline. The subjects were tested while sitting in a comfortable chair with a neck support in a sound-attenuated room with dim lighting. First, the binaural audiometric thresholds were determined at 1,000 Hz for each subject. All stimuli were presented over headphones at 80 dB (each 50 milliseconds in duration). The auditory stimuli consisted of 1,000 Hz pure tone bursts as standard stimuli and 2,000 Hz pure tone bursts as target stimuli. The interstimulus intervals were 1.3 seconds. The probability of each sound category was 84.62% for standard and 15.38% for target. Thus, there were 50 target trials in each block. The two sound types were presented randomly in a stimulus sequence. Subjects were asked to press a button using the right thumb as quickly as possible when they detected the target sound. The experiment consisted of two blocks, with 325 trials in each block. Reaction time was measured relative to target onset for correct trials, whereas accuracy was measured as the percentage of correct responses out of all responses to the target tones. The artifact of vertical eyeball movement was detected using electrodes placed above and below the right eye, and horizontal movement from electrodes placed at the left outer canthus. Individual trials with eye blink artifacts more than 250 mV of peak-to-peak amplitude, reaction time more than 1.4 seconds, and nontarget trials with a response were excluded from the averaging. Separate ERP averages were made for each trial type. Peak amplitudes were measured relative to a 100 milliseconds baseline preceding the stimulus onset. For the highest amplitude distribution, the N100, P200, and N200 were assessed at Cz lead; P300 components at Fz, Cz, and Pz leads for detailed analysis. The latency windows were N100 component as the maximum negativity
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between 75 and 150 milliseconds, P200 component as the maximum positivity between 150 and 260 milliseconds, N200 component as the maximum negativity between 190 and 360 milliseconds, and P300 component as the maximum positivity between 250 and 500 milliseconds.
Statistical Analysis
Sex distribution between the groups was compared by the x2 test. Group differences in age, years of education, and neuropsychological and neurophysiologic assessments were evaluated by the Student’s t-test. Repeat measures analysis of variance with age as covariant were used to compare the follow-up measurements with baseline data in terms of neurophysiologic assessments. Paired t-tests were used to compare the follow-up measurements with baseline data in terms of neuropsychological assessments. The score difference of the pre- and posttreatment cognitive factors correlated with the difference of the pre- and posttreatment statistically significant factors of neurophysiologic components by Pearson’s correlation. Statistical significant was defined as P , 0.05.
RESULTS There was no difference in demographic characteristics, including age, sex, and years of education between the AD patients and the control subjects (Table 1). The statistics of the baseline neuropsychological and neurophysiologic assessments for the patient group and control subjects are summarized in Table 1. Compared with the control subjects, the AD patients performed poorly in the CASI and MMSE-CE. Latency of N200 at Cz lead and latency of P300 at Fz, Cz, and Pz leads in patients group also revealed more prolongation than that in control subjects. There was no significant difference of the mean amplitude of N100, P200, N200, and P300 components among the patient groups and control subjects at baseline. Statistics of the baseline and 22 to 23 weeks of follow-up neuropsychological and neurophysiologic assessments for the patients are summarized in Tables 1 and 2. The patients group showed significant improvement in P300 latency at the Pz lead, MMSE-CE scores, CASI scores, and the subfactors of remote memory, orientation, recent memory, and visual instruction. The N100, P200, and N200 components (both latency and amplitude) and the mean P300 amplitude at Fz, Cz, and Pz leads did not show statistical differences among the patient groups after 22 to 23 weeks of follow-up assessment with 5 mg/day of DPZ. Figure 1 shows the grand average ERP waveforms of the P300 at Fz, Cz, and Pz leads from patients on baseline and follow-up. Because of the reduction in P300 latency at Pz lead and the improvement in cognitive scores, the correlation values changed on the completion of the study (Table 2). The P300 latency at Pz lead difference significantly correlated with the CASI score difference, recent memory score difference, and MMSE-CE score difference, respectively.
DISCUSSION In the study, the mean latencies and amplitudes of N100 and P200 components did not show statistical differences between the patients and control subjects at baseline or between the patients after 22 to 23 weeks with 5 mg/day of DPZ. These findings were similar to those reported in previous researches (Caravaglios et al., 2008; Golob et al., 2002). N100 and P200 reflect early stage of sensory processing (Katada et al., 2004) related to filter mechanisms involved in triggering attention and allocation of attention, Copyright Ó 2014 by the American Clinical Neurophysiology Society
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TABLE 1. Demographic, Neuropsychological, and P300 Variables in Control Subjects and Patients at Baseline and After 22 to 23 weeks of Follow-up
Age (years) Sex (M/F) Education (years) CASI (score)* MMSE-CE (score)* N1 Cz-L (ms)† Cz-A (mV)† P2 Cz-L (milliseconds)† Cz-A (mV) † N2 Cz-L (milliseconds)† Cz-A (mV)† P3 Fz-L (milliseconds)† Fz-A (mV)† P3 Cz-L (milliseconds)† Cz-A (mV)† P3 Pz-L (milliseconds)† Pz-A (mV)†
Control Subjects (n ¼ 20)
AD (n ¼ 100) Baseline
t or x2
df
P
74.60 6 6.95 9/11 7.50 6 4.51 86.05 6 7.27 26.05 6 2.76 98.55 6 9.45 25.52 6 2.72 198.10 6 14.33 3.20 6 2.84 266.60 6 29.14 22.75 6 2.40 367.50 6 24.18 2.88 6 2.40 366.80 6 24.97 2.62 6 1.83 367.90 6 23.81 3.00 6 2.63
76.47 6 6.49 42/58 5.97 6 4.36 52.75 6 13.28 14.94 6 3.79 99.40 6 13.36 25.24 6 3.07 204.87 6 21.41 4.09 6 2.20 315.52 6 21.65 22.45 6 1.77 400.74 6 14.62 2.11 6 1.85 402.97 6 15.77 2.13 6 1.47 403.60 6 16.05 2.32 6 2.02
21.16 0.06 1.42 10.86 12.44 20.27 0.39 21.35 21.57 28.68 0.66 28.16 1.61 28.41 1.30 28.30 1.30
118 1 118 118 118 118 118 118 118 118 118 118 118 118 118 118 118
0.248 0.804 0.157 ,0.001 ,0.001 0.787 0.699 0.179 0.120 ,0.001 0.511 ,0.001 0.110 ,0.001 0.197 ,0.001 0.198
AD (n ¼ 100) Follow-Up d d d 54.88 6 15.80 6 99.42 6 25.19 6 201.81 6 3.89 6 305.01 6 22.38 6 397.18 6 2.41 6 398.66 6 2.27 6 398.05 6 2.54 6
13.53 4.21 15.22 2.85 19.50 2.15 36.95 1.61 12.53 2.32 15.95 1.95 12.68 1.74
F(1, 98) or Pair t-Test
P
d d d 0.008 0.009 0.28 0.14 0.69 ,0.01 0.95 1.40 1.06 0.11 1.08 1.16 5.72 0.56
d d d 0.032 0.018 0.600 0.708 0.410 0.975 0.332 0.241 0.307 0.744 0.301 0.285 0.019 0.458
*Analysis by paired t-test. †Analysis by repeat measures analysis of variance with age as covariant. df ¼ 99; F, female; M, male; L, latency; A, amplitude.
FIG. 1. The grand average mean P300 wave from baseline and at 22 to 23 weeks after the treatment with donepezil (5 mg/day). Copyright Ó 2014 by the American Clinical Neurophysiology Society
respectively (Lijffijt et al., 2009). This suggested that mild AD patients in our study still had intact early stage of sensory processing and the processing was not modulated by ChEIs. The auditory ERP and neuropsychological assessments demonstrated significantly more prolonged P300 (all measured at Pz, Cz, and Fz) and N200 latencies (measures at Cz) and poorer cognitive performance in patients of AD than that in control subjects in the study. However, only P300 latency measured at Pz improved in patients after 22 to 23 weeks of treatment with DPZ. Parallel improvements in CASI and MMSE-CE were also apparent. We replicated the finding that mild AD patients have prolonged N200 and P300 latencies (Caravaglios et al., 2008; Pfefferbaum et al., 1990). Prolongation of N200 and P300 latencies may reflect a pathologic delay in the processes of stimulus evaluation (Kutas et al., 1977) or timing of attentional resources when working memory is update (Polich and Criado, 2006). In our results, the patients showed delayed N200 and P300 latencies and increased behavior errors compared with control subjects, indicating that patients with mild AD compromise the higher-level processes that could influence behavior deviation. The N200 component represents an early alternation of cognitive ability, such as target discrimination (Ritter et al., 1982), while the P300 component reflects information processing, such as target evaluation, judgment, and decision making (Gironell et al., 2005; Katada et al., 2004). Our finding that the patients after 22 to 23 weeks with DPZ showed P300 latency measured at Pz improved but not in N200 latency. This suggested that once the target is identified, ChEIs could modulate alone or together with other neurotransmitters to enhance the speed of information processing. The reduction of P300 latency at Pz place in this study correlated with improvements in cognitive function. The Cohen’s d values were approximately 0.4 for P300 latency and 0.2 for CASI and MMSE-CE scores. The effect size was modest. Table 3 summarized our study and others. Changes in P300 latency and improvement 83
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TABLE 2. Cognitive Function in Patients at Baseline and After 22 to 23 Weeks of Follow-up and the Correlation Values of the Difference of Pre- and Posttreatment Cognitive Function and P300 Latency at Pz on Completion of the Study (n ¼ 100) Baseline CSAI scores Remote memory Orientation Concentration Attention Recent memory Verbal fluency Language Abstract thinking/judgment Visual instruction MMSE-CE scores
52.75 8.05 7.47 4.34 5.62 1.84 3.97 8.14 6.15 6.13 14.94
6 6 6 6 6 6 6 6 6 6 6
13.28 2.00 3.77 3.21 1.45 1.68 2.18 1.71 2.28 3.63 3.79
Follow-up
Paired t-Test
P
r
P
6 6 6 6 6 6 6 6 6 6 6
22.70 22.73 23.74 20.80 21.02 23.59 21.76 20.74 20.97 22.31 22.66
0.008 0.007 0.000 0.424 0.311 0.001 0.082 0.464 0.334 0.023 0.009
20.22 20.03 20.02 0.08 20.18 20.23 20.04 20.06 20.19 20.09 20.24
0.032 0.799 0.867 0.410 0.081 0.023 0.722 0.582 0.060 0.385 0.018
54.88 8.52 8.50 4.30 5.77 2.28 4.31 8.24 6.35 6.73 15.80
13.53 1.82 3.83 3.18 1.42 1.96 2.08 1.64 2.19 3.20 4.21
r, the coefficient of Pearson’s correlation.
in cognitive function after DPZ treatment in this study were similar to those reported by Thomas et al. (2001) and Werber et al. (2003). However, our effect sizes in P300 and neuropsychological tests were smaller than other studies. Because the mean age of our patients was higher and mean MMSE-CE scores was lower compared with other studies, this difference might be derived from the characteristics of the patients and the dosage of ChEIs used. The effect size of the effect of ChEIs on P300 latency was larger than that on psychometric scales, either in our study or that of Thomas et al. (2001) and Werber et al. (2003). Because neurophysiologic change does not necessarily correspond with clinical or behavior changes, the results of neuropsychological tests sometimes remain abnormal or clinical improvement may not be significant despite improvement of P300 latency (Katada et al., 2004). The pretreatment P300 latency in our study were similar to those reported by Katada et al. (2003) who found that P300 latency was significantly
TABLE 3.
improved at 3 months but had a tendency toward being delayed at 6 months. In our study, P300 latency remained improved after 22 to 23 weeks of treatment with DPZ (5 mg/day). Further study is warranted to evaluate P300 latency changes on a monthly basis in response to DPZ (5 mg/day) treatment. Donepezil has no discernible effect on auditory P300 amplitude in our study or others. Previous investigators have advocated that the P300 latency reflects the speed of mental processing, and the amplitude can reflect probability and evaluation of the stimulus (Donchin et al., 1984; Polich and Corey-Bloom, 2005). In general, P300 latency is a measure of mental processing speed and is unrelated to the response selection process (Katada et al., 2004). Because P300 latency is an index of processing time required before response generation, it is more sensitive than P300 amplitude in temporal measure of neural activity underlying the mental process in AD patients after DPZ treatment.
Summarized Demographical, Neuropsychological, and P300 Variables in the Our Study and Other Studies P300 Variables P300 Latency at Pz (Milliseconds) Age (Years)
Present study (n ¼ 100) Katada et al., 2003 (n ¼ 13) Thomas et al., 2001 (n ¼ 20)
76.5 6 6.5 78.6 6 6.1 66.5 6 9.2
Werber et al., 2003 (n ¼ 32)
75 (62–82)
Dose of Medication DPZ 5 mg/day DPZ 5 mg/day DPZ 5 mg/day for 15 days and 10 mg/day thereafter Tacrine 100 mg/day, DPZ 6.5 mg/day or rivastigmine 9.5 mg/day
Follow-up Period
Baseline/Follow-up
Cohen’s d
22–23 weeks 6 months 6 months
403.60 6 16.05/398.05 6 12.68 404.3 6 49.4/405.4 6 51.7 382.7 6 3.4/367.4 6 3.1
0.38 d 4.70
26 weeks
383 6 7.9/359 6 7
3.22
Neuropsychological Variables ADAS-cog or CASI (Score) Baseline/Follow-up 52.75 6 13.28/54.88 6 13.53 23.6 6 12.6/19.9 6 12.2 33.3 6 2.7/31.8 6 2.7 29.4 6 3.0/27.4 6 3.1
MMSE (Score) Cohen’s d
Baseline/Follow-up
Cohen’s d
0.16 0.30 0.56 0.66
14.94 6 3.79/15.80 6 4.21 18.5 6 4.3/20.5 6 4.9 16 6 0.5/16 6 0.5 19.8 6 1.4/20.1 6 1.3
0.21 0.43 d 0.22
ADAS-cog, Alzheimer’s disease assessment scale.
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Journal of Clinical Neurophysiology Volume 31, Number 1, February 2014 P300 Latency in Alzheimer’s Disease With Donepezil
The remote memory, recent memory, visual instruction, and orientation in our AD patients significantly improved after DPZ treatment. The improvement of recent memory significantly correlated with shorter P300 latency. Little research has been conducted examining the impact of ChEIs on the subfactors of cognitive function. However, the results presented herein are consistent with those described in an earlier report published by our group (Chang et al., 2005). The recent memory improvement described in this study is also similar to that reported by López-Pousa et al. (2001), in which recent memory and language function improved in patients with AD following 12 months of treatment with DPZ (5–10 mg/day). Cholinergic blockade by scopolamine (inducing significant memory impairment) was found to be associated with an increased latency or abolition of the auditory P300, thus supporting hypothesized links between P300 and memory (Schneider and Shiffrin, 1977). P300 probably reflects the encoding of information into short-term memory and the limbic system is involved in this process (Dierks et al., 1994; Juckel et al., 2008). However, auditory event-related P300 is mainly generated in temporoparietal regions (Juckel et al., 2008). It seems that drugs that modulate the cholinergic system revealed that P300 latency decreases as cognitive capability increases, especially improves in recent memory. There were a few limitations in our study. First, we cannot rule out the possibility of practice effects resulting in some of the improvements observed in the following assessment. Second, there was no elderly normal control subjects treated with DPZ; therefore, the specificity of these observations for AD is unknown. Third, in the procedure of electrophysiologic assessments, we used the fixed interstimulus interval and did not record the data of the performance measures in ERPs recordings for comparing any performance differences before and after the treatment. That would be a bias for ERP grand average recording. Fourth, the CASI instrument is a preferred research tool for epidemiologic research; however, it does not fulfill a need for psychological assessments in clinical practice. Fifth, this was not a double-blind, placebo-controlled study. In conclusion, mild AD patients had delayed N200 and P300 latencies, no significant differences in N100 and P200 components, and impaired cognitive function compared with control subjects, indicating that patients with mild AD still had intact early sensory processing but impaired higher-level cognitive processes that could influence behavior deviation. The ChEI DPZ that enhances higher-level cognitive processing time revealed that P300 latency decreased as cognitive capability increased, especially improved in recent memory. REFERENCES American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth ed (DSM-IV). Washington: American Psychiatric Press, 1994. Bryson HM, Benfield P. Donepezil. Drugs Aging 1997;10:234–239. Caravaglios G, Costanzo E, Palermo F, Muscoso EG. Decreased amplitude of auditory event-related delta responses in Alzheimer’s disease. Int J Psychophysiol 2008;70:23–32. Chang YS, Tang SH, Chen MC, Chen WJ. Effects of donepezil on the cognitive function in patients with Alzheimer’s disease. Taiwanese J Psychiatry 2005;19:161–163. Dierks T, Frölich L, Ihl R, Maurer K. Event-related potentials and psychopharmacology. Cholinergic modulations of P300. Pharmacopsychiatry 1994;27:72–74. Donchin E, Heffley E, Hillyard SA, et al. Cognition and event-related potentials II. The orientation reflex and P300. Ann N Y Acad Sci 1984;425:39–57. Frodl-Bauch T, Bottlender R, Hegerl U. Neurochemical substrates and neuroanatomical generators of the event-related P300. Neuropsychobiology 1999;40: 86–97.
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Gironell A, Garcia-Sanchez C, Estevez-Gonzalea, et al. Usefulness of P300 in subjective memory complaints: a prospective study. J Clin Neurophysiol 2005;22:279–284. Golob EJ, Johnson JK, Starr A. Auditory event-related potentials during target detection are abnormal in mild cognitive impairment. Clin Neurophysiol 2002;113:151–161. Halgren E, Marinkovic K, Chauvel P. Generators of the late cognitive potentials in auditory and visual oddball tasks. Electroencephalogr Clin Neurophysiol 1998;106:156–164. Hammond EJ, Meador KJ, Aung-Din R, Wilder BJ. Cholinergic modulation of human P3 event-related potentials. Neurology 1987;37:346–350. Homma A, Takeda M, Imai Y, et al. Clinical efficacy and safety of donepezil on cognitive and global function in patients with Alzheimer’s disease. A 24week, multicenter, double-blind, placebo-controlled study in Japan. E2020 Study Group. Dement Geriatr Cogn Disord 2000;11:299–313. Hughes CP, Berg L, Danziger WL, et al. A new clinical scale for the staging of dementia. Br J Psychiatry 1982;140:566–572. Juckel G, Clotz F, Frodl T, et al. Diagnostic usefulness of cognitive auditory event-related P300 subcomponents in patients with Alzheimer’s disease? J Clin Neurophysiol 2008;25:147–152. Katada E, Sato K, Sawaki A, et al. 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. Katada E, Sato K, Ojika K, Ueda R. Cognitive event-related potentials: useful clinical information in Alzheimer’s disease. Curr Alzheimer Res 2004;1:63–69. Kutas M, McCarthy G, Donchin E. Augmenting mental chronometry: the P300 as a measure of stimulus evaluation. Science 1977;197:792–795. Lijffijt M, Lane SD, Meier SL, et al. P50, N100, and P200 sensory gating: relationships with behavioral inhibition, attention, and working memory. Psychophysiology 2009;46:1059–1068. Liu HC, Teng EL, Chuang YY, et al. The Alzheimer’s Disease Assessment Scale: findings from a low-education population. Dement Geriatr Cogn Disord 2002a;13:21–26. Liu HC, Teng EL, Lin KN, et al. Performance on the cognitive abilities screening instrument at different stages of Alzheimer’s disease. Dement Geriatr Cogn Disord 2002b;13:244–248. López-Pousa S, Vilalta-Franch J, Garre-Olmo J, et al. Effectiveness of donepezil on several cognitive functions in patients with Alzheimer’s disease over 12 months [in Spanish]. Neurologia 2001;16:342–347. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984;34:939–944. Meador KJ, Loring DW, Hendrix N, et al. Synergistic anticholinergic and antiserotonergic effects in humans. J Clin Exp Neuropsychol 1995;17:611–621. Pfefferbaum A, Ford JM, Kraemer HC. Clinical utility of long latency cognitive event- related potentials (P3): the cons. Electroencephalogr Clin Neurophysiol 1990;76:6–12. Picton PW. The P300 wave of the human event-related potential. J Clin Neurophysiol 1992;9:456–479. Polich J, Corey-Bloom J. Alzheimer’s disease and P300: review and evaluation of task and modality. Curr Alzheimer Res 2005;2:515–525. Polich J, Criado JR. Neuropsychology and neuropharmachology of P3a and P3b. Int J Psychophysiol 2006;60:172–185. Polich J, Herbst KL. P300 as a clinical assay: rationale, evaluation, and findings. Int J Psychophysiol 2000;38:3–19. Prince M, Acosta D, Chiu H, et al. Effects of education and culture on the validity of the Geriatric Mental State and its AGECAT algorithm. Br J Psychiatry 2004;185:429–436. Ritter W, Simon R, Vaughan HG Jr, Macht M. Manipulation of event-related potential manifestations of information processing stages. Science 1982;218: 909–911. Rogers SL, Friedhoff LT. Long-term efficacy and safety of donepezil in the treatment of Alzheimer’s disease: an interim analysis of the results of a US multicentre open label extension study. Eur Neuropsychopharmacol 1998; 8:67–75. Schneider W, Shiffrin RM. Controlled and automatic human information processing I: detection, search and attention. Psychol Rev 1977;84:1–66. Teng EL, Hasegawa K, Homma A, et al. The Cognitive Abilities Screening Instrument (CASI): a practical test for cross-cultural epidemiological studies of dementia. Int Psychogeriatr 1994;6:45–58. Thomas A, Iacono D, Bonanni L, et al. Donepezil, rivastigmine, and vitamin E in Alzheimer’s disease: a combined P300 event-related potentials/neuropsychologic evaluation over 6 months. Clin Neurpharmacol 2001;24:31–42. Werber EA, Gandelan-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;110:659–669.
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