PSYCHOGERIATRICS 2010; 10: 191–197 doi:10.1111/j.1479-8301.2010.00341.x CASE REPORT Comparing Mini-Mental State Examination and Attention and Digit Span in elderly exposed to polychlorinated biphenyls and polychlorinated dibenzofurans psyg_341 191..197 Kao-Chang LIN,1,2 Po-Chang HUANG,3 Poh-Shiow YEH,1 Jinn-Rung KUO2,4 and Der-Shin KE1,5 Departments of 1Neurology, 3Orthopedics, 4Neurosurgery, and 5Environmental and Occupational Medicine, Chi-Mei Medical Center, and 2Institute of Biotechnology, Southern Taiwan University, Tainan, Taiwan Correspondence: Dr Der-Shin Ke MD PhD, Department of Neurology, Environmental and Occupational Medicine, Chi-Mei Medical Center, 901, Jong Hwa Road, Yang Kung city, 710, Tainan, Taiwan. Email: gaujang@mail2000.com.tw Received 25 April 2010; accepted 9 September 2010. Key words: Attention and Digit Span, Mini-Mental State Examination, polychlorinated biphenyls/polychlorinated dibenzofurans. Abstract Background: Polychlorinated biphenyls (PCB)/polychlorinated dibenzofurans (PCDF) are known to affect central nervous functioning. In recent studies, elderly patients who have been exposed to these have been noted to have psychological deficits. There is little known about which test is sensitive to neurotoxins in cognitive evaluation. The objective of the present study was to compare the significance between selective psychological tests in cognitive assessment in PCB-laden elderly. Methods: A retrospective PCB/PCDF exposed cohort was observed. Exposed elderly aged ⱖ60 years and registered in Central Health Administration were enrolled, and similar age- and sex-matched subjects served as non-exposed controls. The Mini-Mental State Examination (MMSE) and Attention and Digit Span (ADS) were tested in both groups. Student’s t-test, c2-test and linear regression models were used for statistical analysis. Results: A total of 165 exposed patients and 151 controls were analyzed. The exposed group included 49% men, a mean age of 69.3 1 6.4 years and an education level of 4.0 1 3.9 years. The controls included 52% men, a mean age of 69.9 1 5.5 years and an education level of 4.5 1 3.2 years. There was no statistical difference in MMSE before and after adjusting for the confounding variables of age, sex and education (P = 0.16 vs P = 0.12). However, ADS-forward and ADS-total scores showed a significant decline in the exposed subjects (P = 0.0001 vs P = 0.001). Using a linear regression among stratified PCB and cognitive functioning (ⱕ30 ppb; 31–89; ⱖ90), a dose effect was found at the medium (31–89 ppb) and high exposure (⭌90 ppb) levels. Conclusion: Our observations showed attention and short-term memory were impaired in PCB-laden elderly patients. Higher exposure level showed lower cognitive functioning in ADS. The MMSE was insensitive to neurotoxins. The present study shows that the selective test has a decisive role in toxic-related cognitive assessments. INTRODUCTION Polychlorinated biphenyls (PCB) and the products of polychlorinated dibenzofurans (PCDF) are toxic chemicals and have been widely used in the past, but have been abandoned since 1979 in the USA and 1988 in Taiwan.1–3 An outbreak of PCB/PCDF con© 2010 The Authors Psychogeriatrics © 2010 Japanese Psychogeriatric Society tamination occurred in Taiwan in 1979, and led to a series of adverse effects.4–6 The people who consumed toxic rice oil developed skin chloracne, arthritis, peripheral neuropathy, headaches and general malaise.7,8 Longitudinal follow-up studies of these exposed victims disclosed adverse health 191 K-C. Lin et al. consequences, such as hypothyroidism, menstruation abnormalities and reproductive disorders. Even in their descendents, a slowing of developmental milestones was noted.4–6,9–12 Exposure to PCB/PCDF is known to cause cognitive impairments in children.4–6,13,14 Mothers who are exposed to PCB might deliver babies with learning difficulties, motor delays and poor endurance. These babies showed a decline in intelligence scores compared with normal Taiwanese children at age 7 years.4,9 Such effects are similar to a Michigan cohort in which a greater decline was noted at the age of 11 years.14 Cognitive impairment in the elderly has also been found. Schantz et al. reported an existing cohort in 2001 of adult sport-caught fish-eaters exposed to PCB who had impaired memory and learning.15 The results of that study were similar to the results in Taiwanese adults, with cognitive decline limited to memory and learning ability, but not relevant to executive or sensory functions.16 Experimental studies have shown that PCB have effects on the cortical and subcortical brain. In experimental rats fed with Aroclor 1260, the dopamine concentration declined in the basal ganglion and slow kinetic movements were noted.17 A mother rhesus monkey fed with compound Aroclor 1248 for 44 months delivered a baby monkey with learning disabilities and behavior abnormalities.18 Adult animals fed with variable chloride-content food also have spatial disorientation and cubic concept disruption.19,20 These reported findings suggest that in different congeners of PCB, with higher or lower levels of chlorination, the experimental animals had learning disabilities, behavioral retardation, difficulty in doing complex tasks or slow motor activities. It was speculated that neurotoxins could affect the central system integrity in both the immature and mature brain. In the present study, we used the Mini-Mental State Examination (MMSE) and Attention and Digit Span (ADS) assessment, and studied the dose–response effect in elderly patients who had been exposed to PCB/ PCDF. METHODS A retrospective study was carried out with the existing cohort (Yu-Cheng cohort) from the outbreak of PCB/PCDF contamination in 1979 in central Taiwan. Structured questionnaires were introduced to 192 PCB-exposed elderly aged ⱖ60 years and matched 1:3 with controls under similar conditions as described previously.6,8,16 The matched controls were selected in 1980–82 for their similar socioeconomic level and living conditions in the neighborhood. The MMSE and ADS were given to the subjects by well-trained interviewers who were not aware of the subjects’ exposed conditions. All subjects had ceased exposure since 1980. The present study was approved by Ethical Committee for Human Research at Cheng-Kung University Medical College in Tainan. Figure 1 shows the recruitment and participation of the study subjects. Those who agreed to receive cognitive assessments were administered the assessments by interviewers during home visits. Finally, 165 subjects and 151 nonexposed controls completed both MMSE and ADS, and were included for analysis. Serum levels of PCB were analyzed in 1980–1982 in approximately 80% of the Yu-Cheng individuals by means of packed column, electron-capture gas chromatography and an adaptation of the Webb–McCall method to a computer data system in which a Japanese brand of PCB mixture, Kanechlor 500 (Kanegafuchi Chemical Industry, Osaka, Japan), was used Yu-Cheng Cohort 2061,M=998,F=1063 1:3 matched similar conditions for Age 60yrs control in 1980-82 (door by door control) 1178, M=565, F=613 381, M=182, F=199 Limited to 10 counties in central Taiwan 231 on first visit complete tests (E=129, M: 49%; C=102, M: 46%) 43 had incomplete tests, 11 were absent (2 at work, 7 were ill, and 2 were deaf) New random selection on second visit from incomplete and registered persons above 328 participants, E=165 (M=49%), C=151 (M=52%) complete MMSE and ADS tests were enrolled for analysis Figure l Flow chart of eligibilities in Yu-Cheng cohort in Taiwan. ADS, Attention and Digit Span; MMSE, Mini-Mental State Examination. © 2010 The Authors Psychogeriatrics © 2010 Japanese Psychogeriatric Society Cognitive test in elderly exposed to neurotoxin as a reference standard.21 These levels were used to determine the dose–response relationship in different stratifications. MMSE and ADS A standardized simple neurobehavioral test (MMSE), total score of 30, was used to assess a wide range of cognitive domains, including orientation, attention, immediate and short-term recall, visual-construction, organizational skill, and the ability to follow simple verbal and written commands.22 The test has been proven to have good validity in identifying cognitive functions in Chinese subjects.23 In the MMSE, a 3-objects recall in 5 min, time orientation, place orientation, series 7 tests and verbal commends were also scored for comparison. The ADS of the Wechsler Adult Intelligence Scale-Revised (WAIS-R)24 was used to measure attention, learning and immediate memory. It comprised of two subtests of forward and backward, immediate number recalls by verbal command, which involved different cognitive processes. Total scores of 30 were representative of good short-term memory. In a recent report, it was found that exposure to hydrogen sulfide (H2S) had a significantly lower mean value of MMSE scoring than that of the controls.25 Because MMSE is a global test for screening of cognitive impairment or dementia, as ADS is an indicator for toxic evaluation,26,27 we tried to compare MMSE scores and subgroup analysis between PCB-exposed and control elderly for cognitive assessments. Statistical analysis In the present study, records of all subjects with outlying MMSE and ADS values were excluded for a possible poor performance on the assessments or a recording error. Individuals with missing or incomplete information were excluded, and the final data included 165 exposed subjects and 151 reference subjects. To evaluate non-linear or linear correlations between the PCB exposure levels and MMSE and ADS scores, both continuous and stratified PCB variables were estimated. Plots of the relationships were examined to ascertain whether or not the models described and the associations made were driven by outlying points. All significance tests were two-sided. RESULTS A total of 316 eligible subjects, with 57% of the previously exposed group and 61% of the control sub© 2010 The Authors Psychogeriatrics © 2010 Japanese Psychogeriatric Society jects, were analyzed. Overall, the mean age was 69.5 1 5.9 years (range 60.0–91.1 years) and the mean education level was 4.3 1 3.5 years (grading from 0 to 15 years). The mean age of the exposed victims was younger than that of the controls (mean 69.2 vs 69.9 years), as was the educational level (mean 4.01 vs 4.49 years). Exposed females had the lowest education level (n = 84, mean 2.44 years). There were no differences in hearing and visual conditions that might have affected the test accuracy. The demographic data of both groups showed no significant differences, and the exposed females had higher PCB levels, as estimated in 1980–82 (Table 1). MMSE The exposed victims had lower performance scores than the controls in the MMSE. No other covariates were linked, by adjusting each potential confounding variable except for age, sex and education, and the stratification associated with MMSE is shown in Table 2. No statistically significant differences in the MMSE before and after adjusting the three confounders were found (P = 0.16 vs P = 0.12) using Student’s t-test and simple linear regression model (ANOVA). The 3-objects recall (red color, eyeglass and honesty) scores in 5 min showed no significant difference (P = 0.53). In subgroup analysis of series 7 tests, time and place orientation, and verbal comments, there were not shown to be statistically significant between both. ADS The ADS test involves the total number of correct answers in forward and backward digit recalls; the patients with a higher score were shown to have a better memory. Our results in the ADS were sensitive to toxic exposure. The short-term memory tests showed a decline in the exposed victims of ADSforward (P < 0.001) and ADS-total (P = 0.001) recalls (Table 3). There was no statistically significant difference in ADS-backward recalls. Gender links in MMSE and ADS Exposed female victims showed lower scores than the exposed male victims after adjusting confounders in the MMSE (21.5 vs 25.6, P < 0.001) and in the ADS-forward (10.4 vs 11.7, P = 0.02), ADS-backward (3.1 vs 5.1, P = 0.0007) and ADS-total (13.5 vs 16.8, P = 0.0008) scores. This difference was also statistically significant between the female patients and the 193 K-C. Lin et al. Table 1 Age, education, physical illness, alcohol and smoking status of Yu-Cheng and control subjects taking neurocognitive tests in Taiwan No. subjects Age, years (mean 1 SD) Age, distribution 60–64 (%) 65–69 (%) 70–74 (%) ⱖ75 (%) Education, year (mean 1 SD) Education year, distribution 0–3 (%) 4–6 (%) 7–9 (%) >9 (%) Current drinking (%) Current smoking (%) Body height (cm) Bodyweight (kg) Body mass index (kg/m2) Serum levels of PCB (ppb) in 1980–1982 (GSD)† Cataract (%) Hearing impairment (%) Yu-Cheng Male Reference P-value Yu-Cheng Female Reference 81 69.7 1 6.2 80 70.1 1 5.5 0.61 84 68.9 1 6.5 71 69.5 1 5.5 28.1 28.1 20.7 23.2 5.6 1 0.4 24.1 26.4 26.4 23.0 5.5 1 0.4 34.5 27.4 20.2 17.9 2.4 1 0.3 20.0 34.7 26.7 18.7 3.3 1 0.4 26.8 48.8 9.8 14.6 19.2 60.7 164.2 1 0.7 64.6 1 0.9 23.9 1 0.3 68.1 1 7.3 20.7 67.8 5.8 5.8 28.8 53.9 163.2 1 0.8 64.1 1 1.0 23.9 1 0.3 1.5 66.7 28.6 2.4 2.4 15.6 24.1 155.3 1 0.6 56.4 1 0.9 23.6 1 0.3 88.2 1 12.1 49.3 48.0 2.7 0.0 22.2 31.0 156.9 1 0.7 56.8 1 1.1 23.1 1 0.4 1.7 22.1 18.2 10.0 16.2 30.6 16.7 24.0 16.0 0.31 0.88 0.06 0.19 0.43 0.34 0.71 0.88 0.13 0.60 P-value 0.47 0.32 0.09 0.05 0.33 0.36 0.09 0.74 0.31 0.53 1.00 † Data derived from previous studies in Taiwan. Average age/years of education, body height (cm), bodyweight (kg), and body mass index (kg/m2) were compared by unpaired t-test; age/education distribution, smoking, alcohol, hearing and visual problems were compared by c2-test. GSD, geometric standard distribution; PCB, polychlorinated biphenyls; ppb, parts per billion. Table 2 Mini-Mental State Examination and stratified age, sex and education levels in study enrollments Education n 0–3 3–6 6–9 >9 Age (years) 60–64 65–69 70–74 75–79 Sex Male Female 131 149 17 19 0.52 5.92 8.76 12.37 1 1 1 1 88 95 77 52 4.47 3.08 4.07 3.63 1 1 1 1 161 155 Education level (years) MMSE-scores P-value 1.06 0.37 0.66 1.30 21.27 23.75 26.00 25.58 1 1 1 1 4.59 6.57 3.50 7.32 <0.001 0.16 0.06 3.38 3.21 3.36 3.82 24.76 23.29 22.84 20.50 1 1 1 1 5.65 5.21 5.24 7.11 0.27 0.33 0.004 0.50 5.58 1 3.39 2.84 1 3.13 24.08 1 6.43 21.79 1 5.12 0.03 All values are mean 1 standard deviation. c2 statistics. MMSE, Mini-Mental State Examination. control females in the MMSE (21.5 vs 22.9, P = 0.02), ADS-forward (10.4 vs 11.9, P = 0.0001), ADSbackward (3.1 vs 3.9, P = 0.03) and ADS-total (13.5 vs 15.8, P = 0.0003) scores. However, the difference was statistically insignificant between the exposed male patients and the male controls in MMSE (25.3 vs 25.6, P = 0.65), ADS-forward (11.8 vs 12.3, P = 0.09), ADS-backward (5.0 vs 5.0, P = 0.88), and ADS-total (16.8 vs 17.3, P = 0.30) scores. The data showed that 194 the female subjects exposed to PCB had a greater decline in the cognitive tests. Dose–response Effects of serum PCB on MMSE and ADS were also tested using linear or multiple regression models. Both continuous and stratified PCB variables (lower ⱕ30 ppb; medium 31–89 ppb; higher ⱖ90 ppb) were used for statistical analysis, by eliminating the impact © 2010 The Authors Psychogeriatrics © 2010 Japanese Psychogeriatric Society Cognitive test in elderly exposed to neurotoxin Table 3 Mini-Mental State Examination and Attention and Digit Span tests in the exposed and control groups MMSE scores A 3-objects recall Series 7 tests Time orientation Place orientation Verbal comments ADS-forward ADS-backward ADS-total Exposed (n = 165) Mean SE Control (n = 151) Mean SE 23.54 1.41 4.01 4.36 4.64 3.00 11.10 3.75 15.20 24.17 1.47 4.25 4.34 4.72 3.16 12.11 4.25 16.55 4.26 0.07 1.22 0.83 0.72 1.46 0.18 0.17 0.28 3.60 0.08 1.05 0.82 0.68 1.37 0.19 0.18 0.30 t P 1.43 0.62 1.81 0.21 1.00 0.99 0.0002* 0.10 0.002* 0.15 0.53 0.07 0.83 0.32 0.32 0.0001* 0.12 0.001* Student’s t-test was used for comparison between both groups, *significant P < 0.05. ADS, Attention and Digit Span; MMSE, Mini-Mental State Examination. Table 4 Relationships between stratified polychlorinated biphenyls levels and Mini = Mental State Examination and Attention and Digit Span Tests (mean 1 SE) ADS-forward ADS-backward ADS-total MMSE PCB (ⱖ90 ppb) n = 43 11.06 4.10 15.20 24.40 1 1 1 1 0.29 0.31 0.56 0.46 PCB (31–89 ppb) n = 63 11.09 4.14 15.20 23.60 1 1 1 1 0.36 0.25 0.45 0.37 PCB (ⱕ30 ppb) n = 42 11.69 4.18 15.90 23.40 1 1 1 1 0.36 0.31 0.56 0.46 Control n = 151 12.14 4.47 16.60 24.10 1 1 1 1 0.19 0.16 0.29 0.24 P 0.004* 0.56 0.03* 0.25 Post-hoc Tukey HSD analysis. The polychlorinated biphenyls (PCB) level ⱖ30 ppb (as medium and high level) had significant difference in Attention and Digit Span (ADS)-forward and ADS-total than controls adjusted for age and education. Overall, 17 exposed subjects did not have PCB data in 1980–1982. Values are mean 1 standard error. MMSE, Mini-Mental State Examination, *<0.05 of significance. of confounding factors, and there was no correlation with MMSE. In contrast, ADS-forward and ADS-total scores were correlated to the stratified PCB and showed a significant dose effect in medium and high levels (Table 4). DISCUSSION The present study identified neurocognitive dysfunction in the elderly more than 25 years after exposure to PCB/PCDF in Taiwan. The CNS involvement related to the hippocampus as memory and learning, but not cortical domains, was emphasized by several animal and epidemiological studies.12–16 The deficits in attention and learning abilities show that PCB/PCDF neurotoxins can interfere with the integrity of short-term memory recalls, as in the present study. These results suggested that different neurotoxin might have a specific or different neurocognitive influence. The MMSE is not a sensitive test, as a result of the non-specific variables and because many test items regarding executive, organization skill or visual constructive ability might be more related to diffuse brain pathology. A simple short-term memory test involving a recall of three objects in 5 min seems to be more appropriate to study the hippocampus function. © 2010 The Authors Psychogeriatrics © 2010 Japanese Psychogeriatric Society However, 3-object (eyeglass, red color and honesty) recall represents different abstracting memory processes that were not statistically significant between the exposed patients and unexposed controls (P > 0.05). The 3-object list might be too small to be differentiated between both comparisons. The subgroup analysis, including subtract 7 from 100 (series 7) tests, time and place orientation, and verbal comments tests were carried out with Student’s t-test, there were no statistical significance between the PCB exposed group and control group (all P > 0.05), as shown in Table 3. The exposed female patients had a greater decline in the MMSE, and the women with a lower level of education or who were older, had a worse outcome. The ADS has been proven to have a high sensitivity for cognitive deficits in those with elevated levels of persistent organic pollutants (POP).27 In our data, the exposed victims had significantly lower scores in forward (P < 0.001) and total (P = 0.001) digit recalls, similar to POP-related cognitive impairment. There was no relationship among the various PCB concentrations and the MMSE using an ANOVA model. However, a post-hoc dosing effect at medium and high levels was noted, in that a higher exposure level 195 K-C. Lin et al. led to lower ADS forward and total scores. The neurobehavioral deficits in the elderly with memory deficits in domains were different from children exposed to PCB with delayed developmental milestones. The discrepancy between the exposed elderly and children suggested that the selection of parameters in neurobehavioral tests was important. Gender linked differences in MMSE and ADS are obvious, because the exposed females had significantly lower scores in ADS-forward, ADS-backward, ADS-total and MMSE than unexposed controls by adjusted age and education. This significance was not seen in male subjects. This shows that the sex discrimination to toxic effects was different. Changes in androgen status have been reported in studies of animals exposed to PCB perinatally.19 In the Yu-Cheng cohort, the gender difference was noted with a worse executive function in boys and a better spatial ability in girls who were born to PCB-laden mothers.29,30 However the difference was not found in young adults and adolescents.31 Further investigations of sex-linked or estrogen influence to toxic effects are required. In addition, a longitudinal study of the adult sport-caught fish-eaters15 had also shown learning and memory deficits. The differences between both papers included a different sample size (316 to189), an older cohort (69.5 to 64.3 years) and a higher mean PCB blood level (78.3 to 7.9 ppb) in the present study. This comparison was described in another study.16 A weakness of the present study is that there was no imaging study to define the organic brain/vascular lesions with cognitive impairments. The exposed and unexposed subjects were considered to have equally time-dependent cognitive decline by years28 without organic insults. Because the ageing process and organic/vascular lesions are speculated to cause different cognitive deterioration after initial exposure, future research to the toxic-related cognitive deficits in the form of a neuroimaging study for anatomical change, in addition to neuropsychological functional assessment, is required. In conclusion, the elderly patients who had been exposed to PCB/PCDF had a significant impairment in ADS, but not in MMSE of the worldwide test for cognitive assessments. There is a dose effect between ADS and PCB exposure, but not in MMSE. The memory and cognitive dysfunction results were different because different psychological tests were used in the Taiwan cohort study. 196 ACKNOWLEDGEMENTS We thank Professor YL Guo and Professor CC Huang for their guidance. 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