Current Alzheimer Research (www.bentham.org/car), 2004, 1, 55-61
Bentham Science Publishers Ltd.(www.bentham.org)

Cross-Cultural Comparison of Mild Cognitive Impairment between China and USA

Gelin Xu1,2, John Stirling Meyer3,4,*, Yuangui Huang2,Guanghui Chen, Munir Chowdhury3,4 and Minh Quach3, 4

1Department of Neurology, Nanjing General Hospital of PLA, Nanjing, PR China, 2Department of Neurology, Xijing Hospital, Xi’an, PR. China, 3Department of Neurology, Baylor College of Medicine, Houston, USA, 4Cerebrovascular Research Laboratory, Veterans Administration Medical Center, Houston, USA

*Address correspondence to this author at the Neurology Department, Baylor College of Medicine, Director Cerebrovascular Research Laboratory, VAMC Building, 110, Room 225 2002, Holcombe Boulevard Houston Texas 77030, USA; Tel: 713-795-5807; Fax 713-794-7583; E-mail: jmeyer@bcm.tmc.edu

Abstract: Individuals with mild cognitive impairment (MCI) are at increased risk for Dementia of Alzheimer’s type (DAT), vascular dementia (VaD), Lewy Body (LBD) and Fronto-temporal dementias (FTD). Risk factors and conversion rates of MCI to dementia have not been thoroughly investigated in developing countries. Chinese and English versions of Mini-Mental State Examination were administered serially among well-matched subjects from two clinics located in Xi’an, China and Houston, USA. Subtle cognitive impairments were weighed according to MCI criteria as defined previously. Subjects with MCI were followed for an additional 3 years after their identification. Diagnoses of VaD and DAT were made according to established criteria. During screening period, 73 American and 65 Chinese individuals were identified with MCI. After 3 years of MCI follow-up, of the 73 American MCI subjects, 35 (47.9%) developed DAT and 15 (20.5%) developed VaD. Of the 65 Chinese MCI subjects, 12 (18.5%) developed DAT and 19 (29.2%) developed VaD. According to Kaplan-Meier analysis, Chinese MCI subjects, despite their lower educational level, are 1.7 times less likely to progress to DAT and 2.3 times more likely to progress to VaD than American subjects within 3 years of MCI being identified (p<0.01). Data suggest that progression rates of MCI vary considerably among subjects from two countries. American MCI subjects are more prone to DAT, while Chinese subjects are more prone to VaD. Differences in genetic factors, cultures, educational levels, and preventive treatments of vascular risk factors are proposed as responsible for this uneven geographic distribution for different types of dementia.

Keywords: Aging, Alzheimer Disease (DAT), Cross-Cultural Comparison, Vascular Dementia (VAD), Mild Cognitive Impairment (MCI), Psychometrics

Introduction

Mild cognitive impairment (MCI) refers to the transitional stage between normal aging and dementia [1]. Individuals with MCI are at increased risk for dementia of Alzheimer’s type (DAT) [2], vascular dementia (VaD) [3-5] and probably other types of dementia [6,7]. Distinguishing individuals with MCI from cognitively normative elderly is increasing in importance as preventive measures and early pharmacological interventions for dementia continue to emerge [8-10]. Identification criteria and factors influencing outcomes of MCI have been well studied in developed countries [2,4,6,11]. The impact of dementia, as well as MCI, has not been studied as much in developing countries where the tempo of population aging is even faster than that in developed countries [12].

Considerable variations have been reported in prevalence and incidence of DAT and VaD across the world especially between developed and developing countries [13-16]. MCI, as the prodromal stage of dementia, may have different outcomes and progression rates for dementia among ethnic populations inhabiting different geographic regions. Assessment of these variations may provide an opportunity to explore risk factors for dementia and improve methods for early diagnosis and prevention of dementia [17].

Subjects and Methods

Subjects

Subjects were enrolled in two neurological research clinics, located in Xi’an, China and Houston, USA. Both clinics are attached to a medical school. Participants are outpatients in two general hospital and they are permanent dwellers in nearby urban areas of a metropolis, where subjects can be followed feasibly for relatively long terms. Subjects in both clinics were asked to join the research voluntarily. After enrollment, they receive free medical care. Selection of subjects in the two clinics followed the same processes and criteria, which have been reported elsewhere [18]. Briefly, subjects aged 60 years or older were included if they could satisfy the requirements for regular follow-up evaluations over a relatively long period. Subjects with pre-existing dementia, organic brain disorders, epilepsy, previous strokes and infectious central nervous system diseases were excluded. To meet the requirements for screening, subjects selected at both sites must have completed at least 6 years of education. To homologize race components, only Han Chinese at Xi’an site and Caucasian Americans at Houston site were enrolled. The study was approved separately by Institutional Review Boards of Baylor College of Medicine in Houston and by Ethical Committee of Research in Xijing Hospital in Xi’an. Each participant signed informed consent.

Subjects in the two clinics were followed by the same process. They were scheduled for regular clinic visits at three monthly intervals. All subjects enrolled in Houston performed original English versions of Mini-Mental State Examination (MMSE) [19] and Cognitive Capacity Screening Examination (CCSE) [20]. Subjects enrolled in Xi’an performed culturally adapted Chinese versions of MMSE (MMSE-CV) [21] and CCSE (CCSE-CV). It has been reported that Chinese and English versions of MMSE have similar sensitivity and specificity for detecting the cognitively impaired [22]. Ancillary evaluations included medical, neurological and basal laboratory examinations. Cerebrospinal fluid (CSF) analysis, electroencephalography (EEG), electrocardiography (ECG) and transcranial Doppler ultrasonography (TCD) were performed as indicated. Subjects underwent annual CT and/or MRI scans. They were also followed, as necessary, by monthly telephone interviews and if subjects or caregivers expressed concern about possible deterioration in cognition or behavior, subjects were asked to arrange for and attend additional clinic visits for further evaluation. The purpose was to detect cognitive impairments or deterioration at the earliest possibility.

Identification of MCI was made if subjects met following criteria: (1) memory complaints, (2) normal activities of daily living, (3) absence of dementia, and (4) mild quantifiable impairments of cognitive function tested by MMSE, with cut-off points indicating MCI, adjusted for age and education. Cut-off points were set at one standard deviation below means for each population subgroup of that given age and educational level [23]. For example, for 70-74 year-old subjects with college education, cut-off point for MCI was: 28-1.6=26.4, while for the same age-range with only 6-8 years of education, cut-off point for MCI was: 26-1.8=24.2.

After identification of MCI, cognitive performance was tracked at 3-6 monthly intervals to determine whether or not cognitive deterioration reached criteria for dementia. To make the diagnosis of MCI and dementia consistent at the two sites, a neurologist (GX) from the Xi’an site was trained for one year as a research fellow at the Houston site. Diagnosis of DAT was made according to DSM-IV [1] and NINCDS/ADRDA criteria [24], and for VaD according to NINCDS/AIRENS criteria [25].

Neuropsychological Evaluations

MMSE was the principal psychometric instrument for measuring cognitive function. A more sensitive instrument, CCSE, provided supplemental measurements. Because depression is common among the elderly and may confound cognitive evaluations [26], the Hamilton Depression Rating Scale (HDRS) [27] was administered together with MMSE and CCSE to monitor possible influences of depressive symptoms on cognitive performance. Subjects with major depression were excluded from data analysis.

MMSE was administered according to standardized procedures [19], maximal score being 30. Subtests representing five different domains of cognition were analyzed: (1) Orientation: including orientation to time and place, having maximum of 10 points, (2) Memory: including 3 words registration plus delayed recall, with maximum of 6 points, (3) Attention and calculation: tested by serial sevens subtracted from 100, with maximum of 5 points, (4) Language: including naming a watch and pencil, repeating a “tongue-twisting” sentence, obeying a three-step command, reading and writing a sentence, with maximum of 8 points, and (5) Design copying: copying an intersectional double-pentagon figure which tests visuospatial function, with maximum of 1 point [19].

Statistical Analysis

Unadjusted statistical analyses were performed using chi-square analysis for dichotomous data and Mann-Whitney rank sum analysis for ordinal data. Temporal conversion rates from MCI to dementia were compared by Kaplan-Meier’s analysis. Inter-group comparisons of parameter data were evaluated by independent t tests.

Results

During 3 years of continuous follow-up enrollment, a total of 138 subjects, 73 in Houston and 65 in Xi’an, were identified as MCI from more than 2,000 outpatients at each site. The combined incidence of MCI around age 70 in the two countries for MCI is about 3.5%. For the 73 American MCI subjects, after 1-3 (2.45±2.15) years of follow-up, 35 (47.9%) developed DAT; 15 (20.5%) developed VaD and all 23 of the rest (31.5%) showed persistent MCI when follow-up was closed (or had dropped out due to death in 3, and 4 were lost during 3 years of follow-up). For 65 Chinese subjects with MCI, after 1-3 (2.78±1.90) years of follow-up, 12 (18.5%) developed DAT, 19 (29.2%) developed VaD and the rest 34 (52.3%) showed persistent MCI (including 5 deceased and 2 lost during 3 years of follow-up). MCI subjects in both sites were followed for a similar interval (p=0.71).

Table 1.     Demographic Characteristics for American and Chinese Subjects at the Time of MCI Identification

Table 1 shows demographic characteristics and screening scores for MCI subjects from the two countries, at the time of MCI identification. No significant differences were detected regarding age, gender, and preferred handedness between subjects in two sites at time of MCI identification. Chinese MCI subjects had fewer years of education than American subjects (p<0.05). Smoking and drinking habits of subjects from the two sites were at the same level. The rate of transient ischemic attack (TIA) is higher in Chinese than in American MCI subjects (p<0.01). No significant differences were detected regarding rates of heart diseases, hypertension, hyperlipidemia and diabetes mellitus between subjects from two sites. Although there is a tendency for American subjects to have higher prevalence of family history with neurodegenerative disease (NDD) and lower prevalence of family history with cerebrovascular disease (CVD), no significant differences for family history for these two kinds of disease were detected.(p<0.01). No significant differences for MMSE and CCSE total scores between subjects from two countries were detected.

Fig. (1). Spectrum of cognitive impairments, expressed as percentage of normal, based on subtest scores of MMSE, for Chinese and American subjects at the time of MCI identification. * indicates significant difference between subjects from two countries (p<0.01). Memory was less impaired and language was more impaired among Chinese versus Americans

In the analysis of the individual subtests and total score of MMSE at the time of MCI identification, as showed in Fig. (1), Chinese MCI subjects scored lower in language subtest than American subjects (p<0.01). American subjects scored lower in memory subtests than Chinese subjects

Fig. (2). Kaplan-Meier cumulative survival plot showing progression rates for MCI to DAT for Chinese subjects (solid line) and American subjects (dotted line). Log-rank test shows DAT conversion rates for American subjects to be significantly higher than that for Chinese subjects (p<0.01).

Fig. (2) shows the Kaplan-Meier analysis for conversion to DAT among Chinese versus American MCI subjects during 3 years of observation. According to Kaplan-Meier estimates, first year conversion rates to DAT (with 95% confidence interval) are 14.2% (5.0%-23.4%) for Chinese subjects, versus 32.5% (21.3%-43.8%) for American subjects; while 3-year conversion rates to DAT are 35.4% (18.6%-62.2%) for Chinese subjects and 58.8% (45.4%-72.2%) for American subjects. Log-rank (Mantel-Cox) test estimates American MCI subjects to be more prone to convert to DAT compared with Chinese subjects (=6.98, p<0.01).

Fig. (3). Kaplan-Meier cumulative survival plot showing progression rates for MCI to VaD for Chinese subjects (solid line) and American subjects (dotted line). Log-rank test shows VaD conversion rates for Chinese subjects to be significantly higher than that for American subjects (p<0.01).

Fig. (3) shows the Kaplan-Meier survival analysis for conversion to VaD among Chinese versus American MCI subjects during 3 years of observation. First year conversion rates to VaD (with 95% confidence interval) are 28.1% (16.7%-39.5%) for Chinese MCI subjects, versus 14.1% (5.5%-22.7%) for American MCI subjects; three-year VaD conversion rates are 65.3% (50.5%-80.1%) for Chinese subjects versus 28.1% (16.7%-39.5%) for American subjects. Log-rank (Mantel-Cox) test estimates Chinese MCI subjects are more prone to VaD compared with American subjects (=10.13, p<0.01).

Discussion

International comparative studies such as the present one comparing developed versus developing countries provide opportunities for analyzing genetic-environmental factors contributing to nosogeographic differences for the dementias [17, 28]. One of the main conclusions from this study is that Chinese MCI subjects versus America MCI subjects have different conversion rates to both DAT and VaD. American MCI subjects are 1.7 times more likely to convert to DAT than Chinese subjects; while Chinese subjects are 2.3 times more likely to convert to VaD than American subjects, within 3 years after MCI identification. In view of different pharmacological strategies that modify the course of DAT and VaD [9,29,30], these geographic differences for dementia distributions should be considered by clinicians working in different regions when managing patients at risk from dementia.

Epidemiological surveys have demonstrated that prevalence and incidence of DAT and VaD vary considerably across the world [31]. Although there have been trends for increased incidences of both DAT and VaD in developing countries during the 1990s resulting from population aging and declines of infectious disease [32], DAT appears more prevalent in western countries than in most Far Eastern and African countries; while VaD is more prevalent in African and Far East countries than in America [33]. Shorter life expectancy brought about by disadvantageous social-economic living conditions as well as methodological discrepancies among investigators have been regarded as the main cause for lower prevalence of DAT in developing countries [34,35].

Carefully designed cross-country epidemiological studies have confirmed that geographic discrepancies for dementia prevalence and incidences were still present after adjustments for age [17,36]. Japanese have a lower prevalence for DAT and higher prevalence for stroke and VaD compared with populations in most western countries, despite their similar life expectancy and socio-economic development status [16]. After moving to Hawaii, an archipelago dominated by western culture and life styles, the prevalence of DAT increased dramatically among these Japanese immigrants [37]. Thus, beside racial and genetic differences, other factors such as cultural and dietary differences, education, and risk factor control need to be considered when interpreting these geographic distribution discrepancies for the two major dementias.

Data from the present study indicate that Chinese and American MCI subjects have different domains of cognitive impairment. Memory impairments are more prominent among American subjects who are more prone to DAT than Chinese subjects. Language domains of impairments are more prominent among Chinese subjects, who are more prone to VaD. Because MCI subjects in both sites were screened by similar processes and from two well-matched relatively large populations, different domains of impairment in two groups of MCI subjects probably result from genetic and/or environmental divergences, rather than from biases of subject selection. Different domains of impairment in two groups of MCI subjects may reflect early differences of cognitive impairment that are characteristic of VaD and DAT. VaD affects more wide-ranging cognitive functions because of more diversely located neuropathological ischemic foci [38-41], while DAT impairs mainly memory functions in its preliminary stages [6,42].

Educational and occupational attainments have been shown to influence progression of DAT in some studies [43-45]. One hypothesis about this association is that education and occupation are markers for lifelong participation in cognitively stimulating activities including reading and writing [46]. A longitudinal study found that the amount of time spent in reading was significantly correlated with onset of dementia 20 years later [47]. Chinese subjects in the present study have lower educational levels and most take up physical labor as a profession, a situation that limits their access to literary materials. Nevertheless, these Chinese still have lower prevalence of DAT compared with their American peers. There must be other influencing factors, which diluted the contribution of lower educational levels to the prevalence of DAT in these Chinese subjects. One possible influencing factor may be cultural discrepancies, with language differences between China and US. As an example, Chinese characters are pictographic while English words are alphabetically ordinal. Using two types of literal materials may involve different cognitive processes and have different exercise effects influencing cognitive related functions [48-50]. Genetic differences, dietary divergences, little or no control of risk factor for CVD along with lower educational levels (which is a risk factor for both types of dementia) may account for the higher VaD and lower DAT conversion rate in Chinese MCI subjects. Other factors, which may influence MCI conversion, include genotypes of apolipoprotein E (APOE), pharmacotherapy, food, family structure and educational levels of caregiver. The contributions of these factors to nosogeographic discrepancies in the dementias deserve further investigation.

Data from this study suggest discrepancies of MCI progression to DAT and VaD between Chinese and American subjects. These discrepancies may result from genetic and/or environmental differences of the two populations. To elicit the contribution of genetic factors to MCI transition, one optimal condition is to study two ethnic peoples who live in similar environment (eg. Chinese American vs Caucasian American, both of whom grew up and live in USA); While to elicit the impacts of environment on MCI transition, the optimal condition is to study two populations of the same racial origination who live in different environments (eg. Chinese grew up in China vs Chinese grew up in USA). Since most immigrants are scattered in different regions, it is hard to find a big Chinese community in USA available for years of follow-up. Furthermore, after moving to USA, immigrants tend to live in a partly Americanized environment, which makes their living conditions distinct from both native Chinese and local Americans. So optimal situations mentioned above are hard to find.

Some limitations are acknowledged in the present study. Subjects recruited in both Chinese and American sites were outpatients drawn from general hospitals, many of whom had risk factors for dementia, which accounts for the conversion rates for both DAT and VaD, which are higher than reported previously [6,11,51]

We used MMSE for both diagnosis and longitudinal outcome observations of MCI. MMSE, although frequently applied for evaluation of cognitive impairments, has some shortcomings including: insensitivity for detecting very mild cognitive impairments, particularly among the highly educated (ceiling effects) [52,53]. In attempts to compensate for this, another more sensitive cognitive test, CCSE, was administered to supplement MMSE measurements, which produced similar results.

Author Contributions

Drs Xu, Meyer and Huang participated in concept and design of the study, acquisition of data, analysis and interpretation of data, drafting of manuscript, critical revision of the manuscript for scientific validity, statistical analysis, and grant support.

Dr Chen participated in study concept, design, and statistical analysis of data.

Drs Chowdhury and Quach participated in study concept and design, acquisition of data and critical revisions of the manuscript.

AcknowledgEments

This study was supported partly by Natural Science Foundation of China to Dr. Huang (#39770275) and Meyer Research Foundation of Baylor College of Medicine. The authors are grateful to Danhong Liu, Irma Muniz and Yunchun Chen for assisting in data collection and word processing the manuscript.

Selected Abbreviations and Acronyms

ADRDA               =            Alzheimer Disease and Related Disorders Association

AIRENS               =            Association Internationale pour la Réchèrche et l'Enseignement en Neurosciences

APOE                  =            Apolipoprotein E

CCSE                   =            Cognitive Capacity Screening Examination

CIND                   =            Cognitive Impairment, No Dementia

CSF                     =            Cerebrospinal fluid

CT                        =            Computed Tomography

CVD                    =            Cerebrovascular Disease

DAT                     =            Dementia of Alzheimer’s Type

DSM-IV               =            Diagnostic and Statistical Manual of Mental Disorders

(Fourth Edition) American Psychiatric Association

EEG                     =            Electroencephalography

ECG                     =            Electrocardiography

HDRS                  =            Hamilton Depression Rating Scale

MCI                     =            Mild Cognitive Impairment

MMSE                 =            Mini-Mental State Examination

MRI                     =            Magnetic Resonance Imaging

NDD                    =            Neurodegenerative Disease

NINCDS              =            National Institute of Neurological and Communicative Disorders and Stroke

TCD                     =            Transcranial Doppler Ultrasonography

TIA                      =            Transient Ischemic Attack

VaD                     =            Vascular Dementia

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