| | Concordance for cognitive impairment: A study of 50 community-dwelling elderly female-female twin pairs☆☆☆Abstract The present study sought to determine concordance of cognitive impairment among elderly female twins. Cognitive testing was performed by telephone interview in a sample of 100 female-female twins older than 65 years. The participants were 32 monozygotic (MZ) and 18 dizygotic (DZ) female twin pairs, all between the ages of 65 and 86 years; their mean age was 70.2 ± 4.6 years. All were recruited from the Institute of Psychiatry Volunteer Twin Register (IPVTR). We used the Telephone Interview for Cognitive Status (TICS) and analyzed the modified total score. Correlation's of age and zygosity were computed in relation to score on cognitive interview, and differences between MZ twin pairs (n = 32) and DZ pairs (n = 18) were analyzed using the general linear model procedure. Five subjects of the 64 MZ females (7.8%) and one DZ female (2.4%) were found to be cognitively impaired. In no case was the second twin affected. No differences in cognitive score were found between MZ and DZ twin pairs. In both groups a highly significant correlation was found between ageand lower score: R2 = −0.32, P = .009. We conclude that aging-related impairment in cognitive testing did not differ between MZ and DZ elderly female twins. Although the overall sample size was relatively small and error variance may have been introduced by imprecise measures of zygosity, the present findings are suggestive of gender differences in cognitive performance that need further evaluation. Copyright 2003, Elsevier Science (USA). All rights reserved.
Alzheimer's disease (AD) is a progressive degenerative dementing illness that is rapidly becoming a leading cause of death in adults, as well as a personal, familial, and social burden.1, 2 With the introduction of “anti-dementia” drugs, clinicians and researchers are called upon by patients and their families to clarify and characterize the clinical and biological substrates underlying the disorder so that therapeutic and preventive measures may be undertaken. Although epidemiological and molecular data emphasize the multiple etiologies of AD, the contribution of heredity to this disease is widely acknowledged.3
In 1929 a genetic influence in AD was reported by Flugel,4 but it was Kallman et al. in the late 1940s who first undertook the study of twins with AD focusing on senescence.5 However, the nonspecific diagnostic criteria used then do not allow for in-depth analysis of these data.6 In a recent review7 of the genetics of dementia it was estimated that concordance rates among co-twins of monozygotic (MZ) probands with AD are 40% to 60%, more than double that of dizygotic (DZ) twins; this suggests a strong but not absolute genetic influence.
There are numerous obstacles in conducting large-scale epidemiological surveys in elderly persons living in the community. Breitner devised the Telephone Interview for Cognitive Status (TICS) to overcome difficulties related to personnel, distance, and cost.8 Among the many limitations of twin studies in AD, 6, 8 gender differences are extreme. In most of the studies published by Breitner and his colleagues,9, 10, 11, 12, 13, 14 encompassing more than 12,000 twin subjects, only 1.2% were female and only 2.4% were older than 75 years of age. Thus, the issue of generalizability from these large-scale twin studies is raised. As the accumulating knowledge to date is heavily weighted in favor of male subjects, we chose specifically to evaluate female twins. Thus the aim of the present study was to determine concordance for cognitive impairment among elderly female twins living in the community.
Method  Study sample The subjects assessed were elderly female twins (female-female pairs) registered with the Institute of Psychiatry Volunteer Twin Register (IPVTR). To date the IPVTR includes more than 2,000 identified twins. In brief, since 1948 all inpatients and outpatients at the Maudsley and Bethlem hospitals who were twins have been registered with the IPVTR. The registry tracks discharge diagnoses and has been used to study schizophrenia, affective disorders, and other conditions.6 Zygosity was established in the IPVTR through mailed questionnaires.15, 16 Twin pairs" zygosity was not revealed to the researcher administering the TICS. Following completion of the TICS, twin pairs whose zygosity was ambiguous were excluded from the statistical analysis. Approval of the Maudsley Hospital Ethical Committee was granted prior to contact with the subjects. The IPVTR database was used to identify twin pairs born before January 1930 (aged 65 years or older at the time of interviewing) and a letter was mailed to 202 such twins. The letter described the study's purpose and requested agreement to a telephone interview. After 2 weeks the interviewer (Y.B.) called each subject and only after explaining the study and receiving consent was the TICS performed. Of the 202 twins, 147 interviews were completed. Reasons for incomplete interviews with the additional 55 subjects were: 32 could not be traced, 12 had died, six refused, and three were out of the country. Only 4% of subjects approached refused to participate. Methods During the telephone interview common causes of cognitive decline such as recurrent stroke, Parkinson's disease, alcoholism, and use of anticholinegic medications were noted. Cognitive functioning was assessed by means of the TICS-m,9 which is a short questionnaire consisting of 19 items, administered by an interviewer during a 10-minute telephone interview. The TICS is based on the widely used Mini-Mental State Examination (MMSE),17 and has been shown to have high sensitivity (92%), specifity (100%), test-retest reliability (+0.965), and inter-rater reliability (0.97).9, 10, 11, 12, 13 We used the modified interview version, TICS-m, which consists of 12 items in which items from the original version that are difficult to verify in epidemiological studies were deleted and a delayed recall procedure added in order to increase sensitivity. The TICS-m has a gaussian distribution of scores and is not subject to a “ceiling” effect. The interview evaluates and scores a variety of cognitive functions affected by dementia such as orientation, concentration, memory, naming, comprehension, calculation, and reasoning. In addition to items found in the MMSE, the TICS-m evaluates word list learning, counting backwards, finger tapping, word opposites, and delayed recall. The TICS-m is scored from 0 to 50, with a cutoff score of 30 for detection of dementia. Data analysis Demographic characteristics are described by means and standard deviations. The Pearson correlation test was used to assess relationship between age and cognitive score and the general linear model procedure (least squares means) was used to detect similarity or difference within and between twin pairs wherein the dependent variable was the zygosity. Results Of the 147 subjects located and interviewed, 47 were excluded from the analysis for the following reasons: 44 due to ambiguous zygosity (29.9%), two due to Parkinson's dementia, and one due to dialysis-related dementia. Fifty female twin pairs (100 female subjects [32 MZ, 18 DZ]) were included in the final analysis. The mean age of the MZ group was 70.3 ± 4.6 years (range, 65 to 86), and similarly for the DZ group was 70.0 ± 4.6 years (range, 65 to 80). The incidence of significant cognitive impairment (scores below the TICS 30 points cut-off) was 7.8% (5/64) in the MZ group versus 2.8% (1/36) in the DZ pairs (P < .05). In no pair were both twins affected. Ages of the affected subjects were: DZ = 73 years; MZ = 66, 66, 69, 80, and 86 years. TICS-m scores were 35.8 ± 4.9 in the MZ group and 36.1 ± 4.2 in the DZ group. The MZ group TICS-m scores were significantly negatively correlated with age: R2= −0.34, P = .006. In the DZ group no such correlation was found. General linear models analysis (least squares means) for the TICS difference (within pair) disclosed no statistical significance: the mean difference = 3.3 in the MZ group and 3.2in the DZ group (P = .98). Discussion Despite increasing knowledge in the area of molecular genetics, the basic cause of the majority of AD cases is still obscure. Epidemiological studies of the familial aggregation of AD have indicated a genetic role and have identified mutations in families with AD. The relative roles of genetic and environmental influences can be estimated by comparing the concordance rates between MZ and DZ twins.18 As the impact of both genetic and environmental influences on the occurrence of AD are still not fully elucidated, we chose to screen community-dwelling elderly female twin pairs for cognitive impairment in a cross-sectional design. The TICS proved to be a user-friendly tool for both patients and researchers, as we have previously reported.19 Cognition studies among twins demonstrate heritability of full-scale IQ to be in the range of 71% to 87%.20 Additional studies replicated the substantial genetic influences on late-life cognitive functioning.21, 22 Thus, our study needs be viewed in the context of assessing concordance for cognitive impairment in line with said studies but with an emphasis on female twins. The prevalence of cognitive impairment in our sample (6%) was similar to that reported in the literature for this age bracket.7 However, the within-groups distribution demonstrated a significant difference between the prevalence of cognitive impairment in MZ versus DZ twins. A higher prevalence of cognitive impairment was found in the MZ group, although the mean age for both groups was identical. It must be emphasized that in none of the groups were both twins cognitively impaired. In accordance with the study by Brandt et al.,10 the groups' TICS-m score was inversely correlated with age. The mean and the total variance in score in the DZ group was not significantly different from that of the MZ group, again echoing the findings of Brandt et al. The fact that in the present study no concordant pairs for cognitive impairment were detected may be thought to argue against a purely genetic etiology, although our sample size is somewhat limited. It is possible that the age of onset of AD may be widely disparate even between MZ twins,23, 24 and long-term follow-up is needed to exclude genetic etiology. In addition, the present study did not rely on diagnostic criteria for AD but rather screened for cognitive impairment. Small et al.25 recently reported one pair of 81-year-old MZ females discordant for AD. However, Cook et al.26 noted that discordant twins may differ in the onset of disease rather than the presence of disease. Taken together with the Framingham study,27 which reported a greater prevalence of AD in women, this suggests that age of onset and gender may interact with the degree of genetic loading for AD. In the present study prevalence of cognitive impairment was similar to that reported for the general population. To conclude, although the present study does not support a genetic influence in the cognitive impairment possibly predating AD, it should be mentioned that the study was cross-sectional and relied on cognitive functioning as the “tool” for diagnosis; furthermore, zygosity was not confirmed by laboratory methods. The recent demonstration that there is a differential genetic influence for components of memory in aging twins may also have affected the results.20, 21, 22 Nevertheless, the results of the present study should not be ignored as it evaluated a rather unique sample of elderly female twins and as the TICS was recently shown to be strongly correlated with face-to-face measures of cognitive function.28 Acknowledgements We would like to thank Prof. Raymond Levy, M.D., and Alison M. Macdonald, Ph.D., Institute of Psychiatry, Maudsley Hospital, London, UK, for their assistance in this work. References 1.
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Dementia Geriatr Cogn Dis. 2002;13:149–155. Abarbanel Mental Health Center, Bat Yam, Israel; Geha Hospital, Petah-Tikva, Israel; and the Neuroimmunology Unit, Sheba Medical Center, Tel Hashomer, Israel ☆ Address reprint requests to Yoram Barak, M.D., Director-Psychogeriatric Department, Abarbanel M.H.C. 15 Keren Kayemet Blv, Bat Yam, 59100 Israel. ☆☆ 0010-440X/03/4402-0006$30.00/0 PII: S0010-440X(03)00039-7 doi:10.1053/comp.2003.50019 © 2003 Published by Elsevier Inc. | |
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