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Telomere length is not predictive of dementia or MCI conversion in the oldest old
Neurobiology of Aging 31 (2010) 719–720
Negative results
Telomere length is not predictive of dementia or MCI conversion in the oldest old Dina Zekry a,∗ , Franc¸ois R. Herrmann a , Irmingard Irminger-Finger b , Laura Ortolan c , Chantal Genet a , Anna-Maria Vitale a , Jean-Pierre Michel a , Gabriel Gold a , Karl-Heinz Krause b a
Department of Rehabilitation and Geriatrics, Geneva University Hospitals and University of Geneva, Switzerland Department of Pathology and Immunology, Geneva University Hospitals and University of Geneva, Switzerland c Department of Psychiatry, Geneva University Hospitals and University of Geneva, Switzerland
b
Received 13 February 2008; received in revised form 4 April 2008; accepted 18 May 2008 Available online 2 July 2008
Abstract The contribution of telomere shortening to the onset of certain age-related diseases, such as dementia, and its role as a predictor of cognitive impairment remain unclear. We tested these hypotheses by analyzing telomere length in 449 inpatients in a large cohort of the oldest old (mean age 85 years) followed up yearly. No significant difference in telomere length was observed between cognitively normal patients (205), demented patients (195; 82 mixed dementia, 77 Alzheimer’s disease and 21 vascular dementia) and patients (49) with mild cognitive impairment (MCI). Similarly, no significant differences in telomere length were found between patients with different etiologies or severities of dementia. Telomere length and change in cognitive status (from normal to MCI or dementia, or from MCI to dementia) were not associated after two years of follow-up. This longitudinal study in very old patients provided no evidence to suggest that telomere length could be used to distinguish between demented and non demented patients, regardless of the type of dementia, or to predict dementia or MCI conversion. © 2008 Published by Elsevier Inc. Keywords: Alzheimer’s disease; Dementia; Aged; Telomere length
1. Introduction Telomeres are short, repeated DNA sequences at the end of chromosomes. The telomere hypothesis of aging is based on telomere shortening with each cell division, and therefore with age, resulting in cell senescence and aging. Telomere length is considered as a potential biomarker of aging [8,12,15,18,19]. This leads to the hypothesis of whether telomere shortening contributes also to the genesis of certain age-related diseases, such as dementia. We carried out a prospective study in very elderly patients, with yearly followup, to determine whether telomere length predicted dementia ∗ Corresponding author at: Department of Rehabilitation and Geriatrics, Geneva University Hospitals and University of Geneva, 3, chemin du PontBochet, Thˆonex, Switzerland. Tel.: +41 22 305 6355; fax: +41 22 305 6115. E-mail address: [email protected] (D. Zekry).
0197-4580/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.neurobiolaging.2008.05.016
or the conversion of mild cognitive impairment (MCI) to dementia. 2. Methods Patients and data collection have been described elsewhere [44]. Briefly, we carried out a longitudinal study (crosssectional study with yearly follow-up) of patients (aged 70 and above) from a randomized sample of the patients admitted to Geneva Geriatric Hospital over a two-year period. The same team carried out the same assessment yearly: a complete, systematic battery of neuropsychological tests, assessment of clinical criteria and scores for dementia etiology and severity, and measurement of telomere length in peripheral blood lymphocytes by flow cytometry (see supplementary data for details).
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D. Zekry et al. / Neurobiology of Aging 31 (2010) 719–720
3. Results The 449 patients (mean age 85.1 ± 6.8; 76% women) enrolled were assigned to three groups (supplementary Fig. 1): 205 cognitively normal, 49 with MCI [31] and 195 demented (77 with Alzheimer’s disease (AD), 82 with mixed dementia and 21 with vascular dementia (VaD)). Mean age and sex ratio were similar for all groups. 3.1. Baseline results No significant difference in telomere length was found between cognitively normal patients and those with dementia (p = 0.443), or between cognitively normal patients and patients with MCI or dementia (p = 0.213) (supplementary Fig. 2). Telomere length did not differ significantly with dementia etiology (p = 0.769) or severity (p = 0.195) (supplementary Figs. 3 and 4). In multiple linear regression analysis, age, sex and cognitive status were not predictive of telomere length (p = 0.063, 0.232 and 0.542, respectively; r2 = 2.1%) (supplementary Fig. 5). 3.2. Follow-up results (supplementary Fig. 1) 285 patients had one-year and 208 patients two-year assessments (63% and 46% of the included cohort). The incidence of dementia was 15% per year and that of MCI, 12% per year. The rate of MCI conversion was 50% per year. Telomere length was not associated with change in cognitive status from normal to dementia or MCI (p = 0.764), or from MCI to dementia (p = 0.709), from baseline to the first or second yearly assessment. Similarly, telomere length was not associated with dementia severity in demented patients during follow-up (p = 0.791). 3.3. Change in telomere length Telomere length was measured three times for each individual. We therefore calculated the telomere length delta between baseline and first or second yearly follow-up, and between the two years of follow-up. The telomere length delta was not associated with change in cognitive status after one or two years of follow-up (p = 0.934).
4. Discussion The first study to investigate the correlation between telomere length and dementia was a cross-sectional and had a strong selection bias for stroke and VaD inpatients. The authors compared patients with AD, VaD, stroke and/or other cardiovascular risk factors. The odds ratio for VaD was two times lower in individuals with long telomeres, increasing to more than three in patients with short telomeres [40].
Panoussian et al. using the MMSE as a marker of AD disease showed that telomere length and cognitive function were related [30]. These cross-sectional studies were carried out on small cohorts of younger elderly patients, using only the MMSE to assess cognitive function. In a larger study in an older population (n = 598, mean age 90 years), telomere length was not predictive of dementia incidence, again based on MMSE alone [23]. A recent study by this group on 195 non demented stroke survivors with a mean age of 80 years showed that telomere length was predictive of poststroke cognitive decline, dementia and death [24]. However, cognitive evaluation by MMSE alone is not sensitive or specific for detecting changes in a population of this great age (90 years for the first study), particularly after stroke (for the second study). All these studies, including ours, measured telomere length in white blood cells. This is logical with respect to the accessibility of the patient material and previous studies, which suggest that telomere length in blood can be used as a surrogate marker for telomere length in other tissues [13]. The principal strength of our cohort is its clinically rich prospective data collection from a large group of elderly patients. In addition, the same neuropsychologist carried out the same systematic neuropsychological assessment at baseline and during the two years of follow-up, increasing the accuracy of cognitive diagnosis. This study is also the first of its type to consider a group of patients with MCI. This large longitudinal study in very old demented and non demented subjects followed up for two years provides no evidence that telomere length can be used to predict dementia or MCI conversion. It also shows that telomere length cannot be used to distinguish between demented and non demented patients, regardless of the type of dementia considered. In addition, repeated measures of telomere length in the same individual were not associated with change in cognitive status after one or two years of follow-up. More details of the methodology, raw data and references are provided in the supplementary data.
Acknowledgments We would like to thank the teams of Mrs. O. Baumer, L. Humblot and M. Cos for technical assistance. This work was supported by grant 3200B0-102069 from the Swiss National Foundation. Actual or potential conflicts of interest are disclosed.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.neurobiolaging. 2008.05.016.
Negative results
Telomere length is not predictive of dementia or MCI conversion in the oldest old Dina Zekry a,∗ , Franc¸ois R. Herrmann a , Irmingard Irminger-Finger b , Laura Ortolan c , Chantal Genet a , Anna-Maria Vitale a , Jean-Pierre Michel a , Gabriel Gold a , Karl-Heinz Krause b a
Department of Rehabilitation and Geriatrics, Geneva University Hospitals and University of Geneva, Switzerland Department of Pathology and Immunology, Geneva University Hospitals and University of Geneva, Switzerland c Department of Psychiatry, Geneva University Hospitals and University of Geneva, Switzerland
b
Received 13 February 2008; received in revised form 4 April 2008; accepted 18 May 2008 Available online 2 July 2008
Abstract The contribution of telomere shortening to the onset of certain age-related diseases, such as dementia, and its role as a predictor of cognitive impairment remain unclear. We tested these hypotheses by analyzing telomere length in 449 inpatients in a large cohort of the oldest old (mean age 85 years) followed up yearly. No significant difference in telomere length was observed between cognitively normal patients (205), demented patients (195; 82 mixed dementia, 77 Alzheimer’s disease and 21 vascular dementia) and patients (49) with mild cognitive impairment (MCI). Similarly, no significant differences in telomere length were found between patients with different etiologies or severities of dementia. Telomere length and change in cognitive status (from normal to MCI or dementia, or from MCI to dementia) were not associated after two years of follow-up. This longitudinal study in very old patients provided no evidence to suggest that telomere length could be used to distinguish between demented and non demented patients, regardless of the type of dementia, or to predict dementia or MCI conversion. © 2008 Published by Elsevier Inc. Keywords: Alzheimer’s disease; Dementia; Aged; Telomere length
1. Introduction Telomeres are short, repeated DNA sequences at the end of chromosomes. The telomere hypothesis of aging is based on telomere shortening with each cell division, and therefore with age, resulting in cell senescence and aging. Telomere length is considered as a potential biomarker of aging [8,12,15,18,19]. This leads to the hypothesis of whether telomere shortening contributes also to the genesis of certain age-related diseases, such as dementia. We carried out a prospective study in very elderly patients, with yearly followup, to determine whether telomere length predicted dementia ∗ Corresponding author at: Department of Rehabilitation and Geriatrics, Geneva University Hospitals and University of Geneva, 3, chemin du PontBochet, Thˆonex, Switzerland. Tel.: +41 22 305 6355; fax: +41 22 305 6115. E-mail address: [email protected] (D. Zekry).
0197-4580/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.neurobiolaging.2008.05.016
or the conversion of mild cognitive impairment (MCI) to dementia. 2. Methods Patients and data collection have been described elsewhere [44]. Briefly, we carried out a longitudinal study (crosssectional study with yearly follow-up) of patients (aged 70 and above) from a randomized sample of the patients admitted to Geneva Geriatric Hospital over a two-year period. The same team carried out the same assessment yearly: a complete, systematic battery of neuropsychological tests, assessment of clinical criteria and scores for dementia etiology and severity, and measurement of telomere length in peripheral blood lymphocytes by flow cytometry (see supplementary data for details).
720
D. Zekry et al. / Neurobiology of Aging 31 (2010) 719–720
3. Results The 449 patients (mean age 85.1 ± 6.8; 76% women) enrolled were assigned to three groups (supplementary Fig. 1): 205 cognitively normal, 49 with MCI [31] and 195 demented (77 with Alzheimer’s disease (AD), 82 with mixed dementia and 21 with vascular dementia (VaD)). Mean age and sex ratio were similar for all groups. 3.1. Baseline results No significant difference in telomere length was found between cognitively normal patients and those with dementia (p = 0.443), or between cognitively normal patients and patients with MCI or dementia (p = 0.213) (supplementary Fig. 2). Telomere length did not differ significantly with dementia etiology (p = 0.769) or severity (p = 0.195) (supplementary Figs. 3 and 4). In multiple linear regression analysis, age, sex and cognitive status were not predictive of telomere length (p = 0.063, 0.232 and 0.542, respectively; r2 = 2.1%) (supplementary Fig. 5). 3.2. Follow-up results (supplementary Fig. 1) 285 patients had one-year and 208 patients two-year assessments (63% and 46% of the included cohort). The incidence of dementia was 15% per year and that of MCI, 12% per year. The rate of MCI conversion was 50% per year. Telomere length was not associated with change in cognitive status from normal to dementia or MCI (p = 0.764), or from MCI to dementia (p = 0.709), from baseline to the first or second yearly assessment. Similarly, telomere length was not associated with dementia severity in demented patients during follow-up (p = 0.791). 3.3. Change in telomere length Telomere length was measured three times for each individual. We therefore calculated the telomere length delta between baseline and first or second yearly follow-up, and between the two years of follow-up. The telomere length delta was not associated with change in cognitive status after one or two years of follow-up (p = 0.934).
4. Discussion The first study to investigate the correlation between telomere length and dementia was a cross-sectional and had a strong selection bias for stroke and VaD inpatients. The authors compared patients with AD, VaD, stroke and/or other cardiovascular risk factors. The odds ratio for VaD was two times lower in individuals with long telomeres, increasing to more than three in patients with short telomeres [40].
Panoussian et al. using the MMSE as a marker of AD disease showed that telomere length and cognitive function were related [30]. These cross-sectional studies were carried out on small cohorts of younger elderly patients, using only the MMSE to assess cognitive function. In a larger study in an older population (n = 598, mean age 90 years), telomere length was not predictive of dementia incidence, again based on MMSE alone [23]. A recent study by this group on 195 non demented stroke survivors with a mean age of 80 years showed that telomere length was predictive of poststroke cognitive decline, dementia and death [24]. However, cognitive evaluation by MMSE alone is not sensitive or specific for detecting changes in a population of this great age (90 years for the first study), particularly after stroke (for the second study). All these studies, including ours, measured telomere length in white blood cells. This is logical with respect to the accessibility of the patient material and previous studies, which suggest that telomere length in blood can be used as a surrogate marker for telomere length in other tissues [13]. The principal strength of our cohort is its clinically rich prospective data collection from a large group of elderly patients. In addition, the same neuropsychologist carried out the same systematic neuropsychological assessment at baseline and during the two years of follow-up, increasing the accuracy of cognitive diagnosis. This study is also the first of its type to consider a group of patients with MCI. This large longitudinal study in very old demented and non demented subjects followed up for two years provides no evidence that telomere length can be used to predict dementia or MCI conversion. It also shows that telomere length cannot be used to distinguish between demented and non demented patients, regardless of the type of dementia considered. In addition, repeated measures of telomere length in the same individual were not associated with change in cognitive status after one or two years of follow-up. More details of the methodology, raw data and references are provided in the supplementary data.
Acknowledgments We would like to thank the teams of Mrs. O. Baumer, L. Humblot and M. Cos for technical assistance. This work was supported by grant 3200B0-102069 from the Swiss National Foundation. Actual or potential conflicts of interest are disclosed.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.neurobiolaging. 2008.05.016.