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LETTERS TO THE EDITOR
JULY 2014–VOL. 62, NO. 7
JAGS
Table 1. Comparison of Subject Characteristics and Progression Rates Factor
Age, mean SD Sex, n Male Female Duration of disease, years, mean SD Education, years, mean SD Frequency of day service use, d/wk, mean SD MMSE score, mean SD At initial evaluation At last evaluation Follow-up, years, mean SD Progression rate (annual MMSE change), mean SD Medical complications, n Hypertension Diabetes mellitus Dyslipidemia Other
Day Service Nonuser, n = 71
Day Service User, n = 102
Satisfied, n = 64
Unsatisfied, n = 38
80.6 5.7
82.1 5.4
81.7 5.2
82.7 5.7
35 36 2.9 0.9 12.7 2.5 0
38 64 3.0 0.9 12.0 2.8 2.8 1.1
23 41 3.1 0.9 12.1 2.6 3.0 1.0c
15 23 2.8 0.8 11.6 3.1 2.3 1.1
22.7 18.6 3.3 1.2
24 13 8 12
3.1 4.0 0.9 0.9
21.4 17.7 3.5 1.0
3.7a 4.7 1.1 0.9
31 13 18 18
21.0 17.8 3.6 0.8 21 9 14 11
3.8 4.9 1.1 0.9b
22.1 17.5 3.4 1.4
3.3 4.4 1.2 0.9
10 4 4 7
SD = standard deviation; MMSE = Mini-Mental State Examination. a P < .05 vs day service nonusers; bP < .05, c.01 vs unsatisfied group.
the frequency of DS attendance as a covariate, showed that the satisfied group had significantly slower progression rates than the unsatisfied group. No significant correlation was observed between frequency of DS attendance and annual MMSE score change. No significant positive effects of DS use on disease progression were found. Because DS nonusers included some participants who participated in high leisure activities every day and did not need to attend the DS center, no beneficial effects of DS use was detected in individuals with AD. Nevertheless, although the satisfied and unsatisfied groups were divided mainly on the basis of subjective caregiver perceptions of the DS in this study, DS attendance with satisfaction may be associated with slower progression of cognitive deterioration. A previous study4 found improvement in or stabilization of cognitive and noncognitive dementia symptoms in DS users, whereas DS nonusers worsened after 9 months of service. Although the program and intervention may differ depending on the center or unit, DS offers the possibility of rehabilitative processes in different domains of functioning. Mental and physical engagements in complex environments may protect people from the development and progression of symptoms of neurodegenerative damage.6 These positive effects may be related to the individuals’ levels of satisfaction with DS attendance. This retrospective study suggests that active and enjoyable participation in DS may in part be associated with slower progression of cognitive decline in individuals with AD. Hirofumi Sakurai, MD Haruo Hanyu, MD Naruta Namioka, MD Hiroaki Hatanaka, MD Raita Fukasawa, MD Kazumasa Kume, MD Department of Geriatric Medicine, Tokyo Medical University, Tokyo, Japan
ACKNOWLEDGMENTS Conflict of Interest: The authors have no financial disclosures to declare. There are no conflicts of interest regarding this letter. Author Contributions: Hanyu, Sakurai: study concept and design, acquisition of subjects and data, analysis and interpretation of data, preparation of manuscript. Namioka, Hatanaka, Fukasawa, Kume: acquisition of subjects, data analysis, manuscript revisions. Sponsor’s Role: None.
REFERENCES 1. Gitlin LN, Reever K, Dennis MP et al. Enhancing quality of life of families who use adult day services: Short- and long-term effects of the adult day service plus program. Gerontologist 2006;46:630–639. 2. Zarit SH, Kim K, Femia EE et al. Effects of adult day care on daily stress of caregivers: A within-person approach. J Gerontol B Psychol Sci Soc Sci 2011;66B:538–546. 3. Baumgarten M, Lebel P, Laprise H et al. Adult day care for the frail elderly. J Aging Health 2002;14:237–259. 4. Zank S, Schacke C. Evaluation of geriatric day care units: Effects on patients and caregivers. J Gerontol Psychol Sci Soc Sci 2002;57B:348–357. 5. 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. 6. Peterosini L, De Bartola P, Foti F et al. On whether the environmental enrichment may provide cognitive and brain reserves. Brain Res Rev 2009;61:221–239.
ASSOCIATION BETWEEN LEUKOCYTE TELOMERE LENGTH AND VASCULAR DEMENTIA AND CANCER MORTALITY IN AN ELDERLY POPULATION To the Editor: Telomeres are regions of repeating TTA GGG hexanucleotide sequences located at the ends of each chromosome.1 Telomeres prevent loss of genetic
JAGS
JULY 2014–VOL. 62, NO. 7
LETTERS TO THE EDITOR
a
material during cell replication as enzymes that duplicate deoxyribonucleic acid (DNA) are unable to duplicate to the end of a strand of DNA. Consequently, telomeres shorten with each cell cycle, ultimately leading to permanent growth arrest, thus limiting the number of divisions a cell is capable of.1 Previous studies have identified correlations between leukocyte telomere lengths and various lifestyle factors that are frequently associated with cancer and cardiovascular diseases, which represent major causes of mortality in the developed world.2 As a biomarker for cellular stress and aging, particularly of the immune cells and cells of the vascular tree,3 telomere length may be associated with age-related diseases such as cancer and vascular dementia.
1385
b
METHODS Participants aged 75 and older were recruited from the Bankstown-Lidcombe Hospital memory clinic and geriatric wards and the War Memorial Hospital, Sydney, Australia. Individuals with a diagnosis of dementia of predominantly vascular etiology were included. Individuals with dementia of predominantly other causes were excluded. Individuals with vascular dementia with an Alzheimer’s component were included if it was not the dominant cause clinically for dementia. Control participants were determined to be cognitively normal (Mini-Mental State Examination score ≥28). Control participants with evidence of cerebrovascular events through history or on imaging were excluded. Upon recruitment, participants were guided through a comprehensive questionnaire including medical history and lifestyle factors. Participants were examined, and a blood sample was obtained. Relative telomere length in peripheral white blood cells was measured using a previously described real-time quantitative polymerase chain reaction (RT-qPCR) technique.4 Participants were followed up 2 years after initial examination. Nonparametric Mann–Whitney U-tests were used to compare the differences between the groups. P < .05 was considered statistically significant.
Figure 1. Relative telomere length between participants who died with and without cancer diagnosis and those who were alive. Mean standard deviation. aP < .01, bP < .001.
DISCUSSION Cancer Two meta-analyses found a significant association between shorter leukocyte telomeres and overall cancer risk,5,6 although another large population study found a significant correlation between shorter survival after diagnosis of cancer and shorter telomere lengths but no correlation with overall cancer risk.7 The current study focused on older subjects and is in agreement with the latter study. The findings in the current study’s older cohort that shorter leukocyte telomere length at the time of cancer diagnosis may be a predictor of future death from cancer is novel, but further studies are needed because the current study was limited mainly by a small sample size.
Vascular Dementia RESULTS Participants with vascular dementia patients had a MMSE score of 19.4 7.1 (n = 39), which was significantly lower (P < .001) than that of controls (29.0 2.1, n = 14). Participants with vascular dementia had a shorter mean leukocyte telomere length (1.07 0.18) than controls (1.21 0.43), although this result was not statistically significant (P = .25). No significant difference (P = .35) was found in the telomere lengths of participants with a cancer diagnosis (alive or dead) (1.23 0.45) and those who never had cancer (1.15 0.35) at the time of recruitment. At follow-up after a mean period of 2 years on 53 participants, 14 participants had died, of which seven deaths were cancer related (nonhematologic) and seven of other causes. Participants who died of cancer had significantly shorter leukocyte telomere lengths than those who died without a cancer diagnosis (P = .002) and those still alive (P < .001) (Figure 1).
Few studies have examined the association between telomere length and vascular dementia, with contradicting results. One cross-sectional study found that the odds ratio for vascular dementia was significantly higher in those with the shortest telomeres than in those with the longest.8 Another retrospective cohort study found no significant difference in telomere length between individuals with Alzheimer’s disease, mixed dementia, and vascular dementia and controls.9 The current study results are in agreement with the latter study. Telomere shortening in leukocytes may result in a reduction in the potency of immune cells, reflecting a decline in their ability to respond to an insult such as cancer. This provides a possible explanation for the trends observed in the curret study. Studies in colorectal cancer have demonstrated a significant association between tumorinfiltrating T-cell density and better prognosis. A similar role has been observed for macrophage infiltration.
1386
LETTERS TO THE EDITOR
CONCLUSION A significant negative correlation was found between leukocyte telomere length and cancer survival in older adults, and this is novel. Telomere length may be a prognostic indicator in older adults with cancer. Larger studies are required for confirmation. Cecil Chen Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia Ciaran Upton, MBBS Department of Aged Care and Rehabilitation, BankstownLidcombe Hospital, Bankstown, New South Wales, Australia Nady Braidy, PhD Department of Aged Care and Rehabilitation, BankstownLidcombe Hospital, Bankstown, New South Wales, Australia Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia Jinan Khalil Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia Zhi-Ming Fang, PhD School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia Ying-Hua Xu, PhD Daniel K. Y. Chan, MD Department of Aged Care and Rehabilitation, BankstownLidcombe Hospital, Bankstown, New South Wales, Australia University of New South Wales, Sydney, New South Wales, Australia
JULY 2014–VOL. 62, NO. 7
JAGS
REFERENCES 1. Stewart SA, Weinberg RA. Telomeres: Cancer to human aging. Annu Rev Cell Dev Biol 2006;22:531–557. 2. Butt HZ, Atturu G, London NJ et al. Telomere length dynamics in vascular disease: A review. Eur J Vasc Endovasc Surg 2010;40:17–26. 3. Wilson WR, Herbert KE, Mistry Y et al. Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease. Eur Heart J 2008;29:2689–2694. 4. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res 2002;30:e47. 5. Wentzensen IM, Mirabello L, Pfeiffer RM et al. The association of telomere length and cancer: A meta-analysis. Cancer Epidemiol Biomarkers Prev 2011;20:1238–5120. 6. Ma H, Zhou Z, Wei S et al. Shortened telomere length is associated with increased risk of cancer: A meta-analysis. PLoS ONE 2011;6:e20466. 7. Weischer M, Nordestgaard BG, Cawthon RM et al. Short telomere length, cancer survival, and cancer risk in 47102 individuals. J Natl Cancer Inst 2013;105:459–468. 8. von Zglinicki T, Serra V, Lorenz M et al. Short telomeres in patients with vascular dementia: An indicator of low antioxidative capacity and a possible risk factor? Lab Invest 2000;80:1739–1747. 9. Zekry D, Herrmann FR, Irminger-Finger I et al. Telomere length and ApoE polymorphism in mild cognitive impairment, degenerative and vascular dementia. J Neurol Sci 2010;299:108–111.
INFREQUENT OLDER ADULT–PRIMARY CARE PROVIDER DISCUSSION AND DOCUMENTATION OF DIETARY SUPPLEMENTS To the Editor: Almost half of older adults take dietary supplements,1 with 19.5% taking nonvitamin, nonmineral (NVNM) supplements.2 Despite the potential for drug– supplement interactions,3 individuals report disclosing
LETTERS TO THE EDITOR
JULY 2014–VOL. 62, NO. 7
JAGS
Table 1. Comparison of Subject Characteristics and Progression Rates Factor
Age, mean SD Sex, n Male Female Duration of disease, years, mean SD Education, years, mean SD Frequency of day service use, d/wk, mean SD MMSE score, mean SD At initial evaluation At last evaluation Follow-up, years, mean SD Progression rate (annual MMSE change), mean SD Medical complications, n Hypertension Diabetes mellitus Dyslipidemia Other
Day Service Nonuser, n = 71
Day Service User, n = 102
Satisfied, n = 64
Unsatisfied, n = 38
80.6 5.7
82.1 5.4
81.7 5.2
82.7 5.7
35 36 2.9 0.9 12.7 2.5 0
38 64 3.0 0.9 12.0 2.8 2.8 1.1
23 41 3.1 0.9 12.1 2.6 3.0 1.0c
15 23 2.8 0.8 11.6 3.1 2.3 1.1
22.7 18.6 3.3 1.2
24 13 8 12
3.1 4.0 0.9 0.9
21.4 17.7 3.5 1.0
3.7a 4.7 1.1 0.9
31 13 18 18
21.0 17.8 3.6 0.8 21 9 14 11
3.8 4.9 1.1 0.9b
22.1 17.5 3.4 1.4
3.3 4.4 1.2 0.9
10 4 4 7
SD = standard deviation; MMSE = Mini-Mental State Examination. a P < .05 vs day service nonusers; bP < .05, c.01 vs unsatisfied group.
the frequency of DS attendance as a covariate, showed that the satisfied group had significantly slower progression rates than the unsatisfied group. No significant correlation was observed between frequency of DS attendance and annual MMSE score change. No significant positive effects of DS use on disease progression were found. Because DS nonusers included some participants who participated in high leisure activities every day and did not need to attend the DS center, no beneficial effects of DS use was detected in individuals with AD. Nevertheless, although the satisfied and unsatisfied groups were divided mainly on the basis of subjective caregiver perceptions of the DS in this study, DS attendance with satisfaction may be associated with slower progression of cognitive deterioration. A previous study4 found improvement in or stabilization of cognitive and noncognitive dementia symptoms in DS users, whereas DS nonusers worsened after 9 months of service. Although the program and intervention may differ depending on the center or unit, DS offers the possibility of rehabilitative processes in different domains of functioning. Mental and physical engagements in complex environments may protect people from the development and progression of symptoms of neurodegenerative damage.6 These positive effects may be related to the individuals’ levels of satisfaction with DS attendance. This retrospective study suggests that active and enjoyable participation in DS may in part be associated with slower progression of cognitive decline in individuals with AD. Hirofumi Sakurai, MD Haruo Hanyu, MD Naruta Namioka, MD Hiroaki Hatanaka, MD Raita Fukasawa, MD Kazumasa Kume, MD Department of Geriatric Medicine, Tokyo Medical University, Tokyo, Japan
ACKNOWLEDGMENTS Conflict of Interest: The authors have no financial disclosures to declare. There are no conflicts of interest regarding this letter. Author Contributions: Hanyu, Sakurai: study concept and design, acquisition of subjects and data, analysis and interpretation of data, preparation of manuscript. Namioka, Hatanaka, Fukasawa, Kume: acquisition of subjects, data analysis, manuscript revisions. Sponsor’s Role: None.
REFERENCES 1. Gitlin LN, Reever K, Dennis MP et al. Enhancing quality of life of families who use adult day services: Short- and long-term effects of the adult day service plus program. Gerontologist 2006;46:630–639. 2. Zarit SH, Kim K, Femia EE et al. Effects of adult day care on daily stress of caregivers: A within-person approach. J Gerontol B Psychol Sci Soc Sci 2011;66B:538–546. 3. Baumgarten M, Lebel P, Laprise H et al. Adult day care for the frail elderly. J Aging Health 2002;14:237–259. 4. Zank S, Schacke C. Evaluation of geriatric day care units: Effects on patients and caregivers. J Gerontol Psychol Sci Soc Sci 2002;57B:348–357. 5. 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. 6. Peterosini L, De Bartola P, Foti F et al. On whether the environmental enrichment may provide cognitive and brain reserves. Brain Res Rev 2009;61:221–239.
ASSOCIATION BETWEEN LEUKOCYTE TELOMERE LENGTH AND VASCULAR DEMENTIA AND CANCER MORTALITY IN AN ELDERLY POPULATION To the Editor: Telomeres are regions of repeating TTA GGG hexanucleotide sequences located at the ends of each chromosome.1 Telomeres prevent loss of genetic
JAGS
JULY 2014–VOL. 62, NO. 7
LETTERS TO THE EDITOR
a
material during cell replication as enzymes that duplicate deoxyribonucleic acid (DNA) are unable to duplicate to the end of a strand of DNA. Consequently, telomeres shorten with each cell cycle, ultimately leading to permanent growth arrest, thus limiting the number of divisions a cell is capable of.1 Previous studies have identified correlations between leukocyte telomere lengths and various lifestyle factors that are frequently associated with cancer and cardiovascular diseases, which represent major causes of mortality in the developed world.2 As a biomarker for cellular stress and aging, particularly of the immune cells and cells of the vascular tree,3 telomere length may be associated with age-related diseases such as cancer and vascular dementia.
1385
b
METHODS Participants aged 75 and older were recruited from the Bankstown-Lidcombe Hospital memory clinic and geriatric wards and the War Memorial Hospital, Sydney, Australia. Individuals with a diagnosis of dementia of predominantly vascular etiology were included. Individuals with dementia of predominantly other causes were excluded. Individuals with vascular dementia with an Alzheimer’s component were included if it was not the dominant cause clinically for dementia. Control participants were determined to be cognitively normal (Mini-Mental State Examination score ≥28). Control participants with evidence of cerebrovascular events through history or on imaging were excluded. Upon recruitment, participants were guided through a comprehensive questionnaire including medical history and lifestyle factors. Participants were examined, and a blood sample was obtained. Relative telomere length in peripheral white blood cells was measured using a previously described real-time quantitative polymerase chain reaction (RT-qPCR) technique.4 Participants were followed up 2 years after initial examination. Nonparametric Mann–Whitney U-tests were used to compare the differences between the groups. P < .05 was considered statistically significant.
Figure 1. Relative telomere length between participants who died with and without cancer diagnosis and those who were alive. Mean standard deviation. aP < .01, bP < .001.
DISCUSSION Cancer Two meta-analyses found a significant association between shorter leukocyte telomeres and overall cancer risk,5,6 although another large population study found a significant correlation between shorter survival after diagnosis of cancer and shorter telomere lengths but no correlation with overall cancer risk.7 The current study focused on older subjects and is in agreement with the latter study. The findings in the current study’s older cohort that shorter leukocyte telomere length at the time of cancer diagnosis may be a predictor of future death from cancer is novel, but further studies are needed because the current study was limited mainly by a small sample size.
Vascular Dementia RESULTS Participants with vascular dementia patients had a MMSE score of 19.4 7.1 (n = 39), which was significantly lower (P < .001) than that of controls (29.0 2.1, n = 14). Participants with vascular dementia had a shorter mean leukocyte telomere length (1.07 0.18) than controls (1.21 0.43), although this result was not statistically significant (P = .25). No significant difference (P = .35) was found in the telomere lengths of participants with a cancer diagnosis (alive or dead) (1.23 0.45) and those who never had cancer (1.15 0.35) at the time of recruitment. At follow-up after a mean period of 2 years on 53 participants, 14 participants had died, of which seven deaths were cancer related (nonhematologic) and seven of other causes. Participants who died of cancer had significantly shorter leukocyte telomere lengths than those who died without a cancer diagnosis (P = .002) and those still alive (P < .001) (Figure 1).
Few studies have examined the association between telomere length and vascular dementia, with contradicting results. One cross-sectional study found that the odds ratio for vascular dementia was significantly higher in those with the shortest telomeres than in those with the longest.8 Another retrospective cohort study found no significant difference in telomere length between individuals with Alzheimer’s disease, mixed dementia, and vascular dementia and controls.9 The current study results are in agreement with the latter study. Telomere shortening in leukocytes may result in a reduction in the potency of immune cells, reflecting a decline in their ability to respond to an insult such as cancer. This provides a possible explanation for the trends observed in the curret study. Studies in colorectal cancer have demonstrated a significant association between tumorinfiltrating T-cell density and better prognosis. A similar role has been observed for macrophage infiltration.
1386
LETTERS TO THE EDITOR
CONCLUSION A significant negative correlation was found between leukocyte telomere length and cancer survival in older adults, and this is novel. Telomere length may be a prognostic indicator in older adults with cancer. Larger studies are required for confirmation. Cecil Chen Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia Ciaran Upton, MBBS Department of Aged Care and Rehabilitation, BankstownLidcombe Hospital, Bankstown, New South Wales, Australia Nady Braidy, PhD Department of Aged Care and Rehabilitation, BankstownLidcombe Hospital, Bankstown, New South Wales, Australia Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia Jinan Khalil Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia Zhi-Ming Fang, PhD School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia Ying-Hua Xu, PhD Daniel K. Y. Chan, MD Department of Aged Care and Rehabilitation, BankstownLidcombe Hospital, Bankstown, New South Wales, Australia University of New South Wales, Sydney, New South Wales, Australia
JULY 2014–VOL. 62, NO. 7
JAGS
REFERENCES 1. Stewart SA, Weinberg RA. Telomeres: Cancer to human aging. Annu Rev Cell Dev Biol 2006;22:531–557. 2. Butt HZ, Atturu G, London NJ et al. Telomere length dynamics in vascular disease: A review. Eur J Vasc Endovasc Surg 2010;40:17–26. 3. Wilson WR, Herbert KE, Mistry Y et al. Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease. Eur Heart J 2008;29:2689–2694. 4. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic Acids Res 2002;30:e47. 5. Wentzensen IM, Mirabello L, Pfeiffer RM et al. The association of telomere length and cancer: A meta-analysis. Cancer Epidemiol Biomarkers Prev 2011;20:1238–5120. 6. Ma H, Zhou Z, Wei S et al. Shortened telomere length is associated with increased risk of cancer: A meta-analysis. PLoS ONE 2011;6:e20466. 7. Weischer M, Nordestgaard BG, Cawthon RM et al. Short telomere length, cancer survival, and cancer risk in 47102 individuals. J Natl Cancer Inst 2013;105:459–468. 8. von Zglinicki T, Serra V, Lorenz M et al. Short telomeres in patients with vascular dementia: An indicator of low antioxidative capacity and a possible risk factor? Lab Invest 2000;80:1739–1747. 9. Zekry D, Herrmann FR, Irminger-Finger I et al. Telomere length and ApoE polymorphism in mild cognitive impairment, degenerative and vascular dementia. J Neurol Sci 2010;299:108–111.
INFREQUENT OLDER ADULT–PRIMARY CARE PROVIDER DISCUSSION AND DOCUMENTATION OF DIETARY SUPPLEMENTS To the Editor: Almost half of older adults take dietary supplements,1 with 19.5% taking nonvitamin, nonmineral (NVNM) supplements.2 Despite the potential for drug– supplement interactions,3 individuals report disclosing
