Individuals with Exceptional Longevity Manifest a Delayed Association Between Vitamin D Insufficiency and Cognitive Impairment Sofiya Milman, MD,*† Micol Schulder-Katz, MD,* Jennifer Deluty, BA,‡ Molly E. Zimmerman, PhD,§ Jill P. Crandall, MD,*† Nir Barzilai, MD,*†¶ Michal L. Melamed, MD,**††1 and Gil Atzmon, PhD*†¶1
OBJECTIVES: To define vitamin D levels and their association with cognition in subjects with exceptional longevity. DESIGN: Cross-sectional. SETTING: Community and long-term care facilities. PARTICIPANTS: Ashkenazi Jewish subjects (n = 253) with exceptional longevity, with comparison made to the Third National Health and Nutrition Examination Survey (NHANES III) participants aged 70 and older. MEASUREMENTS: Serum 25-hydroxyvitamin D levels were measured using liquid chromatography/tandem mass spectrometry analysis. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and clock drawing test (CDT: command and copy). RESULTS: The median age of the Ashkenazi subjects was 97 (interquartile range (IQR) 95–104). Age-associated rise in the prevalence of vitamin D insufficiency, defined as a serum vitamin D level of less than 30 ng/mL, was noted in NHANES III (P = .001). In the Ashkenazi group with longevity, the rate of vitamin D insufficiency was comparable with that of the NHANES III participants, who were up to 25 years younger. In the cohort with exceptional longevity, 49% demonstrated cognitive impairment as assessed according to MMSE score (impaired cognition, median 9.5 IQR 0–24); normal cognition, median 29 (IQR 18–30) P < .001). Vitamin D From the *Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, †Institute for Aging Research, Albert Einstein College of Medicine, ‡Albert Einstein College of Medicine, § Department of Neurology, Albert Einstein College of Medicine, ¶ Department of Genetics, Albert Einstein College of Medicine, **Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, and ††Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York. 1
Gil Atzmon and Michal L. Melamed are co-senior authors.
Address correspondence to Sofiya Milman, Institute for Aging Research, Albert Einstein College of Medicine, Division of Endocrinology, 1300 Morris Park Ave., Belfer 701, Bronx, NY 10461. E-mail: [email protected]
insufficiency was more prevalent in those with impaired cognition, defined according to the MMSE (71.8% vs 57.7%, P = .02) and the CDT copy (84.6% vs. 50.6%, P = .02), than in those with normal cognition. This association remained significant after multivariable adjustment in logistic regression models for cognitive assessments made using the MMSE (odds ratio (OR) = 3.2, 95% confidence interval (CI) = 1.1–9.29, P = .03) and the CDT copy (OR = 8.96, 95% CI = 1.08–74.69, P = .04). CONCLUSION: Higher vitamin D levels may be a marker of delayed aging, because they are associated with better cognitive function in people achieving exceptional longevity. J Am Geriatr Soc 62:153–158, 2014.
Key words: vitamin D; exceptional longevity; cognitive function
A
ging is a major risk factor for many diseases, including cognitive dysfunction. In cross-sectional studies, vitamin D deficiency in elderly adults has been linked to greater odds of cognitive impairment1,2 and prospectively to greater risk of cognitive decline.2,3 Elderly adults are particularly vulnerable to vitamin D deficiency secondary to physiological changes that affect vitamin D synthesis.4 Although epidemiological data suggest that vitamin D may play a role in protecting against cognitive dysfunction in the general elderly population, whether this association exists in populations with exceptional longevity (centenarians), in whom dementia risk is delayed in proportion to their life span,5 has not been determined. It is also unknown whether centenarians differ in their metabolism of vitamin D and susceptibility to vitamin D deficiency. Thus, it was hypothesized that vitamin D insufficiency would be associated with cognitive impairment in centenarians, and this hypothesis was tested using a well-characterized Ashkenazi Jewish
DOI: 10.1111/jgs.12601
JAGS 62:153–158, 2014 © 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society
0002-8614/14/$15.00
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cohort with exceptional longevity.6 In addition, because it has previously been demonstrated that centenarians frequently have biological profiles similar to those of younger individuals,5,7–9 vitamin D levels in centenarians were compared with those of a cross-sectional younger cohort from the general population using data from the Third National Health and Nutrition Examination Survey (NHANES III). Identification of factors that contribute to delay in ageassociated cognitive decline, as observed in centenarians, may lead to novel therapeutic interventions for dementia and other age-related diseases in the general elderly population.
METHODS Study Participants Ashkenazi Jewish (AJ) individuals aged 95 and older (centenarians, n = 545) living independently at age 95, which was considered a reflection of good health, were recruited for the Longevity Genes Project at Albert Einstein College of Medicine from the northeastern United States starting in 1998, as previously described.6 The AJ population is Caucasian, originating from a small founder population and is relatively homogeneous genetically and socioeconomically. Participants’ ages were verified with government-issued identification. A single study nurse visited participants in their residences and performed measurements of weight and height and evaluations of cognitive function and mood. A thorough medical and social history was obtained using a structured questionnaire. A venous blood sample was collected, and the processed serum was stored at –80°C. Written informed consent was obtained from participants or their proxies, in the event that the participant lacked cognitive capacity. The institutional review board at the Albert Einstein College of Medicine approved the study. A comparison group was selected from NHANES III, a U.S. national survey conducted between 1988 and 1994. A non-Hispanic white subgroup of NHANES III aged 70 to 90 was selected for the analysis because of racial differences in sun-mediated skin synthesis of vitamin D precursors. The age for all of the NHANES III participants who were older than 90 was recorded as 90 to maintain anonymity. Although the oldest NHANES III group may include centenarians, it is highly unlikely, because only approximately one in 6,000 people reach this age in the general population.10
Cognitive and Mood Assessment Cognition was assessed using the Mini-Mental State Examination (MMSE)11 and the clock drawing tests (CDT).12 The MMSE is a test of global cognitive function. It was scored out of 30 points for participants without major visual impairment, with a score of 25 or greater representing normal cognition.13 For participants with severe visual impairment a Blind MMSE14,15 was used, which excluded items that required image processing. The Blind MMSE was scored out of a maximum 22 points,14,15 with a score of 16 or greater representing normal cognition. The cognitive domain of executive function was evaluated using the CDT
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command, and the visuospatial construction was assessed using the CDT copy.16 Both CDTs were scored out of 10 points, with a score
OBJECTIVES: To define vitamin D levels and their association with cognition in subjects with exceptional longevity. DESIGN: Cross-sectional. SETTING: Community and long-term care facilities. PARTICIPANTS: Ashkenazi Jewish subjects (n = 253) with exceptional longevity, with comparison made to the Third National Health and Nutrition Examination Survey (NHANES III) participants aged 70 and older. MEASUREMENTS: Serum 25-hydroxyvitamin D levels were measured using liquid chromatography/tandem mass spectrometry analysis. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) and clock drawing test (CDT: command and copy). RESULTS: The median age of the Ashkenazi subjects was 97 (interquartile range (IQR) 95–104). Age-associated rise in the prevalence of vitamin D insufficiency, defined as a serum vitamin D level of less than 30 ng/mL, was noted in NHANES III (P = .001). In the Ashkenazi group with longevity, the rate of vitamin D insufficiency was comparable with that of the NHANES III participants, who were up to 25 years younger. In the cohort with exceptional longevity, 49% demonstrated cognitive impairment as assessed according to MMSE score (impaired cognition, median 9.5 IQR 0–24); normal cognition, median 29 (IQR 18–30) P < .001). Vitamin D From the *Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, †Institute for Aging Research, Albert Einstein College of Medicine, ‡Albert Einstein College of Medicine, § Department of Neurology, Albert Einstein College of Medicine, ¶ Department of Genetics, Albert Einstein College of Medicine, **Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, and ††Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York. 1
Gil Atzmon and Michal L. Melamed are co-senior authors.
Address correspondence to Sofiya Milman, Institute for Aging Research, Albert Einstein College of Medicine, Division of Endocrinology, 1300 Morris Park Ave., Belfer 701, Bronx, NY 10461. E-mail: [email protected]
insufficiency was more prevalent in those with impaired cognition, defined according to the MMSE (71.8% vs 57.7%, P = .02) and the CDT copy (84.6% vs. 50.6%, P = .02), than in those with normal cognition. This association remained significant after multivariable adjustment in logistic regression models for cognitive assessments made using the MMSE (odds ratio (OR) = 3.2, 95% confidence interval (CI) = 1.1–9.29, P = .03) and the CDT copy (OR = 8.96, 95% CI = 1.08–74.69, P = .04). CONCLUSION: Higher vitamin D levels may be a marker of delayed aging, because they are associated with better cognitive function in people achieving exceptional longevity. J Am Geriatr Soc 62:153–158, 2014.
Key words: vitamin D; exceptional longevity; cognitive function
A
ging is a major risk factor for many diseases, including cognitive dysfunction. In cross-sectional studies, vitamin D deficiency in elderly adults has been linked to greater odds of cognitive impairment1,2 and prospectively to greater risk of cognitive decline.2,3 Elderly adults are particularly vulnerable to vitamin D deficiency secondary to physiological changes that affect vitamin D synthesis.4 Although epidemiological data suggest that vitamin D may play a role in protecting against cognitive dysfunction in the general elderly population, whether this association exists in populations with exceptional longevity (centenarians), in whom dementia risk is delayed in proportion to their life span,5 has not been determined. It is also unknown whether centenarians differ in their metabolism of vitamin D and susceptibility to vitamin D deficiency. Thus, it was hypothesized that vitamin D insufficiency would be associated with cognitive impairment in centenarians, and this hypothesis was tested using a well-characterized Ashkenazi Jewish
DOI: 10.1111/jgs.12601
JAGS 62:153–158, 2014 © 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society
0002-8614/14/$15.00
154
MILMAN ET AL.
cohort with exceptional longevity.6 In addition, because it has previously been demonstrated that centenarians frequently have biological profiles similar to those of younger individuals,5,7–9 vitamin D levels in centenarians were compared with those of a cross-sectional younger cohort from the general population using data from the Third National Health and Nutrition Examination Survey (NHANES III). Identification of factors that contribute to delay in ageassociated cognitive decline, as observed in centenarians, may lead to novel therapeutic interventions for dementia and other age-related diseases in the general elderly population.
METHODS Study Participants Ashkenazi Jewish (AJ) individuals aged 95 and older (centenarians, n = 545) living independently at age 95, which was considered a reflection of good health, were recruited for the Longevity Genes Project at Albert Einstein College of Medicine from the northeastern United States starting in 1998, as previously described.6 The AJ population is Caucasian, originating from a small founder population and is relatively homogeneous genetically and socioeconomically. Participants’ ages were verified with government-issued identification. A single study nurse visited participants in their residences and performed measurements of weight and height and evaluations of cognitive function and mood. A thorough medical and social history was obtained using a structured questionnaire. A venous blood sample was collected, and the processed serum was stored at –80°C. Written informed consent was obtained from participants or their proxies, in the event that the participant lacked cognitive capacity. The institutional review board at the Albert Einstein College of Medicine approved the study. A comparison group was selected from NHANES III, a U.S. national survey conducted between 1988 and 1994. A non-Hispanic white subgroup of NHANES III aged 70 to 90 was selected for the analysis because of racial differences in sun-mediated skin synthesis of vitamin D precursors. The age for all of the NHANES III participants who were older than 90 was recorded as 90 to maintain anonymity. Although the oldest NHANES III group may include centenarians, it is highly unlikely, because only approximately one in 6,000 people reach this age in the general population.10
Cognitive and Mood Assessment Cognition was assessed using the Mini-Mental State Examination (MMSE)11 and the clock drawing tests (CDT).12 The MMSE is a test of global cognitive function. It was scored out of 30 points for participants without major visual impairment, with a score of 25 or greater representing normal cognition.13 For participants with severe visual impairment a Blind MMSE14,15 was used, which excluded items that required image processing. The Blind MMSE was scored out of a maximum 22 points,14,15 with a score of 16 or greater representing normal cognition. The cognitive domain of executive function was evaluated using the CDT
JANUARY 2014–VOL. 62, NO. 1
JAGS
command, and the visuospatial construction was assessed using the CDT copy.16 Both CDTs were scored out of 10 points, with a score
