JAGS
OCTOBER 2014–VOL. 62, NO. 10
LOWER VITAMIN D IS ASSOCIATED WITH WHITE MATTER HYPERINTENSITY IN ELDERLY WOMEN WITH ALZHEIMER’S DISEASE AND AMNESTIC MILD COGNITIVE IMPAIRMENT To the Editor: White matter hyperintensity (WMH) on brain magnetic resonance imaging (MRI) is prevalent in the aging brain and is associated with cognitive decline and mobility impairment.1,2 It is a clinical challenge to establish a prevention strategy for WMH. Although believed to be of vascular origin, the exact etiology of WMH remains unclear. Age and hypertension are consistent risk factors for WMH. High homocysteine levels, diabetes mellitus, hyperlipidemia, smoking, obesity, low vitamin B12 levels, and alcohol consumption are likely to increase WMH.3 There is growing evidence of potential roles of vitamin D in sustaining healthy brain function.4 Low serum vitamin D has been reported in Alzheimer’s disease (AD), which is often associated with WMH,5 but little is known about the link between vitamin D and WMH in elderly adults with AD. This study aimed to clarify the interaction between vitamin D, WMH, brain atrophy in elderly adults with AD and amnestic mild cognitive impairment (aMCI). Two hundred fifty-three women aged 65 and older diagnosed with aMCI (n = 39) or AD (n = 214) were recruited. AD was diagnosed as possible or probable AD according the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, and aMCI was diagnosed based on previously defined criteria.2,6 Individuals with severe cardiac failure, renal disorder, liver dysfunction, or musculoskeletal disease or with cortical lesions on MRI were excluded. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE). Hypertension, diabetes mellitus, lipid abnormalities, and chronic kidney disease were defined as having a history of these diseases or use of medication to treat them. Information on current smoking and drinking habits was obtained from clinical charts. Vitamin D insufficiency was assessed according to serum concentration of 25-hydroxyvitamin D (25(OH)D). A standard series of axial T2-weighted (repetition time (TR), 3,800 ms; echo time (TE), 93 ms) and fluid-attenuated inversion recovery (TR, 8,000 ms; TE, 101 ms; inversion time, 2,500 ms; a 256 9 256 matrix) MR sequences were obtained using a 1.5-T MR scanner (Siemens Avanto, Munich, Germany). Scans in parallel with the anterior commissure–posterior commissure line were performed with 6-mm-thick slices and an interslice gap of 1.2 mm.2 MRI data were processed to measure the total volume of the intracranial space (IC), parenchyma, ventricles, and WMH using a fully automatic segmentation program (Software for Neuro-Image Processing in Experimental Research).7 Statistical analysis was performed using SPSS 19.0 for Windows (SPSS, Inc., Chicago, IL). Because WMH were not normally distributed, their values were converted to rank variables. The association between WMH and clinical variables was analyzed using partial Spearman rank order
LETTERS TO THE EDITOR
1993
Table 1. Clinical Profile and Magnetic Resonance Imaging Results of Study Participants (N = 253) Characteristic
Value
Demographic characteristics and biochemical measurements Age, mean SD 77.5 Education, years, mean SD 10.0 Mini-Mental State Examination score, 19.9 mean SD Hypertension, % 56.9 Diabetes mellitus, % 21.6 Lipid abnormality, % 41.7 Chronic kidney disease, % 32.3 Current smoking, % 2.0 Drinking habit, % 7.7 Systolic blood pressure, mmHg, mean SD 150.1 Diastolic blood pressure, mmHg, mean SD 80.9 21.8 Body mass index, kg/m2, mean SD Glycosylated hemoglobin, %, mean SD 6.1 Total cholesterol, mg/dL, mean SD 221.5 High-density lipoprotein cholesterol, 63.5 mg/dL, mean SD Triglyceride, mg/dL, mean SD 126.5 68.5 Estimated glomerular filtration rate, mL/min per 1.73 m2, mean SD Cystatin C, mg/L, mean SD 1.0 25-hydroxyvitamin D, ng/mL, mean SD 23.6 Homocysteine, nmol/mL, mean SD 11.1 Vitamin B12, pg/mL, mean SD 674.2 Cranial magnetic resonance imaging, mean SD IC, mL 1,324.2 WMH, mL 17.2 WMH/IC, % 1.3 Parenchyma, mL 991.1 Parenchyma/IC, % 74.9
5.0 2.1 5.0
21.2 11.9 3.6 0.8 37.5 15.7 71.9 18.4 0.4 7.2 5.6 476.3 96.4 18.1 1.4 78.3 3.0
SD = standard deviation; IC = intracranial space; WMH = white matter hyperintensity.
correlation analysis and multivariate regression (stepwise). Differences were considered significant at P < .05. Table 1 shows the demographic characteristics, biochemical measurements, and results of MRI analyses of the participants. Serum 25(OH)D levels in individuals receiving vitamin D supplementation (n = 20) were significantly lower than in those who were not (P = .03). Partial Spearman rank order correlation revealed a possible correlation between WMH/IC and age (rs = 0.252, P < .001), hypertension (rs = 0.179, P = .001), MMSE score (rs = 0.157, P < .001), cystatin-C (rs = 0.166, P = .004), 25(OH)D (rs = 0.171, P = .006), and homocysteine (rs = 0.146, P = .01), whereas the other clinical indices were not correlated (data not shown). Multivariate regression analysis using these possible factors, together with education, as variables revealed that older age (b = 0.208, P = .001), hypertension (b = 0.162, P = .009), and lower 25(OH)D (b = 0.163, P = .008) were independently associated with WMH/IC. In contrast, 25(OH)D was not related to parenchyma/IC as an index of global brain atrophy (data not shown). The present study clearly demonstrates that 25(OH)D is negatively correlated with WMH volume in elderly women with aMCI or AD, even after adjusting for classic risk factors for WMH, whereas 25(OH)D was not
1994
LETTERS TO THE EDITOR
associated with brain atrophy. A previous study suggested that individuals with 25(OH)D deficiency had greater WMH volume.8 A correlation between vitamin D and WMH in multiple sclerosis has been demonstrated.9 Another study recently reported an association between WMH and low 25(OH)D in independent outpatients.10 The current study indicates that hypovitaminosis D is a predictor of WMH in individuals with AD or aMCI. WMH has been found to have clinical relevance in cognitive decline and several geriatric syndrome conditions,1,2 and vitamin D plays central roles in muscle weakness and physical frailty in elderly individuals. Taken together, the results of the current study suggest that vitamin D controls two pathways toward cognitive decline and frailty by means of white matter burden and sarcopenia in elderly adults with dementia. Prospective studies are needed to clarify the effects of vitamin D supplementation in prevention of WMH in individuals with AD. Takashi Sakurai, MD, PhD Noriko Ogama, MA Kenji Toba, MD, PhD Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu, Japan
ACKNOWLEDGMENTS We thank BioBank, NCGG for quality control of clinical data. Conflict of Interest: Research funding for Longevity Sciences (24–24, 25–5) was received from the National Center for Geriatrics and Gerontology, Japan (TS) and Health and Labor Sciences Research Grants (H25-Ninchisho-008) (KT). Author Contributions: Sakurai: study concept and design, acquisition of subjects and data, analysis and interpretation of data, preparation of manuscript. Ogama: data acquisition, analysis and interpretation of data. Toba: study concept and design, manuscript editing. Sponsor’s Role: None.
REFERENCES 1. Wakefield DB, Moscufo N, Guttmann CR et al. White matter hyperintensities predict functional decline in voiding, mobility, and cognition in older adults. J Am Geriatr Soc 2010;58:275–281. 2. Ogama N, Sakurai T, Shimizu A et al. Regional white matter lesions predict falls in patients with amnestic mild cognitive impairment and Alzheimer’s disease. J Am Med Dir Assoc 2014;15:36–41. 3. Rostrup E, Gouw AA, Vrenken H et al.; LADIS study group. The spatial distribution of age-related white matter changes as a function of vascular risk factors—results from the LADIS study. Neuroimage 2012;60:1597–1607. 4. Llewellyn DJ, Lang IA, Langa KM et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med 2010;170:1135–1141. 5. Annweiler C1, Llewellyn DJ, Beauchet O. Low serum vitamin D concentrations in Alzheimer’s disease: A systematic review and meta-analysis. J Alzheimers Dis 2013;33:659–674. 6. Petersen R, Doody R, Kurz A et al. Current concepts in mild cognitive impairment. Arch Neurol 2001;58:1985–1992. 7. Admiraal-Behloul F, van den Heuvel DM, Olofsen H et al. Fully automatic segmentation of white matter hyperintensities in MR images of the elderly. Neuroimage 2005;28:607–617. 8. Buell JS, Dawson-Hughes B, Scott TM et al. 25-hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services. Neurology 2010;74:18–26.
OCTOBER 2014–VOL. 62, NO. 10
JAGS
9. Mowry EM, Waubant E, McCulloch CE et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol 2012;72:234–240. 10. Prager JM, Thomas C, Ankenbrandt WJ et al. Association of white matter hyperintensities with low serum 25-hydroxyvitamin D levels. AJNR Am J Neuroradiol 2014;35:1145–1149.
IMPROVING CARE TRANSITIONS IN INDIVIDUALS FREQUENTLY ADMITTED TO THE HOSPITAL To the Editor: Individuals who are frequently admitted to the hospital have high levels of multimorbidity, polypharmacy, and functional impairment,1 and the sudden reduction in intensity of care in the posthospital period may contribute to high rates of hospital readmission.2–5 A multidisciplinary follow-up clinic for frequently admitted patients was piloted to address demonstrated gaps in transitional care.6 This report describes the patient perspective of care in this model.
METHODS Participants were recruited from general medical wards of a metropolitan hospital in Brisbane, Australia, from June to December 2012. Consecutive inpatients aged 60 and older with at least one unplanned hospitalization in the previous 6 months were identified through the admissions database. Individuals were ineligible if they lived outside Brisbane, were discharged to residential care, were receiving palliative care, could not consent, or were receiving care from the heart failure service. Eligible individuals were invited to participate if their treating team agreed. The study received ethical approval. Participants were scheduled for clinic review within 2 weeks of discharge. The first visit included comprehensive assessment of social and medical services, symptoms, care goals, activities of daily living, malnutrition, and depression by a registered nurse. A clinical pharmacist undertook review of medication use after discharge, current medication understanding, and adherence. The physician then reviewed medical conditions and treatments and recommended a treatment plan, including referrals as needed. A physiotherapist or exercise physiologist assessed each participant and prescribed an individualized exercise program in a supervised weekly group exercise class or at home. A comprehensive summary with recommendations was sent to the general practitioner within 5 days, and at least two further reviews were scheduled over 12 weeks to assess progress and adjust management, with telephone support as required. Participant perceptions were measured using the 15-item Care Transitions Measure (CTM-15), a reliable measure of quality of transitional care.7,8 The CTM-15 was administered at the initial visit (reflecting hospital discharge) and at 12 weeks (reflecting clinic experience). Items were scored from 1 (strongly disagree) to 4 (strongly agree), and the CTM-15 score was calculated by averaging and linear transformation as originally described.8 Baseline and 12week CTM-15 scores were compared using paired t-tests; mean nontransformed scores for each item were compared using paired t-tests.
Copyright of Journal of the American Geriatrics Society is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
OCTOBER 2014–VOL. 62, NO. 10
LOWER VITAMIN D IS ASSOCIATED WITH WHITE MATTER HYPERINTENSITY IN ELDERLY WOMEN WITH ALZHEIMER’S DISEASE AND AMNESTIC MILD COGNITIVE IMPAIRMENT To the Editor: White matter hyperintensity (WMH) on brain magnetic resonance imaging (MRI) is prevalent in the aging brain and is associated with cognitive decline and mobility impairment.1,2 It is a clinical challenge to establish a prevention strategy for WMH. Although believed to be of vascular origin, the exact etiology of WMH remains unclear. Age and hypertension are consistent risk factors for WMH. High homocysteine levels, diabetes mellitus, hyperlipidemia, smoking, obesity, low vitamin B12 levels, and alcohol consumption are likely to increase WMH.3 There is growing evidence of potential roles of vitamin D in sustaining healthy brain function.4 Low serum vitamin D has been reported in Alzheimer’s disease (AD), which is often associated with WMH,5 but little is known about the link between vitamin D and WMH in elderly adults with AD. This study aimed to clarify the interaction between vitamin D, WMH, brain atrophy in elderly adults with AD and amnestic mild cognitive impairment (aMCI). Two hundred fifty-three women aged 65 and older diagnosed with aMCI (n = 39) or AD (n = 214) were recruited. AD was diagnosed as possible or probable AD according the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association, and aMCI was diagnosed based on previously defined criteria.2,6 Individuals with severe cardiac failure, renal disorder, liver dysfunction, or musculoskeletal disease or with cortical lesions on MRI were excluded. Cognitive function was evaluated using the Mini-Mental State Examination (MMSE). Hypertension, diabetes mellitus, lipid abnormalities, and chronic kidney disease were defined as having a history of these diseases or use of medication to treat them. Information on current smoking and drinking habits was obtained from clinical charts. Vitamin D insufficiency was assessed according to serum concentration of 25-hydroxyvitamin D (25(OH)D). A standard series of axial T2-weighted (repetition time (TR), 3,800 ms; echo time (TE), 93 ms) and fluid-attenuated inversion recovery (TR, 8,000 ms; TE, 101 ms; inversion time, 2,500 ms; a 256 9 256 matrix) MR sequences were obtained using a 1.5-T MR scanner (Siemens Avanto, Munich, Germany). Scans in parallel with the anterior commissure–posterior commissure line were performed with 6-mm-thick slices and an interslice gap of 1.2 mm.2 MRI data were processed to measure the total volume of the intracranial space (IC), parenchyma, ventricles, and WMH using a fully automatic segmentation program (Software for Neuro-Image Processing in Experimental Research).7 Statistical analysis was performed using SPSS 19.0 for Windows (SPSS, Inc., Chicago, IL). Because WMH were not normally distributed, their values were converted to rank variables. The association between WMH and clinical variables was analyzed using partial Spearman rank order
LETTERS TO THE EDITOR
1993
Table 1. Clinical Profile and Magnetic Resonance Imaging Results of Study Participants (N = 253) Characteristic
Value
Demographic characteristics and biochemical measurements Age, mean SD 77.5 Education, years, mean SD 10.0 Mini-Mental State Examination score, 19.9 mean SD Hypertension, % 56.9 Diabetes mellitus, % 21.6 Lipid abnormality, % 41.7 Chronic kidney disease, % 32.3 Current smoking, % 2.0 Drinking habit, % 7.7 Systolic blood pressure, mmHg, mean SD 150.1 Diastolic blood pressure, mmHg, mean SD 80.9 21.8 Body mass index, kg/m2, mean SD Glycosylated hemoglobin, %, mean SD 6.1 Total cholesterol, mg/dL, mean SD 221.5 High-density lipoprotein cholesterol, 63.5 mg/dL, mean SD Triglyceride, mg/dL, mean SD 126.5 68.5 Estimated glomerular filtration rate, mL/min per 1.73 m2, mean SD Cystatin C, mg/L, mean SD 1.0 25-hydroxyvitamin D, ng/mL, mean SD 23.6 Homocysteine, nmol/mL, mean SD 11.1 Vitamin B12, pg/mL, mean SD 674.2 Cranial magnetic resonance imaging, mean SD IC, mL 1,324.2 WMH, mL 17.2 WMH/IC, % 1.3 Parenchyma, mL 991.1 Parenchyma/IC, % 74.9
5.0 2.1 5.0
21.2 11.9 3.6 0.8 37.5 15.7 71.9 18.4 0.4 7.2 5.6 476.3 96.4 18.1 1.4 78.3 3.0
SD = standard deviation; IC = intracranial space; WMH = white matter hyperintensity.
correlation analysis and multivariate regression (stepwise). Differences were considered significant at P < .05. Table 1 shows the demographic characteristics, biochemical measurements, and results of MRI analyses of the participants. Serum 25(OH)D levels in individuals receiving vitamin D supplementation (n = 20) were significantly lower than in those who were not (P = .03). Partial Spearman rank order correlation revealed a possible correlation between WMH/IC and age (rs = 0.252, P < .001), hypertension (rs = 0.179, P = .001), MMSE score (rs = 0.157, P < .001), cystatin-C (rs = 0.166, P = .004), 25(OH)D (rs = 0.171, P = .006), and homocysteine (rs = 0.146, P = .01), whereas the other clinical indices were not correlated (data not shown). Multivariate regression analysis using these possible factors, together with education, as variables revealed that older age (b = 0.208, P = .001), hypertension (b = 0.162, P = .009), and lower 25(OH)D (b = 0.163, P = .008) were independently associated with WMH/IC. In contrast, 25(OH)D was not related to parenchyma/IC as an index of global brain atrophy (data not shown). The present study clearly demonstrates that 25(OH)D is negatively correlated with WMH volume in elderly women with aMCI or AD, even after adjusting for classic risk factors for WMH, whereas 25(OH)D was not
1994
LETTERS TO THE EDITOR
associated with brain atrophy. A previous study suggested that individuals with 25(OH)D deficiency had greater WMH volume.8 A correlation between vitamin D and WMH in multiple sclerosis has been demonstrated.9 Another study recently reported an association between WMH and low 25(OH)D in independent outpatients.10 The current study indicates that hypovitaminosis D is a predictor of WMH in individuals with AD or aMCI. WMH has been found to have clinical relevance in cognitive decline and several geriatric syndrome conditions,1,2 and vitamin D plays central roles in muscle weakness and physical frailty in elderly individuals. Taken together, the results of the current study suggest that vitamin D controls two pathways toward cognitive decline and frailty by means of white matter burden and sarcopenia in elderly adults with dementia. Prospective studies are needed to clarify the effects of vitamin D supplementation in prevention of WMH in individuals with AD. Takashi Sakurai, MD, PhD Noriko Ogama, MA Kenji Toba, MD, PhD Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, Obu, Japan
ACKNOWLEDGMENTS We thank BioBank, NCGG for quality control of clinical data. Conflict of Interest: Research funding for Longevity Sciences (24–24, 25–5) was received from the National Center for Geriatrics and Gerontology, Japan (TS) and Health and Labor Sciences Research Grants (H25-Ninchisho-008) (KT). Author Contributions: Sakurai: study concept and design, acquisition of subjects and data, analysis and interpretation of data, preparation of manuscript. Ogama: data acquisition, analysis and interpretation of data. Toba: study concept and design, manuscript editing. Sponsor’s Role: None.
REFERENCES 1. Wakefield DB, Moscufo N, Guttmann CR et al. White matter hyperintensities predict functional decline in voiding, mobility, and cognition in older adults. J Am Geriatr Soc 2010;58:275–281. 2. Ogama N, Sakurai T, Shimizu A et al. Regional white matter lesions predict falls in patients with amnestic mild cognitive impairment and Alzheimer’s disease. J Am Med Dir Assoc 2014;15:36–41. 3. Rostrup E, Gouw AA, Vrenken H et al.; LADIS study group. The spatial distribution of age-related white matter changes as a function of vascular risk factors—results from the LADIS study. Neuroimage 2012;60:1597–1607. 4. Llewellyn DJ, Lang IA, Langa KM et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med 2010;170:1135–1141. 5. Annweiler C1, Llewellyn DJ, Beauchet O. Low serum vitamin D concentrations in Alzheimer’s disease: A systematic review and meta-analysis. J Alzheimers Dis 2013;33:659–674. 6. Petersen R, Doody R, Kurz A et al. Current concepts in mild cognitive impairment. Arch Neurol 2001;58:1985–1992. 7. Admiraal-Behloul F, van den Heuvel DM, Olofsen H et al. Fully automatic segmentation of white matter hyperintensities in MR images of the elderly. Neuroimage 2005;28:607–617. 8. Buell JS, Dawson-Hughes B, Scott TM et al. 25-hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services. Neurology 2010;74:18–26.
OCTOBER 2014–VOL. 62, NO. 10
JAGS
9. Mowry EM, Waubant E, McCulloch CE et al. Vitamin D status predicts new brain magnetic resonance imaging activity in multiple sclerosis. Ann Neurol 2012;72:234–240. 10. Prager JM, Thomas C, Ankenbrandt WJ et al. Association of white matter hyperintensities with low serum 25-hydroxyvitamin D levels. AJNR Am J Neuroradiol 2014;35:1145–1149.
IMPROVING CARE TRANSITIONS IN INDIVIDUALS FREQUENTLY ADMITTED TO THE HOSPITAL To the Editor: Individuals who are frequently admitted to the hospital have high levels of multimorbidity, polypharmacy, and functional impairment,1 and the sudden reduction in intensity of care in the posthospital period may contribute to high rates of hospital readmission.2–5 A multidisciplinary follow-up clinic for frequently admitted patients was piloted to address demonstrated gaps in transitional care.6 This report describes the patient perspective of care in this model.
METHODS Participants were recruited from general medical wards of a metropolitan hospital in Brisbane, Australia, from June to December 2012. Consecutive inpatients aged 60 and older with at least one unplanned hospitalization in the previous 6 months were identified through the admissions database. Individuals were ineligible if they lived outside Brisbane, were discharged to residential care, were receiving palliative care, could not consent, or were receiving care from the heart failure service. Eligible individuals were invited to participate if their treating team agreed. The study received ethical approval. Participants were scheduled for clinic review within 2 weeks of discharge. The first visit included comprehensive assessment of social and medical services, symptoms, care goals, activities of daily living, malnutrition, and depression by a registered nurse. A clinical pharmacist undertook review of medication use after discharge, current medication understanding, and adherence. The physician then reviewed medical conditions and treatments and recommended a treatment plan, including referrals as needed. A physiotherapist or exercise physiologist assessed each participant and prescribed an individualized exercise program in a supervised weekly group exercise class or at home. A comprehensive summary with recommendations was sent to the general practitioner within 5 days, and at least two further reviews were scheduled over 12 weeks to assess progress and adjust management, with telephone support as required. Participant perceptions were measured using the 15-item Care Transitions Measure (CTM-15), a reliable measure of quality of transitional care.7,8 The CTM-15 was administered at the initial visit (reflecting hospital discharge) and at 12 weeks (reflecting clinic experience). Items were scored from 1 (strongly disagree) to 4 (strongly agree), and the CTM-15 score was calculated by averaging and linear transformation as originally described.8 Baseline and 12week CTM-15 scores were compared using paired t-tests; mean nontransformed scores for each item were compared using paired t-tests.
Copyright of Journal of the American Geriatrics Society is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
