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. 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. There is growing evidence of potential roles of vitamin D in sustaining healthy brain function. Low serum vitamin D has been reported in Alzheimer’s disease (AD), which is often associated with WMH, 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. 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. 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). 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 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 Table 1. Clinical Profile and Magnetic Resonance Imaging Results of Study Participants (N = 253)