Reader Benefit: Supplementing vitamin D effectively through sun and/or diet could particularly benefit visual long-term memory in patients with multiple sclerosis.
CVLT-II=California Verbal Learning Test, Second Edition; FSIQ=full scale intelligence quotient; M=mean; MS=multiple sclerosis; POMS-SF=Profile of Mood States, Short Form; RCFT=Rey Complex Figure Test; SD=standard deviation; WASI=Wechsler Abbreviated Scale of Intelligence.
In addition to decline in domains of attention and executive functioning as well as processing speed and efficiency, 1 of the most frequently reported cognitive complaints by patients with MS is decline in long-term memory (Bruce and Arnett, 2004; Chiaravalloti and DeLuca, 2008; Rogers and Panegyres, 2007; Smestad et al, 2010). Standardized neuropsychological testing corroborates this decline. In a meta-analysis of 36 studies comparing memory performance of patients with MS against that of healthy controls, Thornton and Raz (1997) found that the degree of long-term memory impairment covaried with disease course, disease duration, and neurologic disability status. They also found that long-term memory deficits appeared to be moderated by the amount of retrieval support provided during testing, with the greatest impairment seen during free recall conditions and less during cued recall and recognition (Thornton and Raz, 1997). Unfortunately, current pharmacologic treatments for MS, which include disease-modifying agents (eg, interferons) and medications to address specific symptoms (glutamate antagonists, acetylcholinesterase inhibitors), are not reliably effective in improving memory and other cognitive problems (Patti et al, 2010).
A promising therapeutic angle to address these memory concerns emerges from the literature on adjunctive treatments for Alzheimer disease and other dementias. Recent research suggests that vitamin D insufficiency is associated with Alzheimer disease (Buell and Dawson-Hughes, 2008; Sutherland et al, 1992) and with increased risk of developing Alzheimer disease (Zittermann, 2003). Not only have vitamin D receptors been located in the human hippocampus (Kalueff and Tuohimaa, 2007), a key area for memory consolidation, but decreased vitamin D receptor density has also been identified in Alzheimer disease (Sutherland et al, 1992).
Furthermore, several studies have reported that vitamin D can play a beneficial role for cognition in nondemented adults (Annweiler et al, 2009). Combined with compelling evidence from the experimental animal literature (Kalueff et al, 2006), there is growing consensus that vitamin D is neuroprotective for its antioxidant, neurotrophic, and anti-inflammatory properties (Annweiler and Beauchet, 2012). The precise mechanisms of this neuroprotection are still being investigated.
For patients with MS, promising data suggest an ameliorative effect of vitamin D for the disease’s physical impairments (Cadden et al, 2011). Still, the question remains as to whether vitamin D has benefits for the cognitive sequelae, particularly long-term memory impairment. The purpose of our study was to examine the relationship between serum levels of vitamin D and performance on verbal and nonverbal long-term memory tests in patients with relapsing-remitting MS.
We chose clinically established neuropsychological tests that provide multiple testing formats to determine whether vitamin D level was associated with memory performance during conditions of greater (free recall format) or lesser (recognition format) retrieval demand. In light of the positive association between vitamin D and memory performance in patients with Alzheimer disease, we expected our patients with MS also to show better memory performance if they had a higher vitamin D level. Further, we hypothesized that the strongest relationship would be in verbal and nonverbal long-term memory testing formats that are most taxing on memory retrieval systems.
Given additional research that indicates relationships between mood, particularly depression and anxiety, and cognition (Kizilbash et al, 2002) and between overall intelligence and memory performance (Unsworth, 2010), we also assessed these variables. Although not directly related to our hypotheses, we included these variables to control statistically for their potential contributions to the patients’ long-term memory performance.
We studied a convenience sample of 35 (31 women, 4 men) white, non-Hispanic, right-handed adults. Author M.K.R. recruited the participants from among his clinic patients during their regular visits. All of the patients had a diagnosis of relapsing-remitting MS, confirmed by a board-certified neurologist as meeting the McDonald diagnostic criteria (McDonald et al, 2001). We excluded patients who were left-handed, were not fluent in English, or had less than a 10th-grade education.
For the 35 patients in the final sample, ages ranged from 24 to 69 years (mean [M]=45.3, standard deviation [SD]=11.4). Education ranged from 12 to 19 years (M=13.9, SD=2.2), indicating an average of some college. Duration of illness since diagnosis ranged from 2 to 32 years (M=10.0, SD=8.8). All patients had an Expanded Disability Status Score (Kurtzke, 1983) <4.5, ie, they were fully ambulatory without aid. All were taking disease-modifying agents at the time of the study, and 76% were taking vitamin D supplements.
The protocol was consistent with ethical guidelines of the Declaration of Helsinki and was approved by the Institutional Review Boards of Bates College and Central Maine Medical Center. All participants gave written informed consent before taking part.
Trained psychometrists did cognitive and mood profiling on the participants in individualized testing sessions. The neuropsychological battery included the Rey Complex Figure Test (RCFT) (Meyers and Meyers, 1995), the California Verbal Learning Test, Second Edition (CVLT-II) (Delis et al, 2000), and the 2-subtest version of the Wechsler Abbreviated Scale of Intelligence (WASI) (Wechsler, 1999). Situational mood was assessed with the Profile of Mood States, Short Form (POMS-SF) (Shacham, 1983).
Close to the date of the cognitive assessment, a certified phlebotomist obtained a fasting blood sample from each participant using standard venipuncture. Vitamin D (25[OH]D) levels were determined by the DiaSorin LIAISON chemiluminescent immunoassay method at ARUP Laboratories (Salt Lake City, UT). The assay has a functional sensitivity of 4 ng/mL and a detection range of 4 to 150 ng/mL. Two levels of controls were run, with a range of 10.3 to 20.3 ng/mL and 37.9 to 63.7 ng/mL.
The RCFT is a measure of visual, nonverbal long-term memory. The participant is shown a complex 2-dimensional geometric figure and asked first to copy it and then to reproduce it from memory after short and long delays. Resulting drawings are scored for accuracy of detail and location on the page, based on established criteria. A final recognition memory trial assesses the participant’s ability to discriminate previously learned from novel figural elements. For our study, the tests were scored by psychometrists who were blind to the patients’ vitamin D status. We converted all scores to z-scores (M=0, SD=1) based on available norms, with higher z-scores indicating better performance (Meyers and Meyers, 1995).
The CVLT-II is a measure of auditory verbal long-term memory. The task involves participants hearing a list of 16 words in the categories of animals, vegetables, modes of transportation, and furniture, across 5 learning trials; their memory is assessed in several ways. Variables of interest include the acquisition score (number of words correctly recalled across learning trials), short-delay free and cued recall scores, long-delay free and cued recall scores, long-delay recognition score, scores that reflect the use of serial and semantic clustering learning strategies, and learning slope for Trials 1 to 3 and Trials 3 to 5. Scores are normed to T-scores (M=50, SD=10) or z-scores as appropriate, with higher scores indicating better performance (Delis et al, 2000).
The short version of the WASI comprises the Vocabulary and Matrix Reasoning subtests, which together derive a full scale intelligence quotient (FSIQ). The Vocabulary subtest assesses crystallized verbal knowledge by requiring the participant to define words of different levels of difficulty. In the Matrix Reasoning subtest of nonverbal reasoning, the participant must select from among 5 options the geometric figure that will complete a sequenced visuospatial pattern. Subtest scores are converted to T-scores (M=50, SD=10), and the FSIQ is reported as a standard score (M=100, SD=15). For both measures, higher scores reflect better performance (Wechsler, 1999).
The POMS-SF is a 37-item self-report questionnaire in which the participant endorses adjectives describing various feeling states. We selected 2 subscales for analysis, given their potential to moderate cognitive performance: Tension-Anxiety, which contains 6 items (eg, “uneasy,” “anxious”), and Depression-Dejection, which contains 8 items (eg, “sad,” “hopeless”). For these subscales, Shacham (1983) reported internal reliability coefficients of 0.80 and 0.91, respectively. For each subscale, higher scores reflect greater distress. Studying a sample of adult medical outpatients, Shacham (1983) reported respective means of 1.44 and 1.19.
We used bivariate correlation analyses to test our hypotheses concerning the relationship between vitamin D level and performance on the RCFT and CVLT-II, as well as to test whether mood and intelligence were associated with long-term memory. To control for confounding effects, we conducted a partial correlation between vitamin D level and memory performance with FSIQ and disease duration entered as control variables. We used 1-tailed tests of significance throughout, as we had predicted directional effects a priori. Because of missing data for some of the participants, degrees of freedom varied slightly across analyses.
We considered results significant at P<0.05.
Table 1 lists descriptive statistics for our participants on all variables. Their performance on the WASI suggests average overall intellectual function, with average verbal and above-average nonverbal reasoning capacity. Performance on the CVLT-II was within normal limits (ie, average score within half of an SD unit above or below the healthy control population mean).
The RCFT, however, yielded mixed results. The average copy performance was nearly 2 SDs below the normative mean, suggesting impoverished visuoperceptual and/or visuomotor skills. The average short- and long-delay free recall scores were a half SD below expectation, suggesting slightly reduced visuospatial recall ability. Recognition memory was within normal limits, suggesting a small improvement in recall with provision of retrieval cues. On the POMS-SF, reported depression was low, but average state anxiety approximated that reported by Shacham (1983).
Vitamin D blood serum levels ranged from 14.7 to 114.1 nmol/L (M=38.4, SD=18.9). Based on National Institutes of Health criteria (Office of Dietary Supplements, National Institutes of Health, 2011), 16 participants had deficient vitamin D levels (<30 nmol/L), 11 participants had inadequate levels (between 30 and 50 nmol/L), and 8 participants had adequate levels (>50 nmol/L). No participant had a serum value indicating potential toxicity (>125 nmol/L). These low-tending values are consistent with findings of vitamin D insufficiency in individuals living in far northern climates (Bodnar et al, 2007; Newhook et al, 2008; Sullivan et al, 2005).
Analysis of Confounds
With regard to intelligence and long-term memory, for the RCFT we found the FSIQ positively associated with scores for immediate recall (r33=0.46, P<0.005) and delayed free recall (r33=0.38, P<0.05). For the CVLT-II, we found the FSIQ positively related to scores for acquisition (r33=0.35, P<0.05), short-delay free recall (r33=0.35, P<0.05), short-delay cued recall (r33=0.38, P<0.05), long-delay free recall (r33=0.45, P<0.01), long-delay cued recall (r33=0.42, P<0.01), and semantic clustering index (r33=0.35, P<0.05).
With regard to mood and cognition, the POMS-SF Depression-Dejection and Tension-Anxiety scores were not related to any WASI, RCFT, or CVLT-II variable.
Relationships Among Vitamin D, Mood, and Long-Term Memory
Vitamin D level was positively associated with the RCFT scores for immediate recall (r34=0.31, P<0.05) and delayed recall (r34=0.31, P<0.05) (Table 1). Vitamin D level was not associated with RCFT recognition memory, any CVLT-II variable, the WASI FSIQ, or the POMS-SF subscale scores.
Given the potential for the relationship between vitamin D and RCFT performance to be governed by confounding variables, we conducted a partial correlation analysis. Because our participants’ overall intelligence was related to their long-term memory performance, we selected FSIQ as a control variable. Also, to determine whether the relationship was independent of disease duration, we included the number of years since MS diagnosis as a second control variable. We did not include the POMS-SF subscale scores as control variables given our previous analysis that had found no relationship between state mood and cognitive performance. Furthermore, we did not include age, sex, or years of education as control variables, as these demographic variables had been taken into account in the process of normalizing many of the neuropsychological raw scores. With these considerations, a partial correlation that controlled for FSIQ and disease duration still showed a relationship between vitamin D level and scores for RCFT immediate recall (r30=0.34, P<0.05) and delayed recall (r30=0.34, P<0.05).
This study examined the relationship between vitamin D serum levels and performance on verbal and nonverbal tests of long-term memory function in patients with relapsing-remitting MS. Although we did not find an association between vitamin D and verbal long-term memory on the CVLT-II, we did find vitamin D positively associated with immediate and delayed recall of nonverbal material on the RCFT. This effect held even when we controlled both for FSIQ, which a separate analysis had found to be broadly associated with memory performance, and for disease duration.
Consistent with our hypothesis, the relationship between memory and vitamin D was specific to test conditions when no retrieval aids were offered to participants as part of the protocol. As free recall conditions are more challenging than recognition memory conditions for retrieval cognitive systems, this finding suggests that patients with MS retrieve nonverbal information more easily if they have higher vitamin D levels. Because our study had a correlational design, we could not test the direction of causality, although the logical speculation is that vitamin D enhances memory retrieval. It is also possible, however, that reduced vitamin D levels could be secondary to dietary and/or behavioral changes associated with memory decline.
Past epidemiologic research has demonstrated a link between vitamin D deficiency and MS onset, course, and severity, and the human and nonhuman animal experimental literature provides additional evidence that vitamin D helps prevent relapses (Cadden et al, 2011). To our knowledge, however, this is the first study to corroborate a beneficial link between cognitive performance and vitamin D level in patients with MS. Our findings echo those in patients with dementia and age-related cognitive decline that suggest a neuro-enhancing role for vitamin D (Annweiler et al, 2011; Annweiler et al, 2012; Hansen et al, 2011; Llewellyn et al, 2009), but there are not yet detailed neuropsychological studies in these other clinical populations to facilitate a precise comparison of the magnitude of memory enhancement and/or the cognitive mechanisms underlying memory performance. It is unknown, for example, whether the connection between vitamin D and memory ability in elderly patients is specific to the encoding, consolidation, or retrieval process.
Although the correlation uncovered here is promising, the mechanisms that mediate the relationship between vitamin D and memory, in MS or in any neurodegenerative disease, are not well understood. As a neurosteroid hormone, vitamin D is a multitarget agent known to regulate neurotransmission, neuroprotection, and neuroimmunomodulation (Annweiler et al, 2009). Several mechanisms of action have been suggested: Vitamin D increases cholinergic levels via effects on choline acetyltransferase, vitamin D increases neurotrophin activity via effects on nerve growth factor synthesis, vitamin D decreases free radicals by downregulating nitric oxide and upregulating γ glutamyl transpeptidase, and vitamin D prevents excitotoxic damage by promoting calcium homeostasis (Przybelski and Binkley, 2007). Because vitamin D receptors are present along neuronal and glial cell membranes, with particular density in the human hippocampus (Kalueff and Tuohimaa, 2007), it makes sense that these neuroprotective effects would have positive cognitive consequences. Because hippocampal function is critical for memory consolidation and retrieval (Winocur et al, 2010), vitamin D could particularly benefit long-term memory.
It is an open question, however, why vitamin D is associated with nonverbal but not verbal memory retrieval in MS. This finding may be idiosyncratic to our sample. Indeed, research on memory impairment in MS confirms both verbal and nonverbal memory deficits (Thornton and Raz, 1997), and the verbal memory deficits in MS have been thoroughly tested with the CVLT and CVLT-II (Stegen et al, 2010). Yet other research suggests that different cognitive mechanisms govern the verbal and nonverbal memory deficits. For example, DeLuca et al (1998) provide evidence that the impaired verbal memory performance in MS is not caused by deficient retrieval from long-term storage, but, rather, by a deficiency in the initial acquisition of verbal information. After controlling for differences in the acquisition of verbal material, DeLuca’s group found that patients with MS did not differ from healthy controls in the magnitude of verbal recall after 30-minute, 90-minute, or 1-week delays (DeLuca et al, 1998).
In our sample, the participants performed within normal limits on all aspects of the CVLT-II, suggesting normal encoding, consolidation, and retrieval of auditory verbal stimuli. Furthermore, the average learning slopes across the sample for CVLT-II Trials 1 to 3 and Trials 3 to 5 suggest a normal rate of acquisition across trials (Delis et al, 2000). Thus, it appears that our participants had sufficient exposure to the verbal stimuli during the learning trials for proper encoding. Perhaps the relationship between vitamin D and long-term memory is most salient for nonverbal tests like the RCFT, in which the challenge for patients with MS is not in acquisition but in later memory processes (DeLuca et al, 1998).
An alternative explanation for our discrepant findings could be that vitamin D supports long-term memory in a lateralized way, whether along the lines of the traditional left-verbal/right-nonverbal dichotomy, which would assert that the RCFT recruits the right hippocampus as a nonverbal memory test, or some other model of hemispheric medial temporal lobe specialty (Kennepohl et al, 2007). We are not aware of any studies in human or nonhuman animals, however, that advance the notion that vitamin D receptor density differs across the medial temporal lobes in normal or neurologically relevant conditions.
Finally, it is also possible that the lack of association between vitamin D level and verbal memory performance in our sample resulted from insufficient statistical power to identify a small effect.
Although important as the first neuropsychological analysis of long-term memory in MS in relation to vitamin D levels, our findings must be considered in the context of the study’s limitations. First, given the modest sample size and imbalanced sex ratio of the participants, we could not evaluate whether there are sex differences in the relationship between vitamin D level and long-term memory. Second, although immunoassay is commonly used clinically for evaluating serum vitamin D levels, there has been question as to its accuracy (Lensmeyer et al, 2006). Recent research suggests comparable quantification of 25(OH)D by immunoassay methods (eg, DiaSorin) and chromatographic methods (eg, liquid chromatography-mass spectrometry), but immunoassay techniques are more prone to random error (Binkley et al, 2010). Third, given that our neuropsychological assessment was limited to indices of long-term memory, we could not independently assess whether vitamin D and processing speed have a separate relationship that could potentially explain our long-term memory findings.
In view of the modest effect size in our correlation analyses, it is best to be somewhat tentative about the statistically significant relationship that we observed between vitamin D level and nonverbal long-term memory performance. Our results should be replicated in a larger, sex-balanced, and ethnically heterogeneous sample, and cognitive change should be verified in a double-blind, placebo-controlled study of vitamin D administration with pre- and post-intervention cognitive testing. We know of 3 large studies underway—2 using vitamin D as an add-on to interferon therapies (subcutaneous interferon beta-1a and interferon beta-1b) and 1 as an add-on to glatiramer acetate—all designed to evaluate whether vitamin D has clinical benefit for patients with MS. We urge that future trials include cognitive measures, as our results lend rationale to the speculation that vitamin D has particular promise as a neuro-enhancing agent.
Clinicians who care for patients with MS should be aware that low-dose vitamin supplementation may not be enough to raise circulating vitamin D to therapeutic levels in people who live in northern climates, as reduced sunlight means reduced cutaneous vitamin D synthesis. Compounding the issue is that patients with motor impairments tend to spend less time outdoors, further limiting their natural vitamin D synthesis. Moreover, patients with cognitive decline may make poor food choices, thereby limiting their intake of vitamin D-fortified foods. Given these concerns, we recommend that practitioners counsel patients about lifestyle choices and effective year-round vitamin D supplementation to complement their ongoing treatment regimen.
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