Original contributionAssessment of brain cognitive functions in patients with vitamin B12 deficiency using resting state functional MRI: A longitudinal study
Introduction
Vitamin B12 is an essential nutrient to maintain the functionality of the brain as it plays a critical role in the myelination of the white matter (WM) and nerves [1]. Vitamin B12 deficiency usually manifests as megaloblastic anemia and neurologic dysfunction, e.g., sub-acute combined degeneration of the spinal cord peripheral neuropathy, and alteration of cognition [2], [3]. The neurological symptoms due to Vitamin B12 deficiency are secondary to the derangement in the myelin sheath [4].
Vitamin B12 deficiency is commonly associated with lack of its intake through food as well as the poor absorption of the vitamin B12 by the intestine. Other causes of this deficiency include undergoing certain types of bariatric surgery, bacterial overgrowth that competes for vitamin B12, and alcohol consumption. It is believed that the manifestations of vitamin B12 deficiency is irreversible if left untreated [5]. Diagnosis of vitamin B12 deficiency is usually performed on the basis of low serum levels of this vitamin; however it has been also reported that this deficiency may exist even in the presence of normal serum levels [6], [7]. It is thought that hematological investigations alone may not be reliable as these may be normal in the presence of subtle neurological symptoms that may progress to become irreversible if not treated early [8].
Magnetic resonance imaging (MRI) features of brain abnormalities associated with Vitamin B12 deficiency have been reported in literature. Several studies have reported changes in WM, cerebral infarcts and changes in brain volume due to vitamin B12 deficiency [9], [10]. Microstructural changes in WM regions have also been observed [11], [12] on diffusion tensor imaging (DTI) in patients with vitamin B12 deficiency. In another recent study [13] changes in structural brain were studied using DTI and arterial spin labeling (ASL) in patients with vitamin B12 deficiency.
There are number of studies that have presented the mild cognition impairment due to the depletion of vitamin B12 level [14], [15], [16]. Studies have also indicated that different brain networks i.e. default mode network (DMN), fronto-parietal network (FPN) and cingulo-opercular network (CON) may affect cognitive control. Moreover, any alteration in any of these above mentioned brain networks due to mild cognitive impairment (MCI) can also affect normal brain functions [17], [18].
The objective of our study was to investigate the functional alterations in different regions of the brain due to the depletion of vitamin B12, and further study the reversibility of these functional changes following vitamin B12 replacement therapy, if any. To the best of our knowledge, this is the first study that shows the functional changes in brain due to vitamin B12 deficiency. In this study, we have exploited resting state functional MRI (rsfMRI) to probe functional alterations in different brain regions (both smaller regions and brain lobes). Although there are examples of the use of EEG and event based conventional fMRI in various MCI studies [19] our preference for selecting resting state fMRI as our preferred investigative tool in this study was due to its superior spatial resolution over EEG, and also to avoid the extensive patient participation that is needed for task based conventional fMRI.
In rsfMRI, there is no specific stimulus, thus, the traditional “model-driven” methods for task-related fMRI data analysis may not be suitable for analyzing resting state fMRI data. The “data driven” [20] methods used in our study include regional homogeneity (ReHo) and low frequency oscillations (LFOs). The ReHo analysis method [21] uses Kendall's coefficient of concordance to quantify spatial variations in resting-state blood oxygenation level dependent (BOLD) times-series. This method assumes that within a functional cluster, the hemodynamic characteristics of each voxel will be synchronous with that of its neighbors and such a similarity could be changed or modulated by different disease conditions. The LFOs method reflects the intensity of regional spontaneous brain activity. Amplitude of low frequency fluctuations (ALFF) and fractional ALFF has been used in this study as LFOs measures [22], [23].
Our study was focused on quantifying the alterations in rsfMRI BOLD signal by using ReHo, ALFF and fALFF methods in patients with vitamin B12 deficiency and to compare the patient results with age-matched healthy controls. Finally, some of these patients were followed up using rsfMRI after vitamin B12 replacement therapy to study the possible reversibility of these changes.
Section snippets
Subjects
In this study, 13 treatment naïve vitamin B12 deficient right-handed patients (males 9, females 4, mean age 33.31 ± 7.9 years; age range, 22–54 years) diagnosed on the basis of biochemical evidence and neurological symptoms were studied with rsfMRI. Age and sex matched 15 healthy right-handed controls were also included in the study (males 11, females 4, mean age 30.07 ± 8.19 years; age range, 18–53 years). Six of these 13 patients were agreed for a repeat MRI study after 6 weeks of replacement
Results
All the enrolled patients in this study had gait abnormalities, sensory disturbance, mental impairment, and suggestion of neuropathy that responded significantly to vitamin B12 supplementation as assessed by improvement at 6 weeks. All the NPT scores except OA, NCT-A and NCT-B showed significant difference between patients and controls (Table 1). The mean serum vitamin B12 concentration in patients at baseline level was 157 ± 42.69 pg/ml (range, 42.4–198 pg/ml) and the serum homocysteine level was
Discussion
In this study ReHo analysis of BOLD signals is presented. Patients with vitamin B12 deficiency showed significantly lower ReHo than controls in entire cerebrum indicating that brain functionality was altered in these patients [21]. ReHo analysis of BOLD signals showed abnormality in all the three brain networks associated with cognitive control. The regions that showed significantly decreased ReHo in patients include MPFC, hippocampus, APFC, FOC, DFC and DLPFC. ReHo was observed to increase in
Conclusions
We conclude ReHo in patients was significantly lower than controls in the entire cerebrum, pre-frontal cortex areas of DMF, CON and FPN. ReHo showed significant correlation with NPT tests. Findings in this study show that cognitive impairment in brain due to vitamin B12 deficiency can be assessed and quantified using ReHo analysis of rsfMRI data. The study provides a method for clinicians to measure the functional alterations in brain due to vitamin B12 deficiency. rsfMRI measure could be used
Acknowledgements
This study was supported by grant no. BT/IN/German/04/RKG/ 2010 from the Department of Biotechnology, Ministry of Science and Technology, Government of India.
References (35)
Vitamin B12, folic acid, and the nervous system
Lancet Neurol
(2006)- et al.
Hippocampus, caudate nucles and entorhinal cortex volumetric MRI measurements in discrimination between Alzheimer's disease, mild cognitive impairment, and normal aging
Egypt J Radiol Nucl Med
(2014) - et al.
Assessment of functional and structural damage in brain parenchyma in patients with vitamin B12 deficiency: a longitudnal perfusion and diffusion tensor imaging study
Magn Reson Imaging
(2015) - et al.
Prevalence of MR imaging abnormalities in vitamin B12 deficiency patients presenting with clinical features of subacute combined degenration of the spinal cord
J Neurol Sci
(2014) - et al.
Resting state fMRI in Alzheimer's disease: beyond the default mode network
Neurobiol Aging
(2012) - et al.
Resting-state fMRI changes in Alzheimer's disease and mild cognitive impairment
Neurobiol Aging
(2012) - et al.
Diagnostic power of default mode network resting state fMRI in the detection of Alzheimer's disease
Neurobiol Aging
(2012) - et al.
Research progress on resting state fMRI of epilepsy
Brain and Development
(2012) - et al.
Regional homogeneity approach to fMRI data analysis
NeuroImage
(2004) - et al.
Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI
Brain and Development
(2007)
An improved approach to detection of amplitude of low-frequency fluctuation (ALFF) for resting-state fMRI: fractional ALFF
J Neurosci Methods
A hybrid approach to the skull-stripping problem in MRI
NeuroImage
Regional homogeneity, functional connectivity and imaging markers of Alzheimer's disease: a review of resting-state fMRI studies
Neuropsychologia
Dorsolateral prefrontal contributions to human working memory
Cortex
The role of B vitamins in preventing and treating cognitive impairment and decline
Adv Nutr
Folate, vitamin B12 and vitamin B6 and one carbon metabolism
J Nutr Health Aging
Cobalamin deficiency, hyperhomocysteinemia, and dementia
Neuropsychiatr Dis Treat
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