Assessment of brain cognitive functions in patients with vitamin B12 deficiency using resting state functional MRI
Lalit Gupta1, Rakesh K Gupta2, Pradeep K Gupta2, Hardeep Singh Malhotra3, Indrajit Saha4, and Ravindra K Garg3

1Philips India Ltd., Bangalore, India, 2Department of Radiology, Fortis Memorial Research Institute, Gurgaon, India, 3Department of Neurology, King George Medical University, Lucknow, India, 4Philips India Ltd., Gurgaon, India

Synopsis

The alterations in the brain cognitive functions due to vitamin B12 deficiency and reversibility of these alterations following therapy was studied using resting state fMRI. Regional Homogeneity (ReHo) was used to assess functional changes in patients with vitamin B12 deficiency. ReHo was significantly lower in patients than controls in the entire cerebrum and in the brain networks associated with cognition control i.e. default mode, cingulo-opercular and fronto-parietal network. We conclude that the brain networks associated with cognition control, in particular pre-frontal regions, are altered in patients with vitamin B12 deficiency that partially recovered following six weeks of replacement therapy.

Purpose

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 intestine1. 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 are irreversible if left untreated. It has been shown in clinical studies that vitamin B12 affects the functional brain; however this effect has not been studied in detail. The objective of our study was to investigate the functional alterations using regional homogeneity analysis2, 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.

Method

Dataset: 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 resting state (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 therapy. The study was approved by the institutional ethics committee. Informed and written consent was obtained from each subject.

Image processing: Using SPM8 software, the functional images were slice-time and motion corrected, co-registered to the anatomical template and smoothed with a kernel of 8 mm (full-width-at-half-maximum). Any signal drifts were corrected by removing the very low frequency components (<0.01 Hz). To correct for physiological fluctuations, the time-series from the cerebrospinal fluid (CSF) and white matter were included as co-variates in the linear regression analysis. Gray matter, white matter, and CSF voxels were segmented from the T1-weighted images using Freesurfer. For regional analysis, regions in default mode network (DMN), frontal-parietal network (FPN) and cingulu-orbital network (CON) areas/regions were also included in this study.

Regional Homogeneity: The time series in our rsfMRI were band pass filtered in the frequency range of 0.01-0.08Hz. Kendall’s coefficient of concordance (KCC)2 was used to measure ReHo of the time series of a given voxel with its nearest 26 neighboring voxels. The KCC-ReHo among given voxels ranged from 0 to 1. ReHo measures the regional homogeneity (i.e. similarity in contiguous voxels) of time-series and was also averaged over all gray matter voxels. This method is based on observations that meaningful BOLD fluctuations are more likely to occur in clusters of several contiguous voxels than in a single voxel.

Results

Analysis of rsfMRI data reveals that ReHo in patients with Vitamin B12 deficiencies was significantly lower than controls in the entire cerebrum (p<0.05). Pre-frontal cortex areas in the three brain networks associated with cognition control (figure 1) showed significantly decreased ReHo. In this study, ReHo was also correlated with NPT of each patient and control showing significant correlation with picture completion, digit symbol, block design and figure connection tests A and B. Six vitamin B12 deficient patients were followed up after therapy showed increased ReHo after 6 weeks of appropriate therapy. Post therapy improvement of NPT scores were reported for of all the patients. Brain regions that showed significant improvement after replacement therapy include pre-frontal cortex areas of the three brain networks and hippocampus (figure 2).

Discussion

ReHo was found to be lower in patients in the prefrontal cortex part of all the three brain networks i.e. medial prefrontal, anterior prefrontal and dorsal lateral prefrontal; and hippocampus. Findings in patients with vitamin B12 deficiency are in sync with neuro-cognition studies that suggest that alterations in prefrontal cortex and hippocampus affect cognitive ability in brain3. ReHo in prefrontal cortex regions was found to increase in patients with vitamin B12 deficiency after six weeks of therapy suggesting that changes in pre-frontal cortex areas in DMN, FPN and CON are reversible. The reversibility in functional damage was associated with improvement in cognition and clinical symptoms in these patients. Improvement in the NPT and its correlation with ReHo in the described cognitive network further confirms the objectivity of functional reversibility seen in ReHo derived from rsfMRI. Rate of increase in ReHo was found to be variable in different patients, suggesting that time required for improvement in cognition vary from patient to patient.

Acknowledgements

No acknowledgement found.

References

1. Reynolds E. Vitamin B12, folic acid, and the nervous system. The Lancet Neurology. 2006;5:949-60.

2. Zang Y, Jiang T, Lu Y, et al. Regional homogeneity approach to fMRI data analysis. NeuroImage. 2004;22:394– 400.

3. Aaron S, Kumar S, Vijayan J, et al. Clinical and laboratory features and response to treatment in patients presenting with vitamin B12 deficiency-related neurological syndromes. Neurology India. 2005;53:55-58

Figures

Figure 1: Regional analysis using ReHo in conventional frequency band in brain networks associated with cognition control i.e. DMN, FPN and CON. * Shown on bar diagram had statistically significantly difference.

Figure 2: Brain regions that show significant decrease in regional homogeneity in patients with vitamin B12 deficiency than healthy controls (in blue and green) and regions that show reversibility in all the six patients after replacement therapy (in green).



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
0223