Evaluation of diffusion tensor imaging changes and neurocognitive effects of asymptomatic vitamin B12 deficiency

  • Ali Zeynal Abidin Tak
  • Erdal Dayan
  • Hacı Taner Bulut
Original Article

Abstract

Vitamin B12 plays an important role in the mechanisms which are responsible for myelinization in the central nervous system. It can particularly lead to hematological and neuropsychiatric symptoms when serum levels fall due to insufficient intake with diet or absorption problems. The purpose of this study was to show the cognitive effects in vitamin B12 deficiency cases that have not reached clinical symptom level using neuropsychological tests, and to show possible cerebral neuronal damage using diffusion tensor imaging (DTI) method. A total of 62 asymptomatic vitamin B12 deficiency patients and 40 healthy subjects were included in the study and both groups were subjected to Standardized Mini-Mental State Examination, Montreal Cognitive Assessment Test, Rey Auditory Verbal Learning Test, forward and backward digit span (WMS-R forward and backward), Visual Reproduction Subtest (WMS-III), Category Fluency Test, Trail Making (Trail A-B) (21) and Similarities (BENZ) tests. DTI examinations were performed on both groups. Patient group was determined to get lower scores in all neuropsychological tests compared to control group. In DTI examination, a significant decrease in FA values of bilateral hippocampus and a prominent increase in apparent diffusion coefficient (ADC) values were determined in the patient group compared to control group. In this study, it was determined that there was microstructural damage in the brain in the presence of vitamin B12 deficiency even in the asymptomatic period, and the patients revealed cognitive decline. In accordance with this result, early treatment of the easily diagnosed and treated vitamin B12 deficiency may prevent possible irreversible damage in the future.

Keywords

Vitamin B12 Homocysteine Diffusion tensor imaging Cognitive assessment 

Introduction

Vitamin B12 is a water-soluble vitamin that plays a role in the function of many molecules and hormones, mainly in DNA synthesis. It should be taken via diet since it is not synthesized at sufficient levels in the human body, and it is particularly rich in foods of animal origin [1]. Vitamin B12 deficiency is an easy-to-diagnose condition with low treatment cost, and it is considered to be a public health problem in our day [2]. Its incidence changes based on community, socioeconomic conditions, nutrition habits, and age groups [3]. There may be several reasons for vitamin B12 deficiency; the most common ones are disrupted absorption, increased need and insufficient intake [4]. Standard plasma vitamin B12 concentration measurement is still a valid method for the detection of vitamin B12 deficiency. Total plasma vitamin B12 concentration levels of < 200 pg/ml (< 148 pmol/l) is recognized to indicate deficiency [5].

Although clinical symptoms of vitamin B12 deficiency are rare, it can present with hematological, neuropsychiatric, gastrointestinal, neoplastic and cardiovascular symptoms [6]. Especially, hematological and neurological systems are significantly affected in vitamin B12 deficiency. Hypercellular bone marrow characterized by anemia, pancytopenia, macrocytosis, hypersegmented neutrophils and ineffective erythropoiesis may be an example of hematological findings of vitamin B12 deficiency [7]. Neurological findings of vitamin B12 deficiency include paresthesia, sensory ataxia, peripheral neuropathy, optic neuritis and cognitive impairment [8]. Also, it may be observed in psychiatric presentations such as mood disorders (depression and mania), chronic fatigue syndrome and psychosis [9].

Magnetic resonance imaging (MRI) changes in patients with vitamin B12 deficiency show white matter demyelinization in spinal cord, optic nerves, optic tracts and brain [10, 11]. In neuroimaging studies using brain and spinal cord MRI, a characteristic white matter degeneration has been demonstrated in some vitamin B12 deficiency cases such as hyperintense signals in FLAIR and T2-weighted images of periventricular white matter areas, similar to MRI results obtained in multiple sclerosis [11]. As a result of vitamin B12 deficiency, re-methylation of homocysteine to methionine is impaired and plasma homocysteine levels are increased [12]. Homocysteine shows direct toxic effect on neurons [13]. It was shown in some studies that vitamin B12 deficiency and corresponding high homocysteine level damages the hippocampus and causes hippocampal atrophy [14]. Diffusion tensor imaging (DTI) based on the random movements of macromolecules and water molecules limited by myelin can be used for the imaging of brain white matter tracts, and their anomalies can be revealed in some neurological disorders that can be detected with normal findings on conventional MRI [15, 16, 17].

Considering the fact that there is no study on this subject in the literature, our purpose in this study is to determine possible cognitive impairment with various cognitive assessment batteries, and to determine possible microstructural damages with DTI examination, which can be developed even in asymptomatic period by vitamin B12 deficiency in the brain, in subjects with asymptomatic vitamin B12 deficiency detected in routine biochemistry examinations who show no symptoms, and whom we frequently encounter in our routine clinical practices.

Material and method

Study protocol

The protocol was designed as prospective, cross-sectional study. One hundred and two individuals between ages 18–50 who have applied to our clinics had normal results in neurological examination and do not have cognitive complaints were assessed according to their serum vitamin B12 levels and they were taken into examination. Sixty subjects with serum vitamin B12 levels below 200 pg/ml constituted the patient group, while 42 subjects with levels above 200 pg/ml constituted the control group. Together with detailed history taking, systemic and neurological examinations were all performed/done for each patient and then routine blood samples were extracted from all patients and sent to laboratory for analysis. Studies on routine blood samples were performed on the same day in central biochemistry and hormone laboratory. The remaining serum samples were transferred in two separate 1.5 ml polypropylene storage tubes for plasma homocysteine measurements and stored at − 80 °C until the study day. Serum vitamin B12 levels were assessed using suitable kits on Roche Elecsys 2010 device operating on electro-chemiluminescence immunoassay (ECLIA) principle, and results were obtained in pg/ml. Homocysteine levels were assessed using suitable kits on HPLC Chromsystems Agilent 1100 Series device operating on chromatographic principles, and results were obtained in μmol/l. The upper limit of homocysteinemia was assumed as 12 μmol/l [18]. The study was conducted in accordance with the ethical principles stated in the “Declaration of Helsinki” and ethical approval was taken from the Ethical Committee of the Adiyaman University Hospital. Written informed consents were taken from both groups for their participation in the study.

Exclusion criteria

Use of any medication affecting vitamin B12 metabolism in the last 3 months (such as multivitamin preparations, oral contraceptives), low serum folic acid levels, chronic diseases (like systemic inflammatory diseases, liver and kidney diseases), malignancies, the conditions that could affect cognitive function such as thyroid dysfunction, multiple sclerosis, epilepsy, brain trauma and/or operations, and psychiatric disorders like depression and psychosis, pregnancy, giving birth within the last 3 months, and mental retardation were exclusion criteria for the present study.

Assessment of cognitive function

By an experienced psychologist and neurologist, Standardized Mini-Mental State Examination (MMSE) which was developed for evaluating memory function, can be applied fast and easily, and consists of 11 items grouped under five titles including orientation, registration memory, attention and calculation, recall and language [19], Montreal Cognitive Assessment Test (MoCA) which was developed as a fast scan test for mild cognitive impairment disorders, and evaluates various cognitive functions such as attention, executive functions, memory, language, visuoconstructional skills, abstract thought, calculation and orientation [20], Rey Auditory Verbal Learning Test (RAVLT) which is based on learning a word list for evaluating verbal memory, and evaluates functions such as short-term memory, learning/obtaining information, retention and long-term verbal memory [21], forward digit span (WMS-R FORWARD) and backward digit span (WMS-R BACKWARD) which evaluate nonverbal memory and mainly measure auditory attention and short-term memory capacity [22] and WMS-III visual reproduction subtest, Category Fluency Test (CAS) which evaluates verbal fluency by the assessment of numerous cognitive functions such as semantics, long-term verbal memory, attention, information processing rate, vocabulary, working memory, suppression of unrelated words and executive function [23], Trail Making (Trail A-B) test which measures frontal executive functions, attention, mental flexibility, eye-tracking and motor speed [24] and Similarities (BENZ) test for abstract thinking skill [25] were applied to patient and control groups as neuropsychological tests.

Magnetic resonance imaging protocol

Magnetic resonance imaging studies were performed on both patient and control groups with the same 1.5 T super-conductive MRI device using circularly polarized head coil (Philips Achieva, Netherlands). All subjects were examined in a single MRI session. Symmetrical head position was particularly used for the subjects. For qualitative examination, T1-weighted Turbo Spin Echo (TSE) [TR/TE 325/15 ms, slice thickness (st): 5 mm], T2-weighted TSE (TR/TE 4841/100 ms, st: 5 mm) images were obtained in standard sagittal and axial plane, and FLAIR images (TR/TE 6000/100 ms, IR: 2000 ms, st: 5 mm) in coronal plane were applied. T1-weighted 3D gradient echo sequences (matrix = 256 × 256 pixels; TR = 7.2 ms, TE = 33 ms; NSA = 1; FOV = 256 mm; slice thickness 1 mm; gap = 0 mm; flip angle = 8°) were applied to patient and control groups including 160 slices as anatomical reference for DTI. DTI was performed with EPI sequence. To fill diffusion sensor, diffusion-weighted images were collected from 32 different directions with 1000 s/mm2 b value and from a no-diffusion weighted image with b = 0 s/mm2. DTI examinations were performed for each subject on some brain regions related to cognitive functions and studied previously for vitamin B12 deficiency; including dorsolateral prefrontal cortex (DLPFC) which is responsible for functions such as mainly working memory, cognitive flexibility, planning, organization, changing, copying and processing new information [26], anterior thalamus (AT) which has an important role on memory, gets input from mammillary bodies and sends the output signal to limbic cortex which is responsible for memory and emotions [27], corpus callosum [genu (CCG), anterior (CCA), posterior (CCP)] which provides motor, sensory and cognitive performance of the brain by connecting stimuli originating from cortex to opposite hemisphere [28] (Fig. 1), and hippocampus which has an important role mainly in memory (especially short-term memory), affection, positioning and navigation [27] (Fig. 2). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values of these regions were determined using region of interest (ROI) method on the work station of manufacturer company by MRI imaging performed by a radiologist with approximately 15 years of experience who is blinded to patient and control group information.
Fig. 1

a Sagittal plane DTI-ROI examination of the corpus callosum (genu, anterior, posterior) of a subject in patient group. b Axial plane DTI-ROI examination of the corpus callosum (genu, anterior, posterior) of a subject in control group

Fig. 2

a Axial plane DTI-ROI examination of left hippocampus of a subject in patient group. b Axial plane DTI-ROI examination of left hippocampus of a subject in control group

Statistical analysis

Statistical analyses were performed using SPSS (Statistical Package for the Social Sciences) V22.0. The compliance of the variables with normal distribution was examined using visual (histogram) and analytical methods (Kolmogorov–Smirnov/Shapiro–Wilk tests). Correlation coefficients and statistical significance were calculated by Spearman test for the relations between variables with non-normal distribution. In the comparison of continuous variables that do not fit into normal distribution, Mann–Whitney U significance test is used for the pairwise comparisons of non-parametric tests. Cases with p values below 0.05 were assessed as statistically significant.

Results

Clinical characteristics

A total of 102 subjects, consisting of 60 patients and 42 controls, were taken into assessment. The average age of the patients was 28.9 ± 10, 25 patients were female (41.6%) and 35 patients were male (58.4%). The average age of the controls was 27.2 ± 8.8, 18 patients were female (42.8%) and 24 patients were male (57.2%). The average educational level was 10.3 ± 3.2 years for the patients, while it was 10.5 + 2.9 years for the controls. There were no significant differences between the two groups with regard to age, gender and educational level.

The average serum vitamin B12 level was 131.3 ± 25.2 pg/ml, and average homocysteine level was 17.7 + 6.16 μmol/l for the patients. The average serum vitamin B12 level was 305.8 + 120.6 pg/ml, and the average homocysteine level was 8.38 + 1.6 μmol/l for the control group. A high significance was detected between serum vitamin B12 (p < 0.001) and homocysteine (p < 0.001) levels upon comparing patients with control group.

Neuropsychological assessment

In the evaluation of neuropsychological test scores which were applied to patients for the assessment of cognitive functions, a statistically significant difference was determined in MoCA test sub-parameters and total MoCA scores of patients compared to controls (Table 1).
Table 1

MoCA test scores of patient and control groups

MoCA sub-parameters

Patient

Control

p value*

Average

Standard deviation

Average

Standard deviation

Visual spatial executive functions

4.4

0.8

4.8

0.4

0.005

Naming

2.8

0.4

3.0

0.2

0.018

Attention

5.2

0.8

5.6

0.5

0.007

Language

2.7

0.5

2.9

0.3

0.047

Abstract thinking

1.7

0.5

2.0

0.2

0.001

Delayed recall

3.2

0.7

4.0

0.8

< 0.001

Orientation

5.9

0.3

6.0

0.2

0.326

Total

26.0

2.0

28.3

1.2

< 0.001

MoCA Montreal Cognitive Assessment Test

*Mann–Whitney U test

A lower performance was detected in the patient group compared to control group in recall sub-test of MMSE test (MMSE-RECALL) and in MMSE total score (MMSE-TOTAL), and a statistically significant difference was determined (Table 2).
Table 2

MMSE test scores of patient and control groups

MMSE sub-parameters

Patient

Control

p value*

Average

Standard deviation

Average

Standard deviation

Orientation

9.8

0.5

9.9

0.3

0.103

Registration

3.0

0

3.0

0

1.000

Attention and calculation

4.1

1.4

4.6

0.7

0.235

Recall

2.3

0.9

2.8

0.5

0.002

Language

7.8

0.4

7.9

0.3

0.158

Figure

0.9

0.3

1.0

0.2

0.088

Total

27.9

1.9

29.2

1.0

< 0.001

MMSE standardized mini mental state examination

*Mann–Whitney U test

In all parameters of RAVLT test evaluating verbal memory, a very low performance was detected in patient group compared to control group and a highly significant difference was determined (Table 3).
Table 3

RAVLT test scores belonging to patient and control groups

 

Patient

Control

p value*

Average

Standard deviation

Average

Standard deviation

AVLT-A1

6.2

1.4

7.7

1.8

< 0.001

AVLT-A2

8.9

1.9

10.0

1.8

0.004

AVLT-A3

10.2

2.0

11.5

1.8

0.001

AVLT-A4

10.9

2.3

12.4

1.5

< 0.001

AVLT-A5

11.7

1.8

12.9

1.5

< 0.001

AVLT-A6

10.3

2.4

12.3

1.6

< 0.001

AVLT-A7

10.8

2.3

12.5

1.7

< 0.001

RAVLT Rey Auditory Verbal Learning Test, AVLT-A1 first try, AVLT-A2 second try, AVLT-A3 third try, AVLT-A4 fourth try, AVLT-A5 fifth try, AVLT-A6 sixth try, AVLT-A7 seventh try

*Mann–Whitney U test

A prominently lower performance was detected in patient group compared to control group and a significant difference was determined in CAS and Trail-B tests which are tests evaluating executive functions (word fluency, problem solving) (Table 4). In addition, no statistically significant difference was determined in Trail-A, one of the tests evaluating attention and working memory, although scores of patient group were lower than control group. A lower performance was determined and a significant difference was found in patients compared to control group in WMS-R forward digit span test (WMS-R FORWARD), WMS-R backward digit span test (WMS-R BACKWARD) and total score (WMS-R TOTAL) evaluating auditory attention and short-term memory capacity (Table 4). A lower performance was determined in the patient group than the control group in WMS-III Visual Reproduction Subtest evaluating non verbal memory in the first try for the measurement of short-term recall (VISUAL-1.D) and the second try for the evaluation of delayed recall (VISUAL-2.D). Lastly, a prominently worse performance was detected in patient group compared to control group in BENZ test for evaluating abstract thinking skill (Table 4). No statistically significant relation was determined by the correlation of decreased serum vitamin B12 level and increased homocysteine level with neuropsychological test scores.
Table 4

Other neuropsychological test scores of patient and control groups

 

Patient

Control

p value*

Average

Standard deviation

Average

Standard deviation

CAS

33.3

9.8

43.5

12.3

< 0.001

TRAIL-A

43.3

15.2

35.0

10.3

0.009

TRAIL-B

95.7

37.7

73.5

22.9

0.003

WMS-R FORWARD

3.9

1.5

4.8

1.3

0.002

WMS-R BACKWARD

3.3

1.6

4.9

1.9

< 0.001

WMS-R TOTAL

7.2

2.9

9.7

2.6

< 0.001

VISUAL-1.D

11.6

2.0

12.7

1.7

0.003

VISUAL-2.D

10.0

3.1

11.6

2.1

0.01

BENZ

8.0

1.5

9.1

1.1

< 0.001

CAS Category Fluency Test, TRAIL-A-B trail making test, WMS-R FORWARD forward digit span, WMS-R BACKWARD backward digit span, WMS-R TOTAL total score, VISUAL-1.D visual reproduction test try-out 1, VISUAL-2.D visual reproduction test try-out 2, BENZ similarities test

*Mann–Whitney U test

Diffusion tensor imaging results

Upon comparing subjects in the patient group and the control group, no significant difference was determined between left DLPFC FA, left DLPFC ADC, right DLPFC FA, right DLPFC ADC, CCG FA, CCG ADC, CCA FA, CCA ADC, CCP FA, CCP ADC, left AT FA, left AT ADC, right AT FA and right AT ADC values (Table 5). A highly significant decrease in left hippocampus and right hippocampus FA values, and a prominent increase left hippocampus and right hippocampus ADC values were detected in patient group compared to control group (Table 5). No statistically significant relation was detected upon correlating neuropsychological tests with FA and ADC values obtained as a result of DTG-ROI performed on hippocampus.
Table 5

Comparison of DTI data of patient and control groups

 

Patient

Control

p value*

Average

Standard deviation

Average

Standard deviation

LEFT DLPFC-FA

0.435

0.049

0.455

0.049

0.126

LEFT DLPFC-ADC

0.807

0.043

0.801

0.072

0.411

RIGHT DLPFC-FA

0.433

0.049

0.451

0.044

0.055

RIGHT DLPFC-ADC

0.813

0.050

0.824

0.061

0.889

CCG-FA

0.728

0.048

0.738

0.036

0.424

CCG-ADC

0.860

0.067

0.863

0.071

0.780

CCA-FA

0.649

0.052

0.662

0.036

0.177

CCA-ADC

0.948

0.113

0.921

0.098

0.201

CCP-FA

0.688

0.051

0.686

0.062

0.523

CCP-ADC

0.952

0.101

0.982

0.112

0.277

LEFT AT-FA

0.433

0.046

0.440

0.055

0.579

LEFT AT-ADC

0.830

0.066

0.841

0.064

0.371

RIGHT AT-FA

0.428

0.054

0.438

0.046

0.348

RIGHT AT-ADC

0.815

0.075

0.831

0.071

0.249

LEFT HIPPOCAMPUS-FA

0.287

0.032

0.351

0.033

< 0.001

LEFT HIPPOCAMPUS-ADC

1.005

0.180

0.923

0.082

< 0.001

RIGHT HIPPOCAMPUS-FA

0.287

0.031

0.351

0.029

< 0.001

RIGHT HIPPOCAMPUS-ADC

1.008

0.124

0.927

0.071

0.001

DTI diffusion tensor imaging, CCA-FA, ADC corpus callosum anterior diffusion tensor data, CCG-FA, ADC corpus callosum genu diffusion tensor data, CCP-FA, ADC corpus callosum posterior diffusion tensor data, RIGHT and LEFT DLPFC-FA, ADC right and left dorsolateral prefrontal cortex diffusion tensor data, RIGHT and LEFT AT-FA, ADC right and left anterior thalamus diffusion tensor data, RIGHT and LEFT HIPPOCAMPUS-FA, ADC right and left hippocampus diffusion tensor data

*Mann–Whitney U test

Discussion

In various studies performed previously on subjects with symptomatic vitamin B12 deficiency; it was shown that mental slowing, weak memory and attention deficit, alteration in verbal fluency, decreased response, behavioral anomalies (mood changes, loss of perception and social awareness, disinhibition and mental rigidity) may be observed with executive impairments on the foreground, vitamin B12 deficiency has negative effects on cognitive test scores, and cognitive functions are recovered after vitamin B12 treatment [8, 29, 30]. For the first time in literature, we have determined that patients obtained similar low scores nearly in all tests when we applied test batteries which evaluate various cognitive and executive function modalities to healthy controls and to patients with asymptomatic vitamin B12 deficiency diagnosis as per serum vitamin B12 and homocysteine levels, although they do not have any clinical complaints associated with vitamin B12 deficiency.

In light of these data, in addition to studies previously performed on symptomatic vitamin B12 deficiency, we consider that vitamin B12 deficiency causes impairment in many cognitive functions such as memory, executive functions and visual memory even in the period it has not reached clinical symptom level. No statistically significant relation was determined by the correlation of decreased serum vitamin B12 level and increased homocysteine level with neuropsychological test scores. This may be because there is no globally approved calibration and standardization study for vitamin B12 and homocysteine serum levels, and there are insufficient number of cases. In various studies in the literature performing DTI examination on subjects with symptomatic vitamin B12 deficiency, decreased FA values and increased ADC values have been determined in various brain sections including genu and splenium of corpus callosum [31, 32]. In parallel to these studies, we have performed DTI examination for determining whether there are microstructural damages in some brain regions related to cognitive functions in subjects with asymptomatic vitamin B12 deficiency.

In our DTI study, no significant difference was determined between patient and control group in FA and ADC values obtained for DLPFC, AT, CCG, CCA and CCP regions. In values obtained on hippocampus, which mainly plays a role in memory (particularly short-term memory), affection, positioning and navigation (27), a significant decrease in FA values and a prominent increase in ADC values were determined. Decreased FA and increased ADC values are often observed upon decreased fiber density or loss of fiber integrity. This indicated a damage of microstructural size on both hippocampus that cannot be demonstrated in conventional MRI, but can be shown with DTI examination. Furthermore, the fact that there is no study evaluating hippocampal damage due to symptomatic or asymptomatic vitamin B12 deficiency in the literature makes our study the first one performed on this subject. Although patient group obtained lower scores than the control group in nearly all neuropsychological tests, we consider that obtaining the only significant difference in bilateral hippocampus by DTI may be probably explained by low patient number or the fact that subclinical vitamin B12 deficiency in patients impairs cognitive functions, but does not reach levels that shows any damage in DTI.

Limitations of our study

Our study was a cross-sectional study. Small sample size was the major limitation. Also the absence of an accepted standard value for vitamin B12 and homocysteine is a limitation for our study.

Conclusion

We have determined in our study that subjects with asymptomatic vitamin B12 deficiency were significantly less successful than controls in tests evaluating various cognitive modalities, and these subjects had microstructural damage in both hippocampal areas in DTI examinations. We think that vitamin B12 deficiency should be treated in the early period even there are no clinical and/or radiological findings since its diagnosis and treatment are easy and low cost, and also considering the positive effects of vitamin B12 treatment on cognitive functions and damages on DTI in the previous studies performed on symptomatic vitamin B12 deficiency. We also think that longitudinal follow-up studies with higher subject numbers are required on this subject.

Notes

Compliance with ethical standards

Ethics committee approval

Ethics committee approval was taken for this study.

Patient consent

Written informed consent was taken from the patients participating in this study.

Peer review

External, independent.

Conflict of interest

The authors reported no conflict of interest.

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Copyright information

© Belgian Neurological Society 2018

Authors and Affiliations

  • Ali Zeynal Abidin Tak
    • 1
  • Erdal Dayan
    • 2
  • Hacı Taner Bulut
    • 3
  1. 1.Department of NeurologyAdiyaman University Faculty of MedicineAdiyamanTurkey
  2. 2.Department of NeurologyMardin State HospitalMardinTurkey
  3. 3.Department of RadiologyAdiyaman University Faculty of MedicineAdiyamanTurkey

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