Relationship Between Vitamin B12 and Sensory and Motor Peripheral Nerve Function in Older Adults

Kira Leishear, PhD, MS; Robert M. Boudreau, PhD; Stephanie A. Studenski, MD, MPH; Luigi Ferrucci, MD, PhD; Caterina Rosano, MD, MPH; Nathalie de Rekeneire, MD, MS; Denise K. Houston, PhD; Stephen B. Kritchevsky, PhD; Ann V. Schwartz, PhD; Aaron I. Vinik, MD, PhD; Eva Hogervorst, PhD; Kristine Yaffe, MD; Tamara B. Harris, MD, MS; Anne B. Newman, MD, MPH; Elsa S. Strotmeyer, PhD, MPH

J Am Geriatr Soc. 2012;60(6):1057-1063. 

Abstract and Introduction

Abstract

Objectives To examine whether deficient B12 status or low serum B12 levels are associated with worse sensory and motor peripheral nerve function in older adults.
Design Cross-sectional.
Setting Health, Aging and Body Composition Study.
Participants Two thousand two hundred and eighty-seven adults aged 72 to 83 (mean 76.5 ± 2.9; 51.4% female; 38.3% black).
Measurements Low serum B12 was defined as serum B12 less than 260 pmol/L, and deficient B12 status was defined as B12 less than 260 pmol/L, methylmalonic acid (MMA) greater than 271 nmol/L, and MMA greater than 2-methylcitrate. Peripheral nerve function was assessed according to peroneal nerve conduction amplitude and velocity (NCV) (motor), 1.4 g/10 g monofilament detection, average vibration threshold detection, and peripheral neuropathy symptoms (numbness, aching or burning pain, or both) (sensory).
Results B12-deficient status was found in 7.0% of participants, and an additional 10.1% had low serum B12 levels. B12 deficient status was associated with greater insensitivity to light (1.4 g) touch (odds ratio = 1.50, 95% confidence interval = 1.06–2.13) and worse NCV (42.3 vs 43.5 m/s) (β = −1.16, P = .01) after multivariable adjustment for demographics, lifestyle factors, and health conditions. Associations were consistent for the alternative definition using low serum B12 only. No significant associations were found for deficient B12 status or the alternative low serum B12 definition and vibration detection, nerve conduction amplitude, or peripheral neuropathy symptoms.
Conclusion Poor B12 (deficient B12 status and low serum B12) is associated with worse sensory and motor peripheral nerve function. Nerve function impairments may lead to physical function declines and disability in older adults, suggesting that prevention and treatment of low B12 levels may be important to evaluate.

Introduction

Vitamin B12 deficiency affects 5% to 20% of older adults, and low serum B12 levels are highly prevalent in older adults, affecting 15% to 40%.[1–4] Studies have reported a wide range of prevalence rates, because of different population characteristics and a lack of agreement on diagnostic criteria for low or deficient B12. Some studies use only serum B12 levels to define deficiency (cut points ranging from 74 to 148 pmol/L) and low (cut points from 185 to 260 pmol/L). Other studies use a combined definition with low serum B12 and high methylmalonic acid (MMA) (e.g., >2 or 3 standard deviations above the mean), because MMA is considered a highly sensitive and specific marker to determine B12 deficiency.[1,4–8] Although no agreed-upon cutpoint for low or deficient B12 serum levels exists, the most commonly used cut points are 148 pmol/L for deficiency and 260 pmol/L for low B12.

There are many different causes of B12 deficiency in older adults. More than half of older adults with B12 deficiency have food-cobalamin malabsorption, defined as impaired digestion and absorption of protein-bound B12.[3,9,10] Other causes of low or deficient B12 are insufficient intake from diet or supplements, pernicious anemia, gastric surgery, gastrointestinal disease, and certain medications (e.g., proton pump inhibitors, metformin).[3]

Vitamin B12 deficiency is clinically recognized to be associated with neurological disorders such as dementia, cognitive impairment, and depression.[1,3,11,12] B12 deficiency may cause demyelination of nerves in the peripheral and central nervous system[13] and has been associated with peripheral neuropathy, loss of sensation in peripheral nerves, and weakness in lower extremities in older adults.[1,14–16] In particular, vitamin B12 deficiency is associated with large-fiber (type A) neuropathy; type A nerve fibers act as sensory and motor fibers,[17] so vitamin B12 may be associated with sensory and motor peripheral nerve function.

In older adults, the prevalence of poor peripheral nerve function and neuropathy is high and increases with age.[18–21] Poor peripheral nerve function, often undiagnosed or at subclinical levels, is related to lower strength, bone mineral density, and physical performance in older adults.[22–26] Identifying risk factors for poor peripheral nerve function is crucial. Although B12 deficiency is a recognized risk factor for clinical peripheral neuropathy, little is known about the relationship between low B12 and subclinical sensory and motor peripheral nerve function in older adults. The purpose of this study was to examine whether deficient B12 status or an alternative definition using low serum B12 levels was associated with worse sensory and motor peripheral nerve function in older adults and whether the same relationship existed for low serum B12 levels and deficient B12 status.

Methods

Study Population

A cross-sectional study of vitamin B12 levels and status and peripheral nerve function was conducted in 2,287 participants of the Health, Aging and Body Composition (Health ABC) Study, an ongoing, prospective cohort study of 3,075 well-functioning black and white men and women aged 70 to 79 at the 1997 to 1998 baseline examination. Participants were recruited from a random sample of Medicare-eligible white adults and all eligible black community-dwelling residents in Pittsburgh, Pennsylvania, and Memphis, Tennessee. Individuals were ineligible if they had difficulty walking one-quarter of a mile (400 m), climbing 10 steps, or performing activities of daily living; had life-threatening cancer or had treatment for cancer in the last 3 years; or were planning to move out of the study area within 3 years. The institutional review boards at the University of Pittsburgh and the University of Tennessee Health Science Center approved the study, and informed consent was obtained from all participants.

Of 3,075 participants at baseline, 2,405 had a 2000 to 2001 clinic examination. The remaining cohort had a home visit (n = 88), telephone follow-up (n = 233), or proxy interview only (n = 49); had died (n = 187); withdrew (n = 9); or missed the examination (n = 104). Participants missing all peripheral nerve function measures (n = 1), serum B12 levels (n = 98), or fasting blood glucose levels (n = 14) or with diabetes mellitus onset before the age of 20 (n = 5) were excluded. Thus, 2,287 participants (48.6% male, 38.3% black) were included, representing 74.4% of baseline participants and 95.1% of those attending the 2000 to 2001 examination.

Assays

Serum samples were frozen at −70°C in cryogenic vials at the time of collection. Tests for serum B12 used 300 μL of serum from the 2000 to 2001 visit and were performed at the Clinical Chemistry Laboratory at Fletcher Allen Health Care, University of Vermont, using a competitive immunoassay on the ADVIA Centaur (Bayer HealthCare, LLC, Tarrytown, NY) with direct chemiluminescent technology. The normal range was 72 to 1,427 pmol/L, as previously determined from 272 serum samples. The assay coefficient of variation (CV) ranged from 4% to 10%, and a 6.7% CV was observed for 5% of the sample blinded for quality control.

For samples with low serum B12 (<260 pmol/L), serum MMA, total homocysteine (Hcy), serum 2-methylcitrate (2-MCA), and cystathionine were measured to determine deficiency status. These additional metabolite assays for the subset of participants with low serum B12 (n = 391) were tested at the University of Colorado Health Sciences Center using capillary gas chromatography mass spectrometry.[27] The normal ranges were 73 to 271 nmol/L for MMA, 5.4 to 13.9 μmol/L for Hcy, 60 to 228 nmol/L for 2-MCA, and 44 to 342 nmol/L for cystathionine. Inflammatory markers, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) were measured at the 1997 to 1998 and 2000 to 2001 visits, respectively, as previously described.[28]

Two definitions were used for poor vitamin B12 in the analyses. Participants were first classified based on serum B12 and MMA levels, with deficient B12 status defined as B12 less than 260 pmol/L and MMA greater than 271 nmol/L with MMA greater than 2-MCA. Low B12 status was defined as B12 less than 260 pmol/L with either MMA of 271 nmol/L or less or MMA equal to or less than 2-MCA. The reference group was B12 of 260 pmol/L or greater.[29] An alternative definition based solely on serum B12 was then used, with low serum B12 levels defined as B12 less than 260 pmol/L and normal levels defined as B12 of 260 pmol/L or greater.[30] Thus, low serum B12 level in this alternate definition was further divided into deficient B12 status and low B12 status in the original definition based on MMA levels.

Peripheral Nerve Function

Sensory and motor peripheral nerve function was measured on the right leg and foot unless contraindicated by amputation, knee replacement, surgery, trauma, or ulcer. Motor nerve conduction amplitude (compound motor action potential (CMAP; mV)) and nerve conduction velocity (NCV; m/s) were measured between the popliteal fossa and ankle (NeuroMax 8; XLTEK, Oakville, ON, Canada). Poor CMAP was defined as less than 1 mV and poor NCV as less than 40 m/s.[31] To assess sensory nerve function, monofilament testing was performed on the dorsum of the great toe. Reduced sensation was defined as being unable to detect three of four touches for each 1.4-g (light) and 10-g (standard) monofilament. Average vibration threshold detection was recorded at the great toe (range 0–130 μ) (VSA-3000 Vibratory Sensory Analyzer; Medoc, Durham, NC). To assess symptoms of peripheral neuropathy, participants were asked "In the past 12 months, have you ever had numbness, an asleep feeling, or a prickly feeling in your legs or feet?" or "sudden stabbing, burning pain, or a deep aching in your legs or feet?"

Covariates

Data on questionnaire and clinical measures were collected at the 2000 to 2001 examination unless otherwise indicated. Demographic characteristics included age, sex, race, and clinic site (Memphis, TN, or Pittsburgh, PA). Lifestyle factors included alcohol use (1997–1998), smoking status (never, former, current) (1999–2000), and weekly physical activity from walking and stair-climbing (kcal/kg per week). To measure body composition, height and weight were used to calculate body mass index (BMI) as weight (kg)/height2 (m2). Whole-body mineral-free lean mass and fat mass was measured using dual-energy X-ray absorptiometry (Hologic 4500A, software version 9.03; Hologic, Inc., Bedford, MA).[32] Physiological factors included blood pressure, cholesterol, ankle–brachial index (low < 0.9, normal 0.9–1.3, stiffening ≥ 1.3); cystatin-C (high ≥ 1 mg/L); and thyroid stimulating hormone (1998–1999). Medications (e.g., fibrate, niacin, statin, thyroid, metformin) and B12 supplement use (multivitamin or oral or intramuscular supplemental B12) were assessed according to a medication inventory[33] at the 1999–2000 visit. Health conditions included diabetes mellitus (determined as fasting glucose ≥ 126 mg/dL, medications, self-reported physician diagnosis);[34] hypertension (determined according to a physiological examination, medications, and self-reported physician diagnosis); and cerebrovascular disease, coronary heart disease, congestive heart failure, and peripheral arterial disease (each determined according to self-reported physician diagnosis at the 1997–1998 examination). For cognitive function, processing speed was assessed using the Digit Symbol Substitution Test (DSST)[35] (1997–1998) and global cognitive function was assessed using the modified Mini-Mental State Examination (3MS) (range 0–100)[36] (1999–2000).

Statistical Analyses

Differences were tested according to vitamin B12 status in demographic characteristics, lifestyle factors, body composition, physiological factors, medication and supplement use, and health conditions using the Pearson chi-square or Fisher exact test for categorical variables and the Kruskal–Wallis test, analysis of variance, or t-test for continuous variables.

Logistic regression was performed for outcomes of 1.4-g (light) and 10-g (standard) monofilaments and peripheral neuropathy symptoms. Linear regression was performed for outcomes of nerve conduction amplitude and velocity. Tobit regression, which is censored linear regression used for a censored outcome, was performed for average vibration threshold because of a ceiling effect.

Multivariable regression modeling was performed separately for each peripheral nerve function variable, with vitamin B12 status as the predictor variable. There was low correlation between peripheral nerve measures (correlation coefficient = −0.29 to 0.34), indicating that different aspects of nerve function were being captured, so each measure was considered separately as an outcome. Adjusting for potential confounders, the models were built progressively in the following order: demographic characteristics, diabetes mellitus, lifestyle factors, body composition, physiological factors, medication and supplement use, health conditions, and inflammatory markers. DSST and 3MS were additionally included for vibration detection, monofilament detection, and peripheral neuropathy symptoms because of the cognitive aspects of these outcomes. Age, sex, race, clinic site, and diabetes mellitus were adjusted for in all models; other variables were removed if P > .10.

Sensitivity analyses were conducted in several ways. First, participants with diabetes mellitus were excluded to verify that associations were consistent in older adults without diabetes mellitus. Analyses were also performed using two additional definitions for vitamin B12 to confirm whether results were consistent for other definitions of B12 deficiency. For the first additional definition, deficient serum B12 levels were defined as B12 less than 148 pmol/L.[30] For the second additional definition, deficient B12 status was defined as B12 less than 148 pmol/L, or normal renal function and Hcy of 13.9 μmol/L or greater. For this definition, normal renal function was estimated as MMA of 271 nmol/L or less, Hcy of 13.9 μmol/L or less, cystathionine of 342 nmol/L or less, and 2-MCA of 228 nmol/L or less.[27] Results of the analyses for these two additional definitions were not significant, although there were very few participants with B12 deficiency using these definitions (n = 26 (1.1%) with B12 < 148 pmol/L; n = 55 (2.4%) using the deficient B12 status definition based on additional markers from the vitamin B12 pathway). Multicollinearity for independent variables was assessed using the variance inflation factor; no variance inflation factor was greater than 2. All analyses were conducted using SAS, version 9.2 (SAS Institute, Inc., Cary, NC).

Results

B12 deficient status was found in 7.0% of the participants, and an additional 10.1% had low serum B12 but did not have MMA levels high enough to be considered to have deficient status. Thus, the prevalence of low serum B12 levels (<260 pmol/L) was 17.1%. shows the descriptive characteristics according to B12 deficiency status (deficient, <260 pmol/L and MMA > 271 nmol/L with MMA > 2-MCA; low, B12 < 260 pmol/L and (MMA ≤ 271 nmol/L or MMA ≤ 2-MCA); normal, B12 ≥ 260 pmol/L). Participants with deficient B12 status were more likely to be older, male, and white; have lower cholesterol levels; and be less likely to take supplemental B12 than those with normal B12 levels. As expected, those with deficient B12 status were more likely to have lower serum B12 levels and to be white than those with low B12 status, although other characteristics were not different. Of the participants taking a supplement containing vitamin B12, 96% were taking a multivitamin. Approximately 8% of those with normal B12 levels and 3% of those with low or deficient B12 status were specifically taking a B12 supplement (oral or intramuscular).

Table 1.  Descriptive Characteristics According to Vitamin B12 Status

Characteristic Normal (n = 1,896) Low (n = 232) Deficient (n = 159) P-Value
Demographic
   Age, mean ± SD 76.5 ± 2.9 76.4 ± 2.8 77.2 ± 2.9 .009
   Male, % 47.0 55.6 57.2 .004
   Black, % 39.6 36.6 25.2, .001
Diabetes mellitus status, % .66
   Impaired fasting glucose 16.0 18.1 16.4 .71
   Diabetes mellitus 21.5 19.4 25.2 .39
      Metformin use 15.6 27.9 23.1 .08
Lifestyle factors
   Smoking status, % .56
      Former 47.1 47.4 53.9 .27
      Current 7.0 7.9 6.5 .85
Number of alcoholic drinks, % .70
      Former 21.1 21.2 20.3 .97
      <1/wk 21.3 21.2 19.6 .89
      1–7/wk 22.7 22.1 24.1 .90
      >1/d 6.7 10.2 9.5 .09
   Physical activity, kcal/kg per week, mean ± SD 31.4 ± 50.7 41.4 ± 76.4 26.1 ± 39.3 .11
Body composition, mean ± SD
   Body mass index, kg/m2 27.2 ± 4.8 27.5 ± 4.4 26.9 ± 4.2 .35
   Height, mm 1,654.1 ± 93.2 1,670.9 ± 99.1 1,663.5 ± 94.2 .02
   Weight, kg 74.9 ± 15.1 77.9 ± 15.2 75.2 ± 14.9 .02
   Total fat mass, kg 26.1 ± 8.8 27.1 ± 8.4 25.6 ± 8.1 .11
   Total lean mass, kg 48.8 ± 10.2 50.5 ± 10.6 49.7 ± 10.4 .06
Physiological factors
   Systolic blood pressure, mmHg, mean ± SD 134.9 ± 19.8 137.1 ± 20.6 135.4 ± 22.7 .40
   Diastolic blood pressure, mmHg, mean ± SD 71.4 ± 10.7 72.7 ± 11.2 70.9 ± 12.4 .16
   Ankle–brachial index, % .27
      Low 15.8 16.4 18.1 .75
      Stiffening 5.6 2.7 3.2 .09
   Total cholesterol, mg/dL, mean ± SD 192.6 ± 37.9 190.5 ± 35.7 182.1 ± 34.9 .009
   Cystatin-C ≥1 mg/L, % 44.7 46.1 56.1 .02
B12 supplement use, % 42.9 19.6 22.1 <.001
Medication use, %
   Fibrate use 1.1 0.5 1.4 .68
   Niacin use 1.1 0.5 0.7 .90
   Statin use 20.1 18.4 19.1 .81
   Thyroid medication 12.7 11.0 12.1 .76
History of comorbidities, %
   Hypertension 72.7 75.1 74.7 .67
   Cerebrovascular disease 6.5 8.7 7.7 .41
   Coronary heart disease 15.2 20.0 20.0 .07
   Congestive heart failure 0.9 0.0 0.6 .38
   Peripheral arterial disease 4.3 3.1 5.7 .45
Inflammatory markers, mean ± SD
   Interleukin-6, pg/mL 3.6 ± 3.7 3.7 ± 3.8 3.7 ± 4.4 .85
   Tumor necrosis factor-alpha, pg/mL 3.4 ± 1.5 3.4 ± 1.9 3.7 ± 1.5 .01
Cognitive test scores, mean ± SD
   Modified Mini-Mental Examination 90.4 ± 8.1 90.8 ± 7.2 90.0 ± 7.7 .50
   Digit Symbol Substitution Test 36.8 ± 14.8 35.8 ± 13.9 35.2 ± 11.9 .15
B12 level (pmol/L) 474.5 ± 203.0 223.2 ± 30.4 200.7 ± 39.8 , <.001

Pairwise P < .05 for alow vs normal, bdeficient vs normal, cdeficient vs low.
Normal: B12 ≥ 260 pmol/L.
Low: B12 < 260 pmol/L with either methylmalonic acid (MMA) ≤271 nmol/L or MMA ≤ 2- methylcitrate.
Deficient: B12 < 260 pmol/L and MMA > 271 nmol/L with MMA > 2-methylcitrate.
SD = standard deviation.

Nearly half (45.6%) of the participants were unable to detect 1.4-g monofilament, 5.9% were unable to detect the maximum vibration (130 μ), 11.0% had poor CMAP (<1 mV), and 22.2% had poor NCV (<40 m/s). demonstrates peripheral nerve function according to B12 deficiency status. Participants with deficient B12 status were less likely to detect 1.4-g monofilament and more likely to have worse (higher) average vibration threshold detection and lower NCV than those with normal B12 levels. No significant differences were found univariately between deficient B12 status and normal B12 in ability to detect standard (10 g) monofilament, CMAP amplitude, or peripheral neuropathy symptoms. When using the alternative definition of low serum B12, univariate associations with peripheral nerve function were similar, although low serum B12 levels were associated with lower CMAP than normal B12 levels (3.1 ± 1.9 vs 3.4 ± 2.0 mV; P = .04).

Table 2.  Peripheral Sensory and Motor Nerve Function According to Vitamin B12 Status

Function Normal (n = 1,896) Low (n = 232) Deficient (n = 159) P-Value
Monofilament
   Unable to detect 10 g, % 8.8 8.3 9.0 .97
   Unable to detect 1.4 g, % 44.4 48.3 56.1a .01
Vibration threshold, μm, mean ± SD 50.5 ± 35.3 53.8 ± 36.9 59.8 ± 36.4a .003
   Unable to detect vibration, % 5.7 5.8 7.9 .54
Compound motor action potential, mV, mean ± SD 3.4 ± 2.0 3.2 ± 1.9 3.0 ± 2.0 .14
   <1 mV, % 10.7 12.0 13.7 .54
Nerve conduction velocity, m/s, mean ± SD 43.8 ± 5.4 43.1 ± 5.5 42.2 ± 5.2a .006
   <40 m/s, % 21.6 23.0 28.7 .21
Numbness, % 29.3 28.1 25.2 .53
Aching/burning pain, % 16.8 19.8 13.8 .29

Pairwise P < .05 for adeficient vs normal; normal: B12 ≥ 260 pmol/L.
Low: B12 < 260 pmol/L with either methylmalonic acid (MMA) ≤271 nmol/L or MMA ≤ 2- methylcitrate.
Deficient: B12 < 260 pmol/L and MMA > 271 nmol/L with MMA > 2-methylcitrate.
SD = standard deviation.

illustrates the multivariable regression results for deficient B12 status. Those with deficient B12 status were 1.5 times as likely to be unable to detect 1.4-g (light) monofilament after adjusting for age, sex, race, clinic site, diabetes mellitus, height, alcohol use, and 3MS score (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.06–2.13). Deficient B12 status was associated univariately with worse vibration detection but not after adjusting for covariates. Sex, race, clinic site, diabetes mellitus, and 3MS score attenuated the association. Lower NCV was associated with deficient B12 status after adjusting for demographics, diabetes mellitus, height, weight, alcohol use, ankle–brachial index, and systolic blood pressure. CMAP was not associated with B12 deficiency. Low B12 status was not associated with any nerve function outcome, although using the low serum B12 definition (<260 pmol/L), findings were consistent with the deficient B12 status definition; low serum B12 was significantly associated with greater insensitivity to 1.4-g (light) monofilament (OR = 1.28, 95% CI = 1.01–1.62) and lower NCV (β = −0.63, P = .04), after adjusting for covariates. Consistent with deficient B12 status, low serum B12 was not associated with CMAP or vibration detection. In addition, no significant association was found between deficient B12 status or low serum B12 and standard (10 g) monofilament detection or symptoms in the multivariable regression models (data not shown). Sensitivity analysis was performed after removing participants with diabetes mellitus, and the results were consistent.

Table 3.  Multivariable Regression Models for the Association Between Vitamin B12 Status and Peripheral Nerve Function

Nerve Function Model 1: Unadjusted Model 2: Adjusted for Demographic Characteristics Model 3: Fully Adjusteda
Low Status Deficient Status Low Status Deficient Status Low Status Deficient Status
Inability to detect 1.4 g monofilament, odds ratio (95% confidence interval) 1.17 (0.89–1.54) 1.60 (1.15–2.23) 1.13 (0.86–1.50) 1.51 (1.08–2.11) 1.15 (0.85–1.54) 1.50 (1.06–2.13)
Vibration detection, μ, β, P-value 3.37, .21 9.68, .002 1.97, .43 5.23, .08 1.27, .61 5.23, .08
Compound motor action potential, mV, β, P-value −0.176, .26 −0.347, .06 −0.120, .44 −0.187, .30 −0.127, .40 −0.159, .38
Nerve conduction velocity, m/s, β, P-value −0.670, .13 −1.58, .002 −0.280, .48 −0.891, .06 −0.256, .52 −1.16, .01

Reference normal: B12 ≥ 260 pmol/L.
aIn addition to demographic characteristics (age, sex, race, clinic site) and diabetes mellitus, monofilament adjusted for height, alcohol use, modified Mini-Mental State Examination (3MS) score; vibration adjusted for height, weight, ankle–brachial index, high cystatin-C, 3MS score, vibration variance; compound motor action potential adjusted for height, ankle–brachial index, cholesterol level, high cystatin-C; nerve conduction velocity adjusted for height, weight, alcohol use, ankle-brachial index, systolic blood pressure.
Low: B12 < 260 pmol/L with either methylmalonic acid (MMA) ≤271 nmol/L or MMA ≤ 2-methylcitrate.
Deficient: B12 < 260 pmol/L and MMA > 271 nmol/L with MMA > 2-methylcitrate.

Discussion

Older community-dwelling adults with deficient B12 status had worse sensory and motor peripheral nerve function. This study is unique in comparing different definitions of poor B12 and their relationship with several measures of sensory and motor nerve function in community-dwelling older adults. These findings are of importance because poor peripheral nerve function may lead to impaired physical function and disability in older adults[20,22,25,26] and it is thus vital to establish potentially modifiable risk factors.

These results show that the association between B12 and peripheral nerve function was consistent for both definitions of deficient B12 status (using MMA) and using solely low serum B12 levels. This is important because much controversy exists over how to define poor vitamin B12 status. Using serum B12 levels alone may not be sensitive or specific enough to determine a tissue deficiency, whereas MMA is considered to be a highly sensitive marker of B12 deficiency,[7] but because MMA is expensive and is not often used in clinical practice,[37] it is important to investigate whether using only serum B12 is adequate and specific to disease-related outcomes in older adults. These results suggest that using MMA with serum B12 may be best for determining B12 deficiency, because the associations were stronger than using serum B12 alone, although it was found that using low serum B12 only (<260 pmol/L) was sufficient, because the associations were consistent with deficient B12 status using serum B12 with MMA.

The prevalence of poor NCV (22.2%) was more than twice as high as of poor CMAP (11.0%), which may be why a significant association was not found with CMAP. Low CMAP is thought to be related to nerve axonal damage, and low NCV is related to nerve demyelination.[38] The results suggest that demyelination may be occurring more often in older adults than axonal damage. It was expected that the prevalence of poor NCV would be higher than that of poor CMAP because demyelination is thought to occur before axonal degeneration.[39] There was no association with deficient B12 status and ability to detect standard (10 g) monofilament or peripheral neuropathy symptoms, common clinical screens for peripheral nerve problems. Light (1.4 g) monofilament may be more sensitive than using a standard (10 g) monofilament, detecting sensory neuropathy at an earlier stage.[40,41] The symptoms of numbness and deep aching or burning pain in the legs or feet may not be specific for peripheral neuropathy in older adults in the context of B12 deficits. Peripheral nerve impairments have been shown to be largely asymptomatic in older adults, even in those with diabetes mellitus.[21]

Strengths of this analysis were that the study had a large cohort of older men and women and that MMA levels were tested for those with serum B12 levels lower than 260 pmol/L.[37] Measures of sensory and motor peripheral nerve function were available. Sensory nerve function was assessed using average vibration threshold and monofilament detection which, even though it is less sensitive, is highly specific and has clinical significance (i.e., it is a low-cost, quick test that can easily be performed in an examination room).[42] Measuring motor nerve function with nerve conduction is considered the criterion standard because it is highly sensitive, reliable, and reproducible.[43]

A limitation of this study was having a small percentage of participants (1.1%) with serum B12 levels of less than 148 pmol/L. Thus, it is likely that there was insufficient statistical power to examine a relationship between clinically deficient serum B12 levels (<148 pmol/L) and peripheral nerve function. The participants in this study were likely to be healthier than older adults in the general population, and 39.2% of participants took a supplement containing vitamin B12. A sensory nerve conduction test (e.g., sural nerve) was not conducted either.

Deficient B12 status is associated with worse sensory and motor nerve function in older adults. These findings have important implications for functioning and disability in older adults. Several studies have shown an association between peripheral neuropathy or poor peripheral nerve function and impaired mobility and falls.[22,25,44–48]

In the aftermath of the 1998 mandatory folic acid fortification in the United States, it is important to study vitamin B12 and consequences of poor B12 status in older adults.[2] A high intake of folic acid may correct megaloblastic anemia, which is caused by a deficiency in B12 or folic acid.[14, 49] Because the classic sign of anemia may not be present, B12 deficiency may go unnoticed, and neurological damage may progress and not be easily reversible.[2] Although current recommendations do not advise monitoring B12 levels in older adults, the current results suggest that low levels are associated with peripheral nerve impairments, which have been associated with lower musculoskeletal function in our population.[22,23,26] Supplemental B12 is easily available, adequately absorbed, and well tolerated in older adults[50] and may correct vitamin B12 deficits associated with impaired peripheral nerve function. Randomized clinical trials are needed to establish that sufficient B12 supplementation can improve peripheral nerve function.

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