Rationale and Design of the PAIRED Trial: Partnered Dance Aerobic Exercise as a Neuroprotective, Motor, and Cognitive Intervention in Parkinson's Disease.

Parkinson's disease (PD), an intractable condition impairing motor and cognitive function, is imperfectly treated by drugs and surgery. Two priority issues for many people with PD are OFF-time and cognitive impairment. Even under best medical management, three-fourths of people with PD experience "OFF-time" related to medication-related motor fluctuations, which severely impacts both quality of life and cognition. Cognitive deficits are found even in newly diagnosed people with PD and are often intractable. Our data suggest that partnered dance aerobic exercise (PDAE) reduces OFF-time on the Movement Disorders Society Unified Parkinson Disease Rating Scale-IV (MDS-UPDRS-IV) and ameliorates other disease features, which motivate the PAIRED trial. PDAE provides AE during an improvisational, cognitively engaging rehabilitative physical activity. Although exercise benefits motor and cognitive symptoms and may be neuroprotective for PD, studies using robust biomarkers of neuroprotection in humans are rare. We propose to perform a randomized, controlled trial in individuals with diagnosed mild-moderate PD to compare the efficacy of PDAE vs. walking aerobic exercise (WALK) for OFF-time, cognition, and neuroprotection. We will assess neuroprotection with neuromelanin-sensitive MRI (NM-MRI) and iron-sensitive (R2*) MRI sequences to quantify neuromelanin loss and iron accumulation in substantia nigra pars compacta (SNc). We will use these biomarkers, neuromelanin loss, and iron accumulation, as tools to chart the course of neurodegeneration in patients with PD who have undergone long-term (16 months) intervention. We will randomly assign 102 individuals with mild-moderate PD to 16 months of PDAE or WALK. The 16-month intervention period will consist of Training (3 months of biweekly sessions) and Maintenance (13 months of weekly sessions) phases. We will assess participants at baseline, 3 months (immediately post-Training), and 16 months (immediately post-Maintenance) for OFF-time and behaviorally and physiologically measured cognition. We will acquire NM-MRI and R2* imaging data at baseline and 16 months to assess neuroprotection. We will (1) examine effects of Training and Maintenance phases of PDAE vs. WALK on OFF-time, (2) compare PDAE vs. WALK at 3 and 16 months on behavioral and functional MRI (fMRI) measures of spatial cognition, and (3) compare PDAE vs. WALK for effects on rates of neurodegeneration.

Internally Guided Lower Limb Movement Recruits Compensatory Cerebellar Activity in People With Parkinson's Disease.

Background: Externally guided (EG) and internally guided (IG) movements are postulated to recruit two parallel neural circuits, in which motor cortical neurons interact with either the cerebellum or striatum via distinct thalamic nuclei. Research suggests EG movements rely more heavily on the cerebello-thalamo-cortical circuit, whereas IG movements rely more on the striato-pallido-thalamo-cortical circuit (1). Because Parkinson's (PD) involves striatal dysfunction, individuals with PD have difficulty generating IG movements (2). Objectives: Determine whether individuals with PD would employ a compensatory mechanism favoring the cerebellum over the striatum during IG lower limb movements. Methods: 22 older adults with mild-moderate PD, who had abstained at least 12 h from anti-PD medications, and 19 age-matched controls performed EG and IG rhythmic foot-tapping during functional magnetic resonance imaging. Participants with PD tapped with their right (more affected) foot. External guidance was paced by a researcher tapping participants' ipsilateral 3rd metacarpal in a pattern with 0.5 to 1 s intervals, while internal guidance was based on pre-scan training in the same pattern. BOLD activation was compared between tasks (EG vs. IG) and groups (PD vs. control). Results: Both groups recruited the putamen and cerebellar regions. The PD group demonstrated less activation in the striatum and motor cortex than controls. A task (EG vs. IG) by group (PD vs. control) interaction was observed in the cerebellum with increased activation for the IG condition in the PD group. Conclusions: These findings support the hypothesized compensatory shift in which the dysfunctional striatum is assisted by the less affected cerebellum to accomplish IG lower limb movement in individuals with mild-moderate PD. These findings are of relevance for temporal gait dysfunction and freezing of gait problems frequently noted in many people with PD and may have implications for future therapeutic application.

Injectable DaxibotulinumtoxinA in Cervical Dystonia: A Phase 2 Dose-Escalation Multicenter Study.

BACKGROUND: Injectable daxibotulinumtoxinA (an investigational botulinum toxin, RT002) may offer a more prolonged duration of response-and therefore less frequent dosing-than onabotulinumtoxinA. OBJECTIVES: To perform a phase 2, open-label, dose-escalation study to assess the efficacy and safety of daxibotulinumtoxinA in cervical dystonia. METHODS: Subjects with moderate-to-severe isolated cervical dystonia were enrolled in sequential cohorts to receive a single open-label, intramuscular dose of injectable daxibotulinumtoxinA of up to 200 U (n = 12), 200-300 U (n = 12), or 300-450 U (n = 13; https://clinicaltrials.gov identifier NCT02706795). RESULTS: Overall, 33/37 enrollees completed the trial. DaxibotulinumtoxinA was associated with mean reductions in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score of 16.8 (38%) at week 4, 21.3 (50%) at week 6, and 12.8 (30%) at week 24. The proportion of subjects who were responders (achieved ≥ 20% reduction in TWSTRS-Total score) was 94% at week 6 and 68% at week 24. The median duration of response (time until > 20% of the improvement in TWSTRS-Total score achieved at week 4 was no longer retained or re-treatment was needed) was 25.3 weeks (95% CI, 20.14-26.14 weeks). There were no serious adverse events and there was no apparent dose-related increase in the incidence of adverse events. The most common treatment-related adverse events were dysphagia (14%) and injection site erythema (8%). CONCLUSIONS: Preliminary assessments suggest that injectable daxibotulinumtoxinA at doses up to 450 U is well tolerated and may offer prolonged efficacy in the treatment of cervical dystonia. Further studies involving larger numbers of patients are now warranted.

A Functional Magnetic Resonance Imaging Study of Head Movements in Cervical Dystonia.

Cervical dystonia (CD) is a neurological disorder characterized by abnormal movements and postures of the head. The brain regions responsible for these abnormal movements are not well understood, because most imaging techniques for assessing regional brain activity cannot be used when the head is moving. Recently, we mapped brain activation in healthy individuals using functional magnetic resonance imaging during isometric head rotation, when muscle contractions occur without actual head movements. In the current study, we used the same methods to explore the neural substrates for head movements in subjects with CD who had predominantly rotational abnormalities (torticollis). Isometric wrist extension was examined for comparison. Electromyography of neck and hand muscles ensured compliance with tasks during scanning, and any head motion was measured and corrected. Data were analyzed in three steps. First, we conducted within-group analyses to examine task-related activation patterns separately in subjects with CD and in healthy controls. Next, we directly compared task-related activation patterns between participants with CD and controls. Finally, considering that the abnormal head movements in CD occur in a consistently patterned direction for each individual, we conducted exploratory analyses that involved normalizing data according to the direction of rotational CD. The between-group comparisons failed to reveal any significant differences, but the normalization procedure in subjects with CD revealed that isometric head rotation in the direction of dystonic head rotation was associated with more activation in the ipsilateral anterior cerebellum, whereas isometric head rotation in the opposite direction was associated with more activity in sensorimotor cortex. These findings suggest that the cerebellum contributes to abnormal head rotation in CD, whereas regions in the cerebral cortex are involved in opposing the involuntary movements.

DNA variants in CACNA1C modify Parkinson disease risk only when vitamin D level is deficient.

OBJECTIVE: To evaluate the association between the genetic variants in CACNA1C, which encodes the α1 subunit of the L-type voltage-sensitive calcium channel (LVSCC) and Parkinson disease (PD) while accounting for interactions with vitamin D concentration. METHODS: Two independent case-control data sets (478 cases and 431 controls; 482 cases and 412 controls) were used. Joint effects of single nucleotide polymorphisms (SNPs) and SNP-vitamin D interaction were analyzed by comparing models containing vitamin D deficiency, SNP genotypes, SNP-vitamin D interaction, and covariates to a restricted model with only vitamin D deficiency and covariates. Meta-analysis was used to combine the joint effects in the 2 data sets. Analysis was stratified by vitamin D deficiency to demonstrate the pattern of SNP-vitamin D interaction. RESULTS: Vitamin D deficiency was associated with PD in both data sets (odds ratio [OR] = 1.9-2.7, p ≤ 0.009). SNP rs34621387 demonstrated a significant joint effect (meta-analysis, p = 7.5 × 10(-5); Bonferroni corrected, p = 0.02). The G allele at rs34621387 is associated with PD in vitamin D-deficient individuals in both data sets (OR = 2.0-2.1, confidence interval = 1.3-3.5, p = 0.002) but is not associated with PD in vitamin D-nondeficient individuals (p > 0.8 in both data sets). CONCLUSIONS: Previous studies suggest that vitamin D deficiency is associated with PD and sustained opening of LVSCC contributes to the selective vulnerability of dopaminergic neurons in PD. Our data demonstrate that the association between genetic variations in CACNA1C and PD depends on vitamin D deficiency, providing one potential mechanism underlying the association between vitamin D deficiency and PD.

Botulinum toxin treatment failures in cervical dystonia: causes, management, and outcomes.

Botulinum toxin (BoNT) is highly effective in the treatment of cervical dystonia (CD), yet a significant proportion of patients report low levels of satisfaction following treatment and fail to follow up for repeated treatments. The goal of this study was to determine the reasons that some patients have unsatisfactory responses. A total of 35 subjects who came to our center requesting alternative treatments due to unsatisfactory responses following BoNT treatment for CD were evaluated. Included were 26 women and 9 men with an average age of 57.1 years (range 25-82 years), and an average duration of illness of 12.5 years (range 1-55 years). Details of unsatisfactory BoNT treatments were methodically collected by a movement specialist using a standardized intake form, including provider subspecialty, product used, the number of satisfactory or unsatisfactory trials, doses given, specific muscles treated, the use of electromyographic guidance, side effects, and tests of resistance. The specialist then provided repeat treatments if indicated, and followed each case until the reasons for unsatisfactory outcomes could be determined. Multiple reasons for unsatisfactory outcomes were found. They included suboptimal BoNT doses, suboptimal muscle targeting, intolerable side effects, complex movement patterns, discordant perceptions, and incorrect diagnoses. Only one patient was functionally resistant to BoNT. Of 32 subjects who received repeat BoNT treatments, 25 (78 %) achieved satisfactory responses after revision of the original treatment plan. These results indicate that the majority of unsatisfactory responses to BoNT treatment of CD were caused by correctible factors and imply a need for improved education regarding optimal treatment methods.

Randomized, controlled pilot trial of solifenacin succinate for overactive bladder in Parkinson's disease.

OBJECTIVE: To evaluate the efficacy of solifenacin succinate in Parkinson's disease (PD) patients suffering from overactive bladder (OAB). BACKGROUND: Urinary dysfunction is a commonly encountered non-motor feature in PD that significantly impacts patient quality of life. DESIGN/METHODS: This was a double-blind, randomized, placebo-controlled, 3-site study with an open label extension phase to determine the efficacy of solifenacin succinate in idiopathic PD patients with OAB. Patients were randomized to receive solifenacin succinate 5-10 mg daily or placebo for 12 weeks followed by an 8-week open label extension. The primary outcome measure was the change in the mean number of micturitions per 24 h period. Secondary outcome measures included the change in the mean number of urinary incontinence episodes and the mean number of nocturia episodes. RESULTS: Twenty-three patients were randomized in the study. There was no significant improvement in the primary outcome measure in the double-blind phase, but there was an improvement in the number of micturitions per 24 h period in the solifenacin succinate group compared to placebo at a mean dose of 6 mg/day (p = 0.01). In the open label phase, the mean number of urinary incontinence episodes per 24 h period decreased (p = 0.03), as did the number of nocturia episodes per 24 h period (p = 0.01). Adverse events included constipation and xerostomia, which resolved after treatment was discontinued. CONCLUSIONS: In this pilot trial, solifenacin succinate treatment led to an improvement in urinary incontinence, despite persistence in other OAB symptoms.

Vitamin D from different sources is inversely associated with Parkinson disease.

An inverse association between Parkinson disease (PD) and total vitamin D levels has been reported, but whether vitamin D from different sources, that is, 25(OH)D2 (from diet and supplements) and 25(OH)D3 (mainly from sunlight exposure), all contribute to the association is unknown. Plasma total 25(OH)D, 25(OH)D2, and 25(OH)D3 levels were measured by liquid chromatography-tandem mass spectrometry in PD patients (n = 478) and controls (n = 431). Total 25(OH)D was categorized by clinical insufficiency or deficiency; 25(OH)D2 and 25(OH)D3 were analyzed in quartiles. Vitamin D deficiency (total 25[OH]D < 20 ng/mL) and vitamin D insufficiency (total 25[OH]D < 30 ng/mL) are associated with PD risk (odds ratio [OR] = 2.6 [deficiency] and 2.1 [insufficiency]; P < 0.0001), adjusting for age, sex, and sampling season. Both 25(OH)D2 and 25(OH)D3 levels are inversely associated with PD (P(trend) < 0.0001). The association between 25(OH)D2 and PD risk is largely confined to individuals with low 25(OH)D3 levels (P(trend) = 0.0008 and 0.12 in individuals with 25[OH]D3 < 20 ng/mL and 25[OH]D3 ≥ 20 ng/mL, respectively). Our data confirm the association between vitamin D deficiency and PD, and for the first time demonstrate an inverse association of 25(OH)D2 with PD. Given that 25(OH)D2 concentration is independent of sunlight exposure, this new finding suggests that the inverse association between vitamin D levels and PD is not simply attributable to lack of sunlight exposure in PD patients with impaired mobility. The current study, however, cannot exclude the possibility that gastrointestinal dysfunction, a non-motor PD symptom, contributes to the lower vitamin D2 levels in PD patients.

How long does it take to diagnose cervical dystonia?

BACKGROUND: Dystonia is a neurological disorder characterized by involuntary twisting movements and postures. The neck is among the most commonly affected regions, and diagnosis can be made readily through a simple clinical evaluation. The goal of this study was to explore how long it took patients to receive a diagnosis of cervical dystonia after symptom onset. METHODS: A structured questionnaire was administered at outpatient clinics of a tertiary care academic medical center to 146 consecutively evaluated patients. The questionnaire addressed the length of time from symptom onset to diagnosis, the numbers and types of providers seen before reaching a diagnosis, and treatments attempted prior to receiving botulinum toxin. RESULTS: A total of 108 patients saw a mean of 3.5 providers over a mean period of 44 months from symptom onset to diagnosis. For patients with symptom onset in the last decade only, patients saw a mean of 3.0 providers over a mean of 14 months. CONCLUSIONS: Although cervical dystonia is the most common form of dystonia with clinical features readily identifiable by a simple history and examination, patients typically see multiple providers over more than a year before reaching a diagnosis and receiving optimal therapy. Improved awareness of the clinical features will enable patients to obtain appropriate therapy more rapidly.

25-Hydroxyvitamin D depletion does not exacerbate MPTP-induced dopamine neuron damage in mice.

Recent clinical evidence supports a link between 25-hydroxyvitamin D insufficiency (serum 25-hydroxyvitamin D [25(OH)D] levels <30 ng/mL) and Parkinson's disease. To investigate the effect of 25(OH)D depletion on neuronal susceptibility to toxic insult, we induced a state of 25(OH)D deficiency in mice and then challenged them with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found there was no significant difference between control and 25(OH)D-deficient animals in striatal dopamine levels or dopamine transporter and tyrosine hydroxylase expression after lesioning with MPTP. Additionally, we found no difference in tyrosine hydroxylase expression in the substantia nigra pars compacta. Our data suggest that reducing 25(OH)D serum levels in mice has no effect on the vulnerability of nigral dopaminergic neurons in vivo in this model system of parkinsonism.

Oral glycopyrrolate for the treatment of chronic severe drooling caused by neurological disorders in children.

Excessive drooling may complicate the care of children with chronic neurological conditions by socially isolating both patients and families and by causing secondary dermatitis and infection. Normal control of saliva requires normal integrity of oral structures, normal oropharyngeal sensation, and motor functioning, as well as normal cognitive awareness and rate of salivary production. Glycopyrrolate is an anticholinergic medication with a quaternary structure that recently received Food and Drug Administration approval to treat sialorrhea due to neurological problems in children ages 3-16 years. This review summarizes the few published studies of safety and efficacy of glycopyrrolate for drooling in children with chronic neurological conditions.

Adult-onset dystonia.

Dystonia is defined as involuntary sustained muscle contractions producing twisting or squeezing movements and abnormal postures. The movements can be stereotyped and repetitive and they may vary in speed from rapid to slow; sustained contractions can result in fixed postures. Dystonic disorders are classified into primary and secondary forms. Several types of adult-onset primary dystonia have been identified but all share the characteristic that dystonia (including tremor) is the sole neurologic feature. The forms most commonly seen in neurological practice include cranial dystonia (blepharospasm, oromandibular and lingual dystonia and spasmodic dysphonia), cervical dystonia (also known as spasmodic torticollis) and writer's cramp. These are the disorders that benefit most from botulinum toxin injections. A general characteristic of dystonia is that the movements or postures may occur in relation to specific voluntary actions by the involved muscle groups (such as in writer's cramp). Dystonic contractions may occur in one body segment with movement of another (overflow dystonia). With progression, dystonia often becomes present at rest. Dystonic movements typically worsen with anxiety, heightened emotions, and fatigue, decrease with relaxation, and disappear during sleep. There may be diurnal fluctuations in the dystonia, which manifest as little or no involuntary movement in the morning followed by severe disabling dystonia in the afternoon and evening. Morning improvement (or honeymoon) is seen with several types of dystonia. Patients often discover maneuvers that reduce the dystonia and which involve sensory stimuli such as touching the chin lightly in cervical dystonia. These maneuvers are known as sensory tricks, or gestes antagonistes. This chapter focuses on adult-onset focal dystonias including cranial dystonia, cervical dystonia, and writer's cramp. The chapter begins with a review of the epidemiology of focal dystonias, followed by discussions of each major type of focal dystonia, covering clinical phenomenology, differential genetics, and diagnosis. The chapter concludes with discussions of the pathophysiology, the few pathological cases published of adult-onset focal dystonia and management options, and a a brief look at the future.

High prevalence of hypovitaminosis D status in patients with early Parkinson disease.

BACKGROUND: Vitamin D insufficiency has been reported to be more common in patients with Parkinson disease (PD) than in healthy control subjects, but it is not clear whether having a chronic disease causing reduced mobility contributes to this relatively high prevalence. OBJECTIVE: To examine the prevalence of vitamin D insufficiency in a cohort of untreated patients with early PD (diagnosed within 5 years of study entry). DESIGN, SETTING, AND PATIENTS The Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) cohort is a well-characterized cohort of subjects with early, nondisabling PD. The cohort is well suited for examining the prevalence of vitamin D insufficiency early in the course of the disease. We conducted a survey study of vitamin D status in stored blood samples from patients with PD enrolled in the placebo group of the DATATOP trial. Samples from baseline visits and end point/final visits (mean [SD], 18.9 [13.1] months) were analyzed for 25-hydroxyvitamin D (25[OH]D) concentration in blinded fashion. MAIN OUTCOME MEASURES: The mean vitamin D concentration and the prevalence of vitamin D insufficiency at baseline and end point/final visits. RESULTS: Among 199 subjects, 170 (85.4%) had samples from the baseline and end point visits available for analysis; 13 were excluded (10 with low probability of having PD and 3 with 25[OH]D concentrations>3 SDs above the mean). In the remaining 157 subjects, the mean (SD) 25(OH)D concentrations at the baseline and end point visits were 26.3 (8.6) ng/mL and 31.3 (9.0) ng/mL, respectively (to convert to nanomoles per liter, multiply by 2.496). The prevalence of vitamin D insufficiency (25[OH]D concentration<30.0 ng/mL) was 69.4% at baseline and 51.6% at the end point. CONCLUSIONS: The prevalence of vitamin D insufficiency in patients with early PD was similar to or higher than those reported in previous studies. Vitamin D concentrations did not decline during progression of PD. Further studies are needed to elucidate the natural history and significance of vitamin D insufficiency in PD.

A cross-sectional study of docosahexaenoic acid status and cognitive outcomes in females of reproductive age with phenylketonuria.

Diet therapy for phenylketonuria (PKU) requires restricted phenylalanine (Phe) intake, with the majority of protein and other nutrients coming from synthetic medical food. The fatty acid docosahexaenoic acid (DHA) is important in brain development and function; however, there are reports of low blood DHA concentrations in people treated for PKU. Although the implications of this low blood DHA are unclear, subtle cognitive deficits have been reported in those treated early and continuously for PKU. For this study, we investigated the relationship between DHA status and cognitive performance in 41 females 12 years and older with PKU. Participants were attending the baseline visit of a research-based camp or a supplementation trial. We assessed the domains of verbal ability, processing speed, and executive function using standardized tests, and the proportions of DHA in plasma and red blood cell (RBC) total lipids using gas chromatography/mass spectrometry. Percent plasma and RBC total lipid DHA were significantly lower in the participants compared with laboratory controls (P < .001), and participants consumed no appreciable DHA according to diet records. Plasma and RBC DHA both negatively correlated with plasma Phe (P < .02), and performance on the verbal ability task positively correlated with RBC DHA controlling for plasma Phe (R = .32, P = .03). The relationship between DHA and domains related to verbal ability, such as learning and memory, should be confirmed in a controlled trial. Domains of processing speed and executive function may require a larger sample size to clarify any association with DHA.

An open-label, sequential dose-escalation, safety, and tolerability study of rimabotulinumtoxinb in subjects with cervical dystonia.

OBJECTIVES: Evaluate the safety and efficacy of a sequential dose escalation of rimabotulinumtoxinB (BoNT-B) in cervical dystonia (CD) subjects. METHODS: This multicenter, open-label, within-subject, sequential dose-escalation study (BoNT-B dosed at 10,000, 12,500, and 15,000 Units) evaluated subjects over each phase of treatment at preinjection and at periodic intervals postinjection. Adverse events, vital signs, and laboratory results were recorded. Efficacy measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and three visual analog scales (VASs). RESULTS: 119 out of 145 CD subjects received all three doses in sequence. Dry mouth and dysphagia were the most common adverse events, and both decreased in frequency by the final injection, despite the increasing doses of the escalation. TWSTRS-Total and subscale scores demonstrated significant improvements following all doses at the week 2, 4, 8, and 12 assessments, with the exception of disability and pain at week 12 with the lowest dose. All VAS scores demonstrated similar improvements following all doses. The mean number of weeks in each phase of the study was 12.1 weeks (10,000 Units), 12.9 weeks (12,500 Units), and 13.9 weeks (15,000 Units). CONCLUSION: BoNT-B was well tolerated and efficacious at 10,000, 12,500, and 15,000 Units in this within-subject, sequential dose-escalation study in CD subjects.

Association between vitamin B12-containing supplement consumption and prevalence of biochemically defined B12 deficiency in adults in NHANES III (third national health and nutrition examination survey).

OBJECTIVE: To explore the association between vitamin B(12) (B(12))-containing supplement use, low B(12) concentrations and biochemically defined B(12) deficiency in US adults. DESIGN: A cross-sectional study with adjustment for survey design. Prevalence ratios for two age groups (18-50 and >50 years) were estimated using unconditional logistic models. Outcome measures included prevalence of low serum B(12) concentration (<148 pmol/l) and biochemical B(12) deficiency (serum B(12)< 148 pmol/l with concomitant homocysteine > 10 mumol/l). SETTING: A population survey of health and nutritional measures. SUBJECTS: Subjects were non-institutionalized adults, aged 18 years and older, who participated in Phase 2 of NHANES III (Third National Health and Nutrition Examination Survey). RESULTS: Low B(12) concentrations were less prevalent among persons consuming B(12)-containing supplements (P = 0.001) with an adjusted prevalence ratio of 0.6 (95 % CI 0.3, 1.0). Biochemical B(12) deficiency showed a similar trend (P = 0.0002), with an adjusted prevalence ratio of 0.3 (95 % CI 0.1, 0.8). Prevalence ratios were similar in adults >50 years of age, although the prevalence of low B(12) and biochemical deficiency was proportionally higher. CONCLUSIONS: Consumption of B(12)-containing supplements was associated with at least 50 % lower prevalence of both low serum B(12) and biochemical B12 deficiency in a nationally representative sample of US adults, suggesting increased consumption of B(12) from supplements or from fortified foods may reduce the prevalence of B(12) deficiency. Additionally, the current Recommended Daily Allowance for B(12) of 2.4 microg may be insufficient for those aged >50 years.