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Vitamin B12 deficiency in dementia and cognitive impairment: The effects of treatment on neuropsychological function
Abstract
Vitamin B12 assay is part of the routine investigation of dementia, although few studies have investigated the effects of treatment on cognition. We examined the effects of B12 treatment on neuropsychological function and disease progression in patients presenting with dementia or cognitive impairment.
From 1432 patients who were assessed at the Bristol Memory Disorders Clinic, 125 patients with low serum B12 were identified. Sixty-six patients presenting with dementia, and 22 with cognitive impairment were seen for a second assessment after treatment. Changes in neuropsychological test scores were compared with those of patients with normal serum B12, matched by age and diagnosis.
The majority of patients with low serum B12 had normal Hb and MCV values. We found no cases of reversible B12 deficiency dementia. The B12 treatment patients who presented with dementia showed no significant improvement, and no less deterioration, in their neuropsychological function than their matched group. However, a treatment effect was demonstrated among the patients presenting with cognitive impairment. These improved significantly compared to matched patients on the verbal fluency test (p<0.01).
All patients with cognitive impairment should be investigated for B12 deficiency. Vitamin B12 treatment may improve frontal lobe and language function in patients with cognitive impairment, but rarely reverses dementia.
... Some case studies suggest cognitive improvement with B 12 supplementation is possible (Evans, Edelsohn & Golden, 1983;Goebels & Soyka, 2000), while others do not (Barcikowska, Czyzewski, Pfeffer & Zawitkowska, 1994). There is limited imaging support for the usefulness of B 12 replacement therapy in bringing about resolution of white matter changes and cognitive deficits associated with B 12 deficiency (Chatterjee, Yapundich, Palmer, Marson & Mitchell, 1996), and several studies suggest supplementation improves neurologic symptoms, including cognition (Lindenbaum et al., 1988;Martin, Francis, Protetch & Huff, 1992;Eastley, Wilcock & Bucks, 2000;van Asselt et al., 2001). However, other studies have not shown B 12 replacement therapy as effective (DeJong et al., 2001; and have refuted cognitive deficits associated with vitamin B 12 deficiency as a reversible dementia syndrome. ...
... Participants' performance on tasks of verbal learning, verbal fluency, and similarities improved and quantitative EEG showed more fast activity and less slow activity. This finding adds to previous research which has suggested improvements in some mental status scores can occur in B 12 -deficient seniors with a short duration of pre-treatment mental symptoms (Martin et al., 1992), or in older adults with predominantly pre-treatment memory problems as opposed to more severe forms of cognitive impairment or dementia (Eastley et al., 2000). ...
... An intervention trial recently showed that vitamin B 12 replacement improved cognitive performance and abnormalities on electroencephalogram in vitamin B 12deficient seniors (van . This finding adds to previous research which has suggested improvements in some mental status scores can occur in B 12 -deficient seniors with a short duration of pre-treatment mental symptoms (Martin, 1992), or in older adults with predominantly pre-treatment memory problems as opposed to more severe forms of cognitive impairment or dementia (Eastley, Wilcock & Bucks, 2000). Vitamin B 12 replacement therapy has not been proven effective in improving mental symptoms in persons with long standing dementia . ...
Cognitive difficulties in later life can be both aversive and disruptive to older adults and bring about the loss of functional independence. One precursor to cognitive impairment in late life may be vitamin B 12 deficiency, and associated elevations in the metabolites methylmalonic acid (MMA) and homocysteine. However, there has been little consensus on a cause-effect relationship between B 12 deficiency and cognitive decrements. Furthermore, there is some controversy with respect to the efficacy of B 12 replacement in reversing associated cognitive decrements. The current experiments address such questions in a longitudinal study of cognitive ability in B 12 -deficient versus B 12 -adequate older adults before and following vitamin B 12 supplementation. Participants were classified as B 12 deficient based upon elevated MMA levels. Those with elevated MMA levels underwent oral B 12 replacement therapy (1000 µg pills) with measurement of serum vitamin levels, and measurement of performance on a battery of neuropsychological tests measuring memory, processing speed, reaction time, attention, verbal fluency and visual abstract reasoning being administered, at three time points over a period of twelve months. In the first experiment, participants with elevated MMA levels at baseline testing showed cognitive impairment relative to those with normal MMA levels in the domains of memory, verbal fluency and abstract reasoning. In the second experiment, following a twelve month trial of vitamin B 12 supplementation, those responding metabolically to treatment demonstrated marked and significantly better improvements in memory and abstract reasoning relative to the placebo group. Findings suggest that reducing plasma MMA concentrations by administering vitamin B 12 supplements may provide protection against cognitive decline as well as reverse potential cognitive deficits related to vitamin B 12 deficiency in this and other elderly populations.
... It could be that patients with vitamin B12 deficiency had a distinctive profile of cognitive impairment, since cognitive domains other than memory were reported to be affected by the deficiency of vitamin B12. In a previous study, non-demented cognitively impaired elderly patients with vitamin B12 deficiency had lower verbal fluency scores as compared with those with normal values of vitamin B12 [9]. In a sample of non-demented elderly subjects from a community based study, both normal and cognitively impaired, the values of methylmalonic acid, which inversely reflect the levels of vitamin B12, were associated with worse performances in language and praxis tests [10]. ...
... Episodic memory and orientation were predominantely affected in MCI patients with vitamin B12 deficiency, which are the cognitive domains typically altered in MCI patients [7,8]. On the other hand, cognitive domains previously reported to be disturbed by vitamin B12 deficiency, namely verbal fluency [9], language and praxis [10], and abstraction and visuospatial abilities [11,12] were not more impaired in MCI patients with vitamin B12 deficiency as compared to MCI patients with normal vitamin B12 levels. ...
... The benefit of vitamin B12 therapy regarding cognition is presently not clear. There are reports of patients with cognitive deficits who improved, namely in language and frontal lobe functions, after vitamin B12 supplementation [9]. However, the hypothesis that supplementation of vitamin B12, together with other vitamins, could have beneficial cognitive effects in subjects with normal or impaired cognition was not demonstrated neither in a randomized controlled trial [33] nor in a recent systematic review and meta-analysis [34]. ...
Vitamin B12 deficiency is common in older people, and may be responsible for reversible dementia. Low serum vitamin B12 levels were also observed in patients with Mild Cognitive Impairment (MCI). It is not known whether patients with vitamin B12 deficiency have a distinctive profile of cognitive impairment different from the episodic memory deficit usually observed in MCI.
From a cohort of 310 patients with MCI followed in a memory clinic in Lisbon, only 10 cases with vitamin B12 deficiency were found. From collaboration with other neurologists, 5 further patients with vitamin B12 deficiency were added. These cases were compared to MCI patients with normal vitamin B12 levels in a ratio 1:3. The duration of subjective cognitive symptoms was significantly shorter in MCI patients with B12 deficiency (1.2+/-1.0 years) as compared to MCI patients with normal vitamin B12 levels (3.4+/-3.0 years, p<0.001, Student' t test). There were no statistically significant differences in the neuropsychological tests between MCI patients with and without vitamin B12 deficiency. Vitamin B12 was started in MCI patients with vitamin B12 deficiency, with no noticeable clinical improvement.
MCI patients with low levels of vitamin B12 had no particular profile of cognitive impairment, however vitamin B12 deficiency might have precipitated the onset of symptoms. The effect of vitamin B12 supplementation in patients with MCI and low vitamin B12 levels should be clarified by future prospective studies.
... A retrospective study found that vitamin B12 therapy improves cognitive impairment but does not reverse dementia. [19] Here study refined that dementia of short duration and lesser degree reversed on treatment, in contrast to some previous studies. [6,19] Depression, apathy, irritability, dementia, catatonia, delirium, and hallucinations are well reported in the literature. ...
... [19] Here study refined that dementia of short duration and lesser degree reversed on treatment, in contrast to some previous studies. [6,19] Depression, apathy, irritability, dementia, catatonia, delirium, and hallucinations are well reported in the literature. [7] A study conducted on psychiatric inpatients had shown vitamin B12 deficiency in 4%-6% cases. ...
Abstract
Background:
Vitamin B12 deficiency leads to a diversity of symptoms and affects many systems. It is often overlooked or sometimes even misdiagnosed in clinical practice.
Aims and Objectives:
The purposes of this study were to report the prevalence of vitamin B12 deficiency, the spectrum of clinical features and to draw attention to the possibility of rare hidden characteristics.
Materials and Methods:
This study was a multicenter, retrospective, and prospective conducted at a tertiary care teaching hospital and multispecialty hospital. All cases of vitamin B12 deficiency of either sex or age attending the Medicine Department were enrolled in this study from Aug 2015 to Dec 2020. Parenteral vitamin B12 was given, and cases were evaluated for the response on follow-up for more than three months.
Results:
Of 220 cases, 52.27% were males. Maximum cases were reported from the age group 50 to 65 years (27.27%) and belonged to urban areas (59.1%). The majority were strict vegetarian (86.36%). Among comorbidities, diabetes (20.91%) followed by malabsorption (10.45%) were most common. The cutaneous manifestations were revealed at 38.18%. The most frequent neurological manifestation was paraesthesia (98.18%). Head heaviness/ache was the most frequent (95%) psychiatric manifestation. Anemia was revealed in 87.73% of cases with 88.64% macrocytosis. Axonal sensorimotor (52.63%) neuropathy was a prevalent finding of NCV study.
Conclusions:
A high index of clinical suspicion is needed in cases with vague manifestations, especially in the pure vegetarian population. Early recognition can prevent further damage as most of its related disorders are generally reversible with treatment.
... Vitamin B 12 deficiency has been implicated in cognitive impairment and dementia. Vitamin B 12 replacement is more likely to improve cognition in deficient patients with mild cognitive impairment than in those with dementia (Eastley 2000). However, B 12 deficiency is thought to be the cause of only 1% of reversible dementias (Harrison 2009). ...
... From the data overall this is not clear, although in the case that we describe at the beginning of this article and one other (Van Atta 2004), this appeared to be so. Where B 12 deficiency itself has caused mild cognitive impairment and dementia, there is evidence that individuals (not nitrous oxide users) with mild cognitive impairment improve with B 12 treatment and those with dementia do not (Eastley 2000 BOX 2 Treatment recommendations for nitrous oxide misuse ...
Objectives/Aims
The abuse of nitrous oxide (N2O) may be increasing globally and users and clinicians may not be aware of harms. We highlight these potential harms through the case of a woman treated for psychotic disorder for 11 months before developing severe N2O induced myeloneuropathy which should have been preventable. We review the clinical literature regarding N2O abuse to raise the profile of this emerging neuropsychiatric disorder.
Methods
A case study was undertaken and a literature review performed of relevant databases for cases of N2O abuse presenting with psychiatric symptoms.
Results
In our case a 37 year old woman presented with florid polymorphic psychosis and subtle cognitive impairment two weeks after inhaling large amounts of N2O. This was treated with antipsychotics and her symptoms waxed and waned over eleven months by which time she had developed a severe myeloneuropathy, confirmed on MRI cervical spine, and a functional B12 deficiency confirmed by high homocysteine and methylmalonic acid (MMA) which was then treated with intramuscular B12. N2O has a variety of effects including the stimulation of endogenous opioids; GABAA receptor stimulation; NMDA receptor antagonism; BDNF receptor activation; cortical excitation and depression on the encephalogram; activation of the anterior cingulate and deactivation of the hippocampal and parahippocampal cortices; and importantly, the deactivation of Vitamin B12 leading to build up of toxic homocysteine and MMA. There are 13 cases excluding this described in the literature of N2O abuse presenting primarily with psychiatric symptoms. They range from 23–64 years old and 12 were male. The most common presenting psychiatric symptoms in the 13 cases were delusions (reported by 8 individuals); cognitive impairment (6); visual hallucinations (4); bizarre or inappropriate behaviour (4); affective lability (3); anxiety (3); and depression, mania or auditory hallucinations in two respectively. Investigations were inconsistently reported but where tested, B12 was mostly low or low normal, and homocysteine and MMA were raised. In nine out of ten cases reported, the outcome was favourable, following cessation of N2O, administration of intramuscular B12, and antipsychotics.
Conclusions
N2O abuse is widespread in the UK and may be increasing. Heavy users are at risk of psychosis, cognitive impairment and myeloneuropathy, which may be irreversible. Importantly, some patients initially present with psychiatric symptoms before myeloneuropathy, and N2O abuse should always be considered in cases of new onset psychosis or cognitive impairment. Testing of homocysteine, MMA and B12 should be considered in these cases, and intramuscular B12 given without delay.
... Vitamin B 12 deficiency has been implicated in cognitive impairment and dementia. Vitamin B 12 replacement is more likely to improve cognition in deficient patients with mild cognitive impairment than in those with dementia (Eastley 2000). However, B 12 deficiency is thought to be the cause of only 1% of reversible dementias (Harrison 2009). ...
... From the data overall this is not clear, although in the case that we describe at the beginning of this article and one other (Van Atta 2004), this appeared to be so. Where B 12 deficiency itself has caused mild cognitive impairment and dementia, there is evidence that individuals (not nitrous oxide users) with mild cognitive impairment improve with B 12 treatment and those with dementia do not (Eastley 2000 BOX 2 Treatment recommendations for nitrous oxide misuse ...
Nitrous oxide (N 2 O) misuse is widespread in the UK. Although it is well-known that it can cause devastating myeloneuropathy, psychiatric presentations are poorly described. There is little understanding of who it affects, how it presents, its mechanism of action and principles of treatment. We begin this article with a case study. We then review the literature to help psychiatrists understand this area and deal with this increasing problem, and make diagnosis and treatment recommendations. We describe a diagnostic pentad of weakness, numbness, paraesthesia, psychosis and cognitive impairment to alert clinicians to the need to urgently treat these patients. Nitrous oxide misuse is a pending neuropsychiatric emergency requiring urgent treatment with vitamin B 12 to prevent potentially irreversible neurological and psychiatric symptoms.
LEARNING OBJECTIVES
After reading this article you will be able to: • understand the epidemiological and clinical features of nitrous oxide misuse
• understand the mechanisms of action of nitrous oxide
• describe potential treatment options in nitrous oxide misuse.
DECLARATION OF INTEREST
None.
... This leads to the paradoxical situation where physicians routinely screen for defi ciency, but subsequently ignore its discovery. The four key intervention studies are those of Martin et al. (Martin et al. 1992), Carmel et al. (Carmel et al. 1995), Teunisse et al. (Teunisse et al. 1996) and Eastley et al. (Eastley et al. 2000). ...
... Last, Eastley et al. identifi ed 125 patients out of 1,432 attending a memory disorders clinic who had low serum B12 (Eastley et al. 2000). They assessed 66 patients with dementia and 22 with cognitive impairment before and after B12 supplementation. ...
... 4,5 Reports indicated that, cerebral oxidative damage was due to increased oxidation of Vit B 12 generated by methylene synthase activity and the resulting disruption of homocysteine metabolism in AD. 6,7 Current data is not adequate to elucidate the exact correlation between the pathogenesis of AD and Vit B 12. 8,9 However low levels of Vit B 12 were reported in patients with dementia and significant improvement in cognitive functions were observed by Vit B 12 replacement therapy. 10 Vit B 12 deficiency in rats and humans was associated with a decrease in epidermal growth factor (EGF) levels and an increase in tumor necrosis factor alpha (TNF-α). 11 These results suggest a role for EGF and TNF- in the neuropathologic mechanisms in dementia patients. ...
... A negative correlation was reported between total homocysteine and plasma Vit B 12 levels. 10,[32][33][34] The neuron damage in AD was associated with the oxidative stress due to Vit B 12 deficiency. ...
Background: It was previously reported that vitamin B 12 (Vit B 12 ) has the regulatory effects on epidermal growth factor (EGF) and tumor necrosis factor alpha (TNF-α). The role of Vit B 12 , EGF and TNF-α in the pathogenesis of alzheimer dementia has not been elucidated yet. In this study the plasma Vit B 12 , EGF and TNF-α level were examined in individuals, between 65-99 years old with and without alzheimer dementia (AD). Methods: The study group comprised 47 patients with AD and 38 cases without dementia. EGF and TNF-α were analyzed by ELISA, and Vit B 12 was analyzed by chemiluminescence method. Results: Vit B 12 and EGF levels were significantly lower (p<0.0001), whereas TNF-α levels were significantly higher (p<0.0001) in the AD group in comparison to those without AD. Conclusions: Our results suggest that Vit B 12 , EGF and TNF-α may have a role in the pathophysiology of AD.
... Short-term vitamin B 12 injections were without benefit in 3 Alzheimer patients [292], as was oral vitamin B 12 during four [321] or ten [322] months in mixed dementia groups. A non-demented group treated with vitamin B 12 had higher verbal fluency than an untreated one [323]. However, vitamin B 12 alone or combined with folate for 6 months had no effect on cognitive performance in normal elderly subjects [324]. ...
... Vitamin B 12 : Apart from one study concerning a non-demented elderly group which improved after vitamin B 12 administration [323], there is no indication that this vitamin alone leads to cognitive benefits. [1] ...
Severe deficiencies in vitamins B1 (thiamine), B6 (pyridoxine), B9 (folate), and B12 cobalamin cause often reversible neurological damage, but their role in development, aging, and dementia are less well established. There is plenty of experimental evidence that thiamine deficiency causes anterograde amnesia in both humans and animals as a result of diencephalic lesions. However, it remains to be determined whether memory functions can be improved with thiamine supplements in young or aged subjects. There is preliminary evidence indicating that thiamine supplements are of value in accelerating information processing. Folate affects myelination in mature and developing organisms. Like thiamine deficiency, folate deficiency causes learning deficits in animals and neuropsychological disorders in humans. Folate replacement therapy is effective in cases when more folate enters the brain and blood levels are low. Subnormal folate and the consequent rise in homocysteine levels are related to poorer cognition, the associations being stronger in non-demented than demented subjects and in specific rather than global evaluations of cognitive function. Like folate deficiency, vitamin B6 deficiency is associated with myelin loss throughout the life-span. However, unlike folate, there is insufficient evidence linking vitamin B6 levels with age-related cognitive decline. Like B6 and B9 deficiencies, vitamin B12 deficiency damages myelin sheaths throughout the lifespan. Like folate, vitamin B12 is associated with specific cognitive abilities in the normal elderly population. However, the evidence linking vitamin B12 administration with cognitive benefits appears insufficient in either demented or non-demented subjects. There is meager evidence of cognitive benefits in Alzheimer's disease or normal aging after the administration of multiple B vitamins. However, such treatment appears to benefit children, though perhaps mostly poorly fed ones. Negative results of B vitamin supplements may be caused by not isolating subjects with marginally low levels of B vitamins, by too short a treatment period, or by overdosing.
... Wang et al (22) found no significant association between vitamin B-12 at baseline and incidence of dementia, but reported that the combination of low vitamin B-12 and low folic acid was significantly related to poor cognitive function. Five nonrandomized vitamin B-12 supplementation studies have been reported (23)(24)(25)(26)(27), 4 of which showed beneficial results on cognitive function (23)(24)(25)(26), whereas 1 study showed no effect (27). However, all studies were seriously flawed because none used a randomized design and some did not have a control group. ...
... Wang et al (22) found no significant association between vitamin B-12 at baseline and incidence of dementia, but reported that the combination of low vitamin B-12 and low folic acid was significantly related to poor cognitive function. Five nonrandomized vitamin B-12 supplementation studies have been reported (23)(24)(25)(26)(27), 4 of which showed beneficial results on cognitive function (23)(24)(25)(26), whereas 1 study showed no effect (27). However, all studies were seriously flawed because none used a randomized design and some did not have a control group. ...
Background: High concentrations of homocysteine and low concentrations of vitamin B-12 and folic acid are frequently observed in subjects with dementia. Objective: We assessed whether serum concentrations of homocysteine, vitamin B-12, or folic acid predict cognitive decline in old age. Design: This was a prospective, population-based, longitudinal study of 599 subjects (Leiden 85-Plus Study, Netherlands). The subjects were administered a battery of cognitive tests (including the Mini Mental State Examination, the Stroop test, a letter digit coding test, and a word recall test) at 85 y of age and yearly thereafter until 89 y of age. Serum concentrations of homocysteine, vitamin B-12, and folic acid were measured at 85 and 89 y of age. Cross-sectional associations between serum concentrations and cognition were assessed at 85 and 89 y of age. The association between baseline serum concentrations and subsequent longitudinal cognitive decline was assessed with the use of mixed linear models. Results: In the cross-sectional analyses, serum concentrations of homocysteine and folic acid were significantly associated with cognitive performance, but serum concentrations of vitamin B-12 were not. In the longitudinal analyses, there were no significant associations of serum concentrations of homocysteine, vitamin B-12, or folic acid with rate of cognitive decline. Conclusions: Elevated serum concentrations of homocysteine and reduced folic acid are associated with cognitive impairment in elderly persons but do not predict an increased rate of cognitive decline. The association of high serum concentrations of homocysteine and low folic acid with cognitive impairment in old age is likely to be a consequence of disease and not a contributory cause.
... Short-term vitamin B 12 injections were without benefit in 3 Alzheimer patients [292], as was oral vitamin B 12 during four [321] or ten [322] months in mixed dementia groups. A non-demented group treated with vitamin B 12 had higher verbal fluency than an untreated one [323]. However, vitamin B 12 alone or combined with folate for 6 months had no effect on cognitive performance in normal elderly subjects [324]. ...
... Vitamin B 12 : Apart from one study concerning a non-demented elderly group which improved after vitamin B 12 administration [323], there is no indication that this vitamin alone leads to cognitive benefits. [1] ...
... Chiu pointed out that this might explain why there are so few clinical guidelines concerning the treatment of low serum B 12 in patients with dementia, and how this leads to the paradoxical situation where physicians routinely screen such for such a deficiency but then tend to ignore the findings of a low level [56]! The most important early intervention studies are those of Martin et al. [57], Carmel et al. [58], Teunisse et al. [59], and Eastley et al. [60]. ...
... Eastley et al. identified 125 patients out of 1432 attending a memory disorders clinic who had low serum B 12 [60]. They assessed 66 of these with dementia and 22 with cognitive impairment before and after B 12 supplementation. ...
The classic neurological and psychiatric features associated with vitamin B12 deficiency have been well described and are the subject of many excellent review articles. The advent of sensitive diagnostic tests, including homocysteine and methylmalonic acid assays, has revealed a surprisingly high prevalence of a more subtle ‘subclinical’ form of B12 deficiency, particularly within the elderly. This is often associated with cognitive impairment and dementia, including Alzheimer's disease. Metabolic evidence of B12 deficiency is also reported in association with other neurodegenerative disorders including vascular dementia, Parkinson's disease and multiple sclerosis. These conditions are all associated with chronic neuro-inflammation and oxidative stress. It is possible that these clinical associations reflect compromised vitamin B12 metabolism due to such stress. Physicians are also increasingly aware of considerable inter-individual variation in the clinical response to B12 replacement therapy. Further research is needed to determine to what extent this is attributable to genetic determinants of vitamin B12 absorption, distribution and cellular uptake.
... In parallel, the vitamin B12 deficiency has been negatively correlated with cognitive functioning particularly for elderly people (Moore et al. 2012). Reversal of cognitive deficits, in the absence of dementia, by using B12 supplement has also been reported (Eastley et al. 2000). ...
In previous studies, decreased vitamin B12 and increased plasma homocysteine levels were reported as risk factors for dementia. The aim of this study was to clarify this relationship in earlier ages. Twenty-one healthy middle-aged adults (9 females, 12 males) with a mean age of 46.21 ± 7.99 were retrospectively included in the study. A voxel-based morphometry analysis was performed to measure brain volume. Plasma homocysteine, vitamin B12 levels, verbal and non-verbal memory test performances were recorded. Correlation analyses showed that increased plasma homocysteine was associated with lower memory score. Decreased vitamin B12 level was found to be associated with smaller brain volume in temporal regions. These results suggest that vitamin B12 and plasma homocysteine levels are associated with brain and cognition as early as middle adulthood. Future studies are needed to clarify whether they might be utilized as early hematological biomarkers to predict cognitive decline and neural loss.
... Reviews and lectures показали существенное улучшение в тесте на вербальную беглость (p < 0,01) [100]. При всех положительных эффектах терапии кобаламином получены свидетельства связи высокого уровня B 12 с переломами бедренной кости, раком легких и общей смертности от всех причин [101][102][103]. Высокий уровень кобаламина (> 700 пмоль/л) был ассоциирован с повышенной смертностью от сердечно-сосудистых заболеваний (HR 1,45, 95% CI 1,01, 2,06, p = 0,042) [104]. ...
Vitamin B 12 (cobalamin) is a collective name for a group of water-soluble cobalt-containing biologically active compounds belonging to corrinoids. Vitamin B 12 is essential for hematopoiesis, the formation of epithelial tissue; as a coenzyme, it is involved in the metabolism of fatty acids, carbohydrates, nucleic acids. Cobalamin defi ciency is associated with the development of anemia, polyneuropathy, and decreased cognitive function. Due to the nonspecifi city of symptoms and the possible development of severe and potentially irreversible complications, it is important to conduct timely screening among patients from risk groups. Among endocrine disorders, vitamin B 12 defi ciency is found in patients with diabetes mellitus, obesity and autoimmune thyroid disease mostly. In particular, metformin may cause a decrease in vitamin B 12 levels and polyneuropathy, which is diffi cult to diff erentiate from diabetic polyneuropathy. In patients with autoimmune thyroid lesions, other autoimmune diseases are often observed, atrophic gastritis and pernicious anemia notably. Vitamin B 12 malabsorption can lead to defi ciency even when consumed adequately, which possibly explains the relatively high prevalence of B 12 defi ciency in patients with autoimmune thyroid disease. This literature review summarizes recent advances on the role of vitamin B 12 metabolism, potential risk groups for vitamin B 12 defi ciency among common endocrine diseases, and the benefi t for its replacement with high-dose oral forms, cyanocobalamin 1 mg in particular
... In this study, the supplementation of cobalamin (1 month with placebo plus five months of treatment with an intramuscular injection of hydroxycobalamin (weekly 1000 µg for 4 weeks and monthly 1000 µg for 4 months) produced a decrease in Hcy and improved the scores in a verbal word learning test and verbal fluency. In another study, patients with cognitive impairment, defined as memory impairment or cognitive impairment insufficient for a diagnosis of dementia, with lower B12 levels, were supplemented by B12 [186]. The results showed that B12 supplementation in those patients significantly improved their verbal fluency, which reflects an improvement in frontal lobe function [169]. ...
Metabolism and nutrition have a significant role in epigenetic modifications such as DNA methylation, which can influence gene expression. Recently, it has been suggested that bioactive nutrients and gut microbiota can alter DNA methylation in the central nervous system (CNS) through the gut–brain axis, playing a crucial role in modulating CNS functions and, finally, behavior. Here, we will focus on the effect of metabolic signals in shaping brain DNA methylation during adulthood. We will provide an overview of potential interactions among diet, gastrointestinal microbiome and epigenetic alterations on brain methylation and behavior. In addition, the impact of different diet challenges on cytosine methylation dynamics in the adult brain will be discussed. Finally, we will explore new ways to modulate DNA hydroxymethylation, which is particularly abundant in neural tissue, through diet.
... Assim, um bebê nascido de uma mãe vegetariana ou vegana corre alto risco de nascer com baixos estoques de vitamina B12 e desenvolver sinais clínicos graves de deficiência durante o primeiro ano de vida se a ingestão da mãe for inadequada e seus estoques forem baixos. É importante destacar que mulheres vegetarianas que têm gestações repetidas colocam seus bebês em risco maior, porque seus estoques de vitamina B12 provavelmente foram esgotados nas gestações anteriores 29 . ...
Introdução: A vitamina B12 apresenta importância para o sistema nervoso central, estando envolvida em processos como o desenvolvimento cerebral, mielinização neural e função cognitiva. Objetivo: Examinar as evidências que relacionam a vitamina B12 materna e na infância com o desenvolvimento neurológico e cognitivo. Materiais e métodos: Revisão da literatura dos últimos 60 anos, buscando nas bases SciELO, LILACS, PubMed, MEDLINE e CINAHL. Foram selecionados estudos realizados em humanos do tipo observacional, de coorte, caso-controle e ensaios clínicos, randomizados ou não. Resultados: O status de vitamina B12 materno durante a gravidez e no período da amamentação apresenta influência no status de B12 dos filhos. Durante a infância a deficiência de B12 se correlaciona com falhas no desenvolvimento cerebral e no crescimento, enquanto os dados sobre sua influência em parâmetros cognitivos infantis apresentam resultados conflitantes. Mulheres veganas ou vegetarianas devem garantir uma ingestão adequada de vitamina B12 para fornecer para seu bebê em desenvolvimento uma vez que apresentam maior risco de insuficiência. Conclusões: O status de vitamina B12 materno é um determinante essencial do status de B12 na prole. Ainda é necessário pesquisas para analisar a influência da vitamina B12 na cognição, enquanto seu papel no desenvolvimento cerebral já é bem estabelecido.
... Moreover, vitamin B12 plays a necessary role in myelin biosynthesis, manufacturing, and development of erythrocytes (hematopoiesis) 11,25,26 . Therefore, vitamin B12 deficiency is associated with serious neurological, hematological, and metabolic disorders 21,[27][28][29][30] . Vitamin B12 deficiency is most prevalent in the elderly, children, pregnant women, nursing mothers, and vegetarians [31][32][33][34] . ...
... Another study demonstrated that vitamin B12 treatment might improve frontal lobe and language function in patients with cognitive impairment, but rarely reverses dementia [160]. ...
... Patients with cognitive impairment should be screened for hypothyroidism and vitamin B 12 deficiency, because these entities can cause cognitive decline that may improve with treatment. [17][18][19] It is reasonable to obtain a complete blood count with differential and comprehensive metabolic panel to screen for other general medical problems (eg, anemia, kidney or liver failure, electrolyte derangements) that could affect cognition. 17,20 Depending on clinical context, clinicians may consider ordering other laboratory tests, such as folate, vitamin D, heavy metal screen, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies, Lyme serologies, human immunodeficiency virus-1/2 immunoassay, and rapid plasma reagin. ...
Clinicians should use a systematic approach to evaluating patients presenting with a concern for cognitive impairment. This approach includes interviewing a knowledgeable informant and performing a thorough mental status examination in order to determine the presence of functional impairments and the domains of cognition that are impaired. The results of this interview and examination determine the next steps of the diagnostic work-up. The pattern of cognitive impairment shapes the differential diagnosis. Treatment should address symptoms, and environmental, psychological, and behavioral interventions are essential.
... 8 There was a prominent correlation between the duration of cognitive symptoms and response to therapy. 18 Patients symptomatic for <12 months gained an average of six points on the MMSE (paired t-test P = 0.0065), whereas patients symptomatic >12 months gained an average of four points (paired ttest p = 0.25). Similar reversibility observed in other studies from UK. 8 There are also other reports to suggest that supplementing B12 causes improvement in the blood-brain barrier and thus stabilizing cognitive functions. ...
Background: Objective of the study was to determine the prevalence of Isolated B12deficient dementia in patients presenting to a tertiary care hospital. The MMSE was much lower in B12 deficiency compared to irreversible causes Thus, shorter duration, severe dementia, focal neurological signs, and a vegetarian diet were significantly associated with the development of B12 deficiency.Methods: Based on exclusion and inclusion criteria 100 patients were included in this study, a detailed history of the patient were taken with respect to duration of dementia and its symptoms, type and treatment. Study in terms of the correlation of the clinical features with investigations and diet. Estimation of the prevalence of dementia with reference to B12 deficiency. Mean MMSE analysis, assessment of the improvement in MMSE after treatment with B12 injections after a6-8 wks period.Results: In this study most of our patients were in the 60-69 age groups across all causes of dementia, 22out of 26, B12 deficient patients were vegetarians. This value was in keeping with the known fact that a vegetarian diet predisposes a person to develop B12 deficiency. The association between B12 deficiency, high MCV and megaloblastic blood picture in peripheral blood smear was significant. The MMSE scores were significantly lower 13.42 in patients with B12 deficiency as compared to those with Alzheimer's 14.3 means and those with multi-infarct state 17.3 means.Conclusions: The duration of the presentation in B12 deficiency was10-12months averagely. There was a significant improvement in MMSE after treatment in pureB12 deficient patients (by 9 points) if they presented within one year of symptoms. Except for myelopathy, there was an improvement in other neurological symptoms and signs. Early diagnosis and proper treatment can make improvements in a patient's memory and quality of life.
... Supplementation with B12 in individuals with dementia has been inconclusive. For example, there was no significant improvement in memory or cognition in individuals with dementia who had low levels of vitamin B12 and were subsequently supplemented, however the supplemented individuals showed better verbal fluency scores compared to nonsupplemented controls (47) . However, the VITACOG trial showed that B-vitamin supplementation was related to positive cognitive outcomes in individuals in the top tertile of Accepted manuscript baseline omega-3 fatty acids, compared to individuals with lower baseline omega-3 fatty acid levels, perhaps due to a synergistic effect on phospholipid production for the brain (48) . ...
Epidemiological studies show mixed findings for serum vitamin B12 and both cognitive and regional volume outcomes. No studies to date have comprehensively examined, in non-supplemented individuals, serum B12 level associations with neurodegeneration, hypometabolism, and cognition across the Alzheimer's disease (AD) spectrum. Serum vitamin B12 was assayed from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL). Voxel-wise analyses regressed B12 levels against regional gray matter (GM) volume and glucose metabolism (p<.05, family-wise corrected). For ADNI GM, there were 39 cognitively normal (CN), 73 mild cognitive impairment (MCI), and 31 AD participants. For AIBL GM, there were 311 CN, 59 MCI, and 31 AD participants. Covariates were age, sex, baseline diagnosis, APOE4 status, and Body Mass Index (BMI). In ADNI, higher B12 was negatively associated with GM in the right precuneus and bilateral frontal gyri. When diagnostic groups were examined separately, only participants with MCI or above an established cutoff for CSF total tau showed such associations. In AIBL, higher B12 was associated with more grey matter in the right amygdala and right superior temporal pole, which largely seemed to be driven by CN participants that constituted most of the sample. Our results suggest that B12 may show different patterns of association based on clinical status and, for ADNI, AD CSF biomarkers. Accounting for these factors may clarify the relationship between B12 with neural outcomes in late-life.
... Although many studies have been dedicated to the implementation of folic acid, vitamin B12, or both, in vascular condition, AD or advanced dementia patients, or the old population, de facto results have never been reproducible, and the debate thus remains open [388][389][390][391][392][393][394][395][396][397][398][399][400][401][402][403][404][405]. ...
Many studies have been written on vitamin supplementation, fatty acid, and dementia, but results are still under debate, and no definite conclusion has yet been drawn. Nevertheless, a significant amount of lab evidence confirms that vitamins of the B group are tightly related to gene control for endothelium protection, act as antioxidants, play a co-enzymatic role in the most critical biochemical reactions inside the brain, and cooperate with many other elements, such as choline, for the synthesis of polyunsaturated phosphatidylcholine, through S-adenosyl-methionine (SAM) methyl donation. B-vitamins have anti-inflammatory properties and act in protective roles against neurodegenerative mechanisms, for example, through modulation of the glutamate currents and a reduction of the calcium currents. In addition, they also have extraordinary antioxidant properties. However, laboratory data are far from clinical practice. Many studies have tried to apply these results in everyday clinical activity, but results have been discouraging and far from a possible resolution of the associated mysteries, like those represented by Alzheimer’s disease (AD) or small vessel disease dementia. Above all, two significant problems emerge from the research: No consensus exists on general diagnostic criteria—MCI or AD? Which diagnostic criteria should be applied for small vessel disease-related dementia? In addition, no general schema exists for determining a possible correct time of implementation to have effective results. Here we present an up-to-date review of the literature on such topics, shedding some light on the possible interaction of vitamins and phosphatidylcholine, and their role in brain metabolism and catabolism. Further studies should take into account all of these questions, with well-designed and world-homogeneous trials.
... La alteración cognitiva en niños y pacientes jóvenes no tiene una caracterización precisa; se requieren estudios en este campo para establecer una comparación con los hallazgos en adultos, ya que en las investigaciones con pacientes mayores se ha encontrado que el tratamiento con vitamina B 12 puede mejorar la función del lóbulo frontal y las alteraciones de lenguaje [26]. ...
Introduction. Cyanocobalamin (vitamin B 12) is an essential cofactor of various metabolic pathways. Lack of it leads to symptoms which may be constitutional, of skin or mucous membranes, hematological or neuropsychiatric disorders. Neurological involvement in adults has been well described and analyzed in the literature, however there are fewer cases of children. In the cases described in children the deficiency was related to maternal malnutrition, and socioeconomic and cultural problems. Since vegetarianism is a custom followed by different social groups we wish to draw attention to this as a cause of vitamin B 12 deficiency and the neurological disorder this may cause. Clinical case. We describe the case of a 10 year old boy, a member of a religious community who were strict vegetarians. Over three months he developed: a cognitive disorder, pyramidal syndrome of his legs, involvement of the posterior spinal cord, peripheral motor and sensory alterations which, together with the complementary investigations, was found to be compatible with subacute combined degeneration due to vitamin B 12 deficiency. Conclusion. We draw attention to the clinical and laboratory aspects of this disorder and the importance of taking the possibility of this diagnosis into account in children with nutritional risk factors. [REV NEUROL 2001; 33: 1154-7] Key words. Cyanocobalamin. Malnutrition. Subacute combined degeneration. Vegetarianism. Vitamin B 12 deficiency. INTRODUCCIÓN La degeneración combinada subaguda, debida al déficit de cia-nocobalamina, se ha descrito ampliamente en la población de adultos [1-3] y, desde hace algunos años, han empezado a apa-recer informes en la literatura médica de niños afectados debi-do a déficit nutricionales, los cuales pueden tener su origen en un inadecuado aporte vitamínico por situaciones sociocultura-les –como la pobreza– o a consecuencia de dietas vegetarianas estrictas en las que no se consume ningún producto de origen animal [4-6]. Otras causas menos frecuentes son los síndromes de malabsorción y las deficiencias innatas en su transporte o en su metabolismo. Presentamos este caso clínico para llamar la atención sobre un trastorno que puede observarse en la población infantil sometida a hábitos dietéticos especiales. Mencionamos los aspectos clíni-cos de la degeneración combinada subaguda para alertar de los hallazgos que pueden encontrarse en estos pacientes, que en nuestro caso conformaban el síndrome completo, pero que pueden hallar-se en diferentes combinaciones de signos y síntomas.
... Another study demonstrated that vitamin B12 treatment might improve frontal lobe and language function in patients with cognitive impairment, but rarely reverses dementia [160]. ...
Homocysteine (Hcy) is a sulfur-containing amino acid that is generated during methionine metabolism. Physiologic Hcy levels are determined primarily by dietary intake and vitamin status. Elevated plasma levels of Hcy can be caused by deficiency of either vitamin B12 or folate. Hyperhomocysteinemia (HHcy) can be responsible of different systemic and neurological disease. Actually, HHcy has been considered as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD) and HHcy has been reported in many neurologic disorders including cognitive impairment and stroke, independent of long-recognized factors such as hyperlipidemia, hypertension, diabetes mellitus, and smoking. HHcy is typically defined as levels >15 micromol/L. Treatment of hyperhomocysteinemia with folic acid and B vitamins seems to be effective in the prevention of the development of atherosclerosis, CVD, and strokes. However, data from literature show controversial results regarding the significance of homocysteine as a risk factor for CVD and stroke and whether patients should be routinely screened for homocysteine. HHcy-induced oxidative stress, endothelial dysfunction, inflammation, smooth muscle cell proliferation, and endoplasmic reticulum (ER) stress have been considered to play an important role in the pathogenesis of several diseases including atherosclerosis and stroke. The aim of our research is to review the possible role of HHcy in neurodegenerative disease and stroke and to understand its pathogenesis.
... Low B12 status is associated with an increased risk of pathologically confirmed Alzheimer disease (46,47) but by the time the patient has moderate to severe dementia, the brain is probably too damaged to benefit from cobalamin treatment (48). Reversal of cognitive deficits has been observed in B12deficient patients with cognitive impairment, but not dementia (49). Thus, all patients with cognitive impairment should have their cobalamin status investigated. ...
This report on vitamin B-12 (B12) is part of the Biomarkers of Nutrition for Development (BOND) Project, which provides state-of-the art information and advice on the selection, use, and interpretation of biomarkers of nutrient exposure, status, and function. As with the other 5 reports in this series, which focused on iodine, folate, zinc, iron, and vitamin A, this B12 report was developed with the assistance of an expert panel (BOND B12 EP) and other experts who provided information during a consultation. The experts reviewed the existing literature in depth in order to consolidate existing relevant information on the biology of B12, including known and possible effects of insufficiency, and available and potential biomarkers of status. Unlike the situation for the other 5 nutrients reviewed during the BOND project, there has been relatively little previous attention paid to B12 status and its biomarkers, so this report is a landmark in terms of the consolidation and interpretation of the available information on B12 nutrition. Historically, most focus has been on diagnosis and treatment of clinical symptoms of B12 deficiency, which result primarily from pernicious anemia or strict vegetarianism. More recently, we have become aware of the high prevalence of B12 insufficiency in populations consuming low amounts of animal-source foods, which can be detected with ≥1 serum biomarker but presents the new challenge of identifying functional consequences that may require public health interventions.
... En conclusión, hasta la fecha ninguna evidencia muestra una relación causal entre la hipovitaminosis B12 y el déficit cognitivo, pero existe evidencia de la comorbilidad del déficit de vitamina B12 en pacientes con demencia y déficit cognitivo leve, por lo que sería un grupo de riesgo que siempre se debería tamizar. Se necesita nueva evidencia que determine si la reposición vitamínica puede revertir el daño cognitivo (37). ...
Levels of vitamin B12 are commonly requested in psychiatric patients, specifically in units for acute patients. Despite the abundant literature available about the correlation between this hypovitaminosis and neuro-psychiatric symptoms, there are still many doubts about the risk groups that should be screened, the tests that should be applied, how to treat, and the real usefulness of vitamin supplementation in the resolution of affective, cognitive or psychotic symptoms. This article presents a narrative review of the available literature, and summarizes the main recommendations about theoretical and practical questions concerning this subject matter, with emphasis on the correlation between low levels of vitamin B12 and cognitive impairment, depression and psychotic disorders.
... However, there are many different studies which have documented the effectiveness of vitamin B 12 supplementation, in improving cognition in demented patients [6,[69][70][71][72]. Another well-conducted study demonstrated that vitamin B 12 treatment may improve frontal lobe and language function in patients with cognitive impairment, but rarely reverses dementia [6,73]. Many other works have failed to confirm the optimistic results [68,74,75] and one of the prominent author on the topic declared that subnormal serum vitamin B 12 levels are not an important cause of reversible dementia [75]. ...
Vitamin B12 and folate are supplied via two major pathways, the conversion of homocysteine
to methionine and the conversion of methyl malonyl coenzyme A to succinyl coenzyme
A. Therefore, the defect in both the vitamins results in an increase in both serum homocysteine and
methylmalonic acid. Hence, homocysteine, vitamin B12, and folate are closely linked together in
the so-called one-carbon cycle, making vitamin B12 the necessary co-enzyme for the methyl
donation from 5-methyl-tetra-hydrofolate in tetra-hydro-folate, necessary for methionine
synthetase. Folate is a cofactor in one-carbon metabolism, and it promotes the remethylation of
homocysteine, which can cause DNA strand breakage, oxidative stress and apoptosis. Vitamin B12
and folate are involved in nucleic acid synthesis and in the methylation reactions, and their deficit
causes the inhibition of S-adenosylmethionine mediated methylation reactions, and through the
related toxic effects of homocysteine, a possible direct alteration of the vascular endothelium and
inhibition of N-methyl-D-Aspartate receptors take place. We discussed the possible and still
controversial role of homocysteine accumulation in cerebral pathologies, starting from vascular
events to neurodegeneration and to endothelium damage mechanism
... It is still a common practice to treat patients with neurological symptoms with intramuscular cyancobalamin injections [12]. Patients with cognitive deficits demonstrated notable improvement, namely in language and frontal lobe functions, after the vitamin B12 supplementation [4]. In light of these surrounding studies, the study aimed to supplement vitamin B12 deficient MCI geriatric patients with injectable doses of vitamin B12 followed by impact evaluation. ...
Background:The Neurodegenerative diseases are increasingly affecting the elderly with a severe impact on their brain health. There is a wide gap in supplementation based studies for increasing the cognition levels of the geriatric population,especially in developing countries like Indiawhich are at extreme risk of developing neurological disorders. And recently Vitamin B12 has drawn considerable attentiondue to its ability to improvethe cognitive status. Current literaturehas linked the possibility of alleviating neurologicaldisorders in the elderly with effective vitamin B12 management. Abundant animal and human models have proved that supplementation of vitamin B12 is beneficial for the restoration of cognitive functions.Objective: To supplementvitamin B12 deficient mild cognitively impaired geriatric patients with injectable doses of vitamin B12 followed byimpact evaluation.Methods:Screening of the mild cognitively impaired patients was carried out using the Mini-Mental State Examinationand Yamaguchi Fox Pigeon Imitation test. Baseline information was elicited from the patients residing in urban Vadodara (a district in the state of Gujarat), India.This included socio-demographic, medical and drug history, anthropometric andphysical activity pattern, in addition tobiochemical parameterscomprising of serum vitamin B12 and glycated haemoglobin profile.Asub-sample of 60 patients with mild cognitive impairment (MCI) demonstrating severe vitamin B12 deficiency were conveniently enrolledfor injectable doses ofVitamin B12inthedosage of 1,000 μg every day for one week, followed by 1,000 μg every week for 4 weeks & finishing with1,000 μg for the remaining 4 months.An intervention six-monthafter the experimentwith all the parameters were elicited.Results: Vitamin B12 supplementation resulted in a significant (p<0.001) improvement in the MMSE scores of the patients with a rise of 9.63% in the total patients. Gender-wise division also highlighted a significant increase (p<0.001) in the scores by 6.79% and 12.46% in overall males and females and a 10.20% and 8.24% rise for young-old (60-69 yrs) and old-old (70-85 yrs) categories,respectively. As a result, 27 patients progressed towards the normal category from the MCI state being assessed by MMSE scores. In the same manner, YGFPIT too demonstrated a 38% increasein normalwith 35% males, 42% females, 41% young–old and 31% old-old moving to normal status. Thus, a total number of 28 patients progressed to the normal condition as per YGFPIT.Conclusion: Ultimately, vitamin B12 supplementation was discovered to besignificantlyeffective, as theplacing ofserum vitamin B12 withinMCI patientscaused a turnfrom the deficiency state to sufficient levels and in turn increased their performance in MMSE and YFPIT scores.Keywords: Mild Cognitive Impairment, vitamin B12,geriatrics, cognition
... 43 Those with obvious dementia usually show no improvement when treated with vitamin B12. 44 In the Newcastle 85þ Study, 9% of the participants had been diagnosed with dementia/Alzheimer disease at baseline, which might have skewed the results and partly explained the lack of association. However, in sensitivity analyses, when we excluded participants with dementia from the models, the lack of association between plasma vitamin B12 and cognitive performance at baseline and at follow-up remained. ...
Objectives:
Although the biological rationale for the association between folate, vitamin B12, and homocysteine with cognitive function seems plausible, conflicting results have been reported. This study aimed to determine the associations between 1-carbon (1-C) metabolism biomarkers (folate, vitamin B12, and homocysteine), and cognitive impairment at baseline and the rate of cognitive decline over 5 years in the very old.
Design:
The Newcastle 85+ Study was a prospective longitudinal study of people 85 years old and followed over 5 years in Northeast England.
Setting:
Community-dwelling and institutionalized.
Participants:
The analytical sample included 765 very old participants with 1-C metabolism biomarkers and cognitive measures.
Measurements:
Global cognition was measured by the Standardized Mini-Mental State Examination (SMMSE) at baseline, and at 3 and 5 years of follow-up and, attention-specific cognition with the Cognitive Drug Research (CDR) System at baseline, and at 1.5 and 3.0 years of follow-up. Baseline red blood cell folate (RBC folate), plasma vitamin B12, and total homocysteine (tHcy) concentrations were determined by immunoassay. Linear mixed models were used to estimate the associations between quartiles of 1-C metabolism biomarkers and cognition over 3 (CDR) and 5 years (SMMSE).
Results:
Compared with participants in the lowest quartile of RBC folate concentrations (<612 nmol/L), those in the highest quartile of RBC folate concentrations (>1280 nmol/L) had 1 more point on the SMMSE at baseline (β = +1.02, SE = 0.43, P = .02). Those in quartile 4 of tHcy (>21.4 μmol/L) had 1 point less in the SMMSE at baseline than those in the lowest quartile (<13.5 μmol/L) (β = -1.05, SE = 0.46, P = .02). Plasma vitamin B12 was not predictive of global or attention-specific cognition at baseline and at follow-up. None of the 1-C metabolism biomarkers except tHcy was associated with the rate of decline in attention scores over 3 years.
Conclusion:
RBC folate and tHcy, but not plasma vitamin B12, were associated with better global cognition in the very old at baseline but were not predictive of rate of decline over 5 years.
... Both the cognitive and autonomic dysfunction also improved in this case. There have been several reports that cognitive impairment is occasionally reversible after B12 replacement therapy in patients with vitamin B12 deficiency (10)(11)(12)(13). In another report, a patient with vitamin B12 deficiency and autonomic dysfunction of orthostatic hypotension, improved after 2 weeks of treatment with vitamin B12 (14). ...
An impaired awareness of hypoglycemia is a serious problem in diabetic patients, which can lead to life-threatening severe hypoglycemia. Recurrent hypoglycemia attenuates the function of the central, mainly hypothalamic, nervous system and it causes an impaired awareness of hypoglycemia. Vitamin B12 deficiency is also associated with the dysfunction of central nervous system. We report a 72-year-old type 1 diabetic patient with vitamin B12 deficiency whose impaired awareness of hypoglycemia improved after 4 weeks of vitamin B12 administration with an increased counter-hormone secretion in response to hypoglycemia. We should recognize vitamin B12 deficiency as one of the causes of an impaired awareness of hypoglycemia in diabetic patients.
... Although cognitive impairment caused by B 12 deficiency has been reported in elderly persons [27], the underlying mechanisms are poorly understood. To clarify 22 effects of B 12 deficiency on learning and memory functions involving the insulin/phosphoinositide 3 kinase signaling pathway in the central nervous system, the C. elegans salt (NaCl) chemotaxis associative learning assay system was used. ...
Oxidative stress is implicated in various human diseases and conditions, such as a neurodegeneration, which is the major symptom of vitamin B12 deficiency, although the underlying disease mechanisms associated with vitamin deficiency are poorly understood. Vitamin B12 deficiency was found to significantly increase cellular H2O2 and NO content in Caenorhabditis elegans and significantly decrease low molecular antioxidant [reduced glutathione (GSH) and l-ascorbic acid] levels and antioxidant enzyme (superoxide dismutase and catalase) activities, indicating that vitamin B12 deficiency induces severe oxidative stress leading to oxidative damage of various cellular components in worms. An NaCl chemotaxis associative learning assay indicated that vitamin B12 deficiency did not affect learning ability but impaired memory retention ability, which decreased to approximately 58% of the control value. When worms were treated with 1mmol/L GSH, l-ascorbic acid, or vitamin E for three generations during vitamin B12 deficiency, cellular malondialdehyde content as an index of oxidative stress decreased to the control level, but the impairment of memory retention ability was not completely reversed (up to approximately 50%). These results suggest that memory retention impairment formed during B12 deficiency is partially attributable to oxidative stress.
... [5] A study of 22 patients with various degrees of cognitive impairment and 66 patients with dementia by Eastley et al. found that Vitamin B12 treatment improves impairment of cognition, but does not reverse dementia. [6] In contrast, de la Fourniere et al. studied 11 Alzheimer's disease patients with low serum Vitamin B12 levels (<240 pg/ml) and prepared them to receive injections of either Vitamin B12 (1000 μg) or placebo daily for 5 days followed by one intramuscular injection per month for 5 months. The authors concluded that the two groups did not differ greatly in cognitive outcome. ...
Objectives:
To determine the relationship between Vitamin B12 levels and thyroid hormones in patients with multiple sclerosis (MS).
Materials and Methods:
One hundred and ten patients with MS were recruited for this study after Institutional Review Board approval. All patients signed a written informed consent form and donated a single blood sample. Plasma Vitamin B12 levels, triiodothyronine (T3), and thyroxine (T4) hormone levels were measured. Data were analyzed using the Statistical Package for Social Sciences (SPSS) software.
Results:
Analysis of Vitamin B12 levels in 110 patients with MS revealed that 65% had normal levels of Vitamin B12 (200–900 pg/ml), 30% had low levels of Vitamin B12 (<200 pg/ml), and 5% high levels of Vitamin B12 (higher than 900 pg/ml). Further analysis of patients with low levels of Vitamin B12 revealed that this cohort exhibited a significantly high number of patients with low levels of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) (P < 0.005).
Conclusion:
This study suggests a relationship between Vitamin B12 levels and thyroid hormones. This opens the possibility that the use of therapies that increase triiodothyronine (T3) and thyroxine (T4) levels might be beneficial to patients with MS.
... However hyperhomocysteinaemia may be seen even in subjects 19 who have adequate serum B12 and folate levels and hence therapeutic supplementation may not reverse cognitive deficits completely. Vitamin B12 supplementation may improve executive functions and language impairments without actually 20 reversing dementia. Therefore, while routine supplementation with Vitamin B12 is not recommended for subjects with Dementia, they may be encouraged to maintain adequate levels 21 of Vitamin B12 through dietary interventions. ...
... W koncepcji tej ważna jest obserwacja, że rzeczywista odwracalność otępienia dotyczy tylko niewielkiej grupy chorych, co jest, naj prawdopodobniej, związane z długotrwałością narażenia na czynnik sprawczy. Długotrwały niedobór witaminy B 12 prowadzi do powstawania nieodwracalnych zmian w ośrodkowym układzie nerwowym o typie demielinizacji, dlatego tak istotna jest skuteczna i szybka diagnostyka niedoboru, a wcześniej zapobieganie rozwojowi deficytów witaminowych [29,30]. Wnioski 1. Niedobór witaminy B 12 i niedokrwistość mogą być istotnymi czynnikami ryzyka rozwoju zaburzeń poznawczych. ...
Background. In recent years, in Poland, an increase in the elderly population is observed. Older people are the main users of health care system. Anemia, dementia and malnutrition are common health problems in the elderly. The causes of these disorders are complex and include, characteristic of old age problems: multidiseases, lack of social support and poor economic situation. Objectives. The aim of this study was to analyze the correlation between cognitive impairment, vitamin B12 deficiency and anemia. Material and methods. The study was conducted in a group of 48 older patients, which were treated in Clinic of Internal Medicine in Bytom, using laboratory tests and a MMSE questionnaire. The statistical analysis was performed in the Statistica 10. Results. There is a correlation between vitamin B12 deficiency and the cognitive impairment in patients with anemia. The incidence of these disorders increases with age and involves a large group of respondents. Conclusions. Due to the existence of the relationshi p between the development of dementia, anemia and vitamin deficiencies it is important to early diagnose these disorders and effectively prevent them to improve the quality of life. Many of these tasks are the responsibility of the GP. Effective implementation of the objectives of prevention of anemia, nutritional deficiencies, and the development of dementia can significantly improve the quality of life.
... Thus, early intervention is indicated. Further support for this concept comes from a clinical trial (Eastley et al., 2000) showing that 66 patients with dementia and low B12 did not improve their cognitive scores after 7 months of B-vitamin treatment. However, 21 patients with early cognitive impairment and low B12 did improve their verbal fluency scores after 9 months of treatment. ...
Few B-vitamin trials to lower homocysteine (Hcy) have reported evidence of beneficial effects on cognition in older adults with cognitive impairment or Alzheimer's disease. This article reviews the role of Hcy in cognitive decline. It also considers some reasons why meta-analyses have failed to find effects of B-vitamin treatment. Findings from the successful VITACOG trial are examined from a new perspective of critical levels of Hcy and brain atrophy that may impact on the efficacy of B-vitamin treatment. It appears that there is a critical level of brain shrinkage, possibly mediated by elevated Hcy, which when reached, results in cognitive decline, especially in episodic memory performance. Supplements, food sources, and effects of folic acid fortification are discussed in relation to B12 deficiency.
... Les dosages systématiques de la vitamine B 12 (cyanocobalamine) chez les sujets âgés déments montrent souvent des concentrations sanguines subnormales (de l'ordre de 150 pg/mL pour une limite inférieure de 200 pg/mL). Plusieurs études ont cependant clairement montré que, dans ce cas, les troubles cognitifs ne sont pas imputables à cette carence relative : au pire, la supplémentation en vitamine B 12 ne change rien [5,34], au mieux elle les atténue marginalement [35]. Des carences plus sévères peuvent, en revanche, engendrer d'authentiques syndromes démentiels, dont la sémiologie est dominée par un ralentissement idéique, parfois une confusion, une détérioration de la mémoire et des troubles d'allure dépressive, voire des hallucinations [36]. ...
... Decreased levels of certain nutrients as observed in AD patients suggest a potential role for the supplementation of specific nutrients in the management of AD. Until now, several intervention studies investigated the effects of supplementation with single nutrients, for instance vitamin B12, vitamin E, or n-3 LC-PUFA in dementia patients, showing no or little improvements of cognitive function and other outcomes [63][64][65]. The outcomes of single nutrient studies may be explained by the fact that nutrients most likely act in a synergistic way [66]. ...
Background:
Studies on the systemic availability of nutrients and nutritional status in Alzheimer's disease (AD) are widely available, but the majority included patients in a moderate stage of AD.
Objective:
This study compares the nutritional status between mild AD outpatients and healthy controls.
Methods:
A subgroup of Dutch drug-naïve patients with mild AD (Mini-Mental State Examination (MMSE) ≥20) from the Souvenir II randomized controlled study (NTR1975) and a group of Dutch healthy controls were included. Nutritional status was assessed by measuring levels of several nutrients, conducting the Mini Nutritional Assessment (MNA®) questionnaire and through anthropometric measures.
Results:
In total, data of 93 healthy cognitively intact controls (MMSE 29.0 [23.0-30.0]) and 79 very mild AD patients (MMSE = 25.0 [20.0-30.0]) were included. Plasma selenium (p < 0.001) and uridine (p = 0.046) levels were significantly lower in AD patients, with a similar trend for plasma vitamin D (p = 0.094) levels. In addition, the fatty acid profile in erythrocyte membranes was different between groups for several fatty acids. Mean MNA screening score was significantly lower in AD patients (p = 0.008), but not indicative of malnutrition risk. No significant differences were observed for other micronutrient or anthropometric parameters.
Conclusion:
In non-malnourished patients with very mild AD, lower levels of some micronutrients, a different fatty acid profile in erythrocyte membranes and a slightly but significantly lower MNA screening score were observed. This suggests that subtle differences in nutrient status are present already in a very early stage of AD and in the absence of protein/energy malnutrition.
... On a retrospective study on the effects of B12 treatment on neuropsychological function and disease progression in patients with dementia or cognitive impairment, Eastley et al. [48] found that vitamin B12 treatment improves cognitive impairment, but does not reverse dementia. Although evidence of vitamin B12 efficacy in improving the cognitive function of people with dementia and B12 serum concentrations is insufficient [49], it is advisable to screen for vitamin B12 in all patients with cognitive impairment [23]. ...
Vitamin B12 deficiency causes a wide range of hematological, gastrointestinal, psychiatric and neurological disorders. Hematological presentation of cobalamin deficiency ranges from the incidental increase of mean corpuscular volume and neutrophil hypersegmentation to symptoms due to severe anemia, such as angor, dyspnea on exertion, fatigue or symptoms related to congestive heart failure, such as ankle edema, orthopnea and nocturia. Neuropsychiatric symptoms may precede hematologic signs and are represented by myelopathy, neuropathy, dementia and, less often, optic nerve atrophy. The spinal cord manifestation, subacute combined degeneration (SCD), is characterized by symmetric dysesthesia, disturbance of position sense and spastic paraparesis or tetraparesis. The most consistent MRI finding is a symmetrical abnormally increased T2 signal intensity confined to posterior or posterior and lateral columns in the cervical and thoracic spinal cord. Isolated peripheral neuropathy is less frequent, but likely overlooked. Vitamin B12 deficiency has been correlated negatively with cognitive functioning in healthy elderly subjects. Symptoms include slow mentation, memory impairment, attention deficits and dementia. Optic neuropathy occurs occasionally in adult patient. It is characterized by symmetric, painless and progressive visual loss. Parenteral replacement therapy should be started soon after the vitamin deficiency has been established.
The aim of this study is to demonstrate the prevalence of the long‐term side effects of Covid19, namely memory impairment among recovered patients, and obtaining the associated factors that link with memory impairment. It is a cross sectional retrospective cohort study, that has been conducted from September to November 2022 in Iraq. People who were previously infected with COVID‐19 were included. The study was performed by asking people to complete a questionnaire platform by either online or face to face interview. The Memory Assessment Clinic‐Q (MAC‐Q) test were utilized, scores that are equal or higher than 25 are indicative of memory decline. 1287 participated in this study. However only 1157 were included for the final analysis. Three hundred ninety‐nine (34.49%) have memory impairment after Covid19 recovery. Female gender, older age group, repeated exposure to COVID‐19 infections, severe diseases, and exposure to multiple SARS‐CoV‐2 variants were independent risk factors of memory deficit in post‐COVID‐19 survivors with a p value of 0.0001, 0.02, 0.0001, 0.001, 0.0001 respectively. It is crucial to pay particular attention to psychosocial rehabilitation of such risky groups. COVID‐19 vaccine administrations with booster shots are necessary steps to decrease the disease incidence and avoid subsequent post‐COVID‐19 symptoms. This article is protected by copyright. All rights reserved.
Se realiza un estudio en dos fases acerca de la prevalencia de demencia y de Enfermedad de Alzheimer (EA) y factores relacionados en una población de 402 sujetos de 65 o más años, residentes en siete instituciones geriátricas de la provincia de Zamora. Se analizan las propiedades psicométricas del Mini-Examen Cognoscitivo (MEC) en sus dos versiones de 11 y 13 ítems (MEC-30 y MEC-35), así como concordancia y equivalencia con el Mini-Mental State Examination (MMSE) en esta población. Se investiga la relación entre sintomatología depresiva, demencia y deterioro cognoscitivo, así como la influencia de éste último en la mortalidad de esta población anciana institucionalizada.
La prevalencia de demencia es muy superior a la de la población general, y varía en función del análisis de las pérdidas poblacionales y de la corrección de los falsos negativos de la prueba de cribado. Sin ajustar es del 22,89%; del 27,12% (IC 95% 23,17% - 31,06%) con corrección para los falsos negativos; y del 37,47% corregida para la ausencia de respuesta en la segunda fase.
La prevalencia estimada de EA con corrección para falsos negativos es del 12,96% (IC 95% 9,57% - 16,34%). Las prevalencias de demencia y EA no siguen un crecimiento exponencial con la edad, como en la población general, aunque sí se incrementan en función de ésta, sobre todo en el caso de la EA. La prevalencia de demencia, y sobre todo de EA, es superior en mujeres (sin diferencias significativas) y en el estrato con menor nivel educativo.
La demencia y la EA se asocian con un peor estado nutricional. La hipoalbuminemia supone una probabilidad 2,86 mayor de demencia y 3,61 de EA. Una cifra de vitamina B12 menor 179 pg/ml, se asocia significativamente con una probabilidad 7,13 veces mayor de EA.
La consistencia interna del MEC-35 y MEC-30 es buena (a de Cronbach de 0,78 y 0,74, respectivamente). La fiabilidad test-retest de ambos a los 15 meses es moderada con valores similares. Link: https://uvadoc.uva.es/handle/10324/54760
Background
Vitamin B12 deficiency is an easily treatable cause of reversible dementia. It is likely to be more common in Indian population due to traditionally vegetarian culture. This study was conducted to estimate the prevalence of Vitamin B12 deficiency in elderly patients (>60 years) with dementia attending outpatient department.
Methods
This study was conducted in two phases. The first phase was a cross sectional observational study to estimate the prevalence of Vitamin B12 deficiency in the elderly population with dementia. The second phase was a pilot study done in subjects with Vitamin B12 deficiency to assess the change in cognition following Vitamin B12 supplementation.
Results
Out of 2920 study eligible subjects, 200 were diagnosed as dementia with Mini Mental Status Examination (MMSE) score of ≤ 24. Vitamin B12 deficiency was seen in 7.5% of patients. Vitamin B12 deficiency was associated with shorter and more severe dementia. Macrocytosis was more common in Vitamin B12 deficiency (p value < 0.001) where as vegetarian diet did not show significant correlation (p value 0.69). There was significant improvement in the median MMSE score in the intervention group with increase in MMSE by 2 points at 6-8 weeks and 3 points at 12 weeks (p value 0.009 and 0.003 by Mann Whitney test).
Conclusion
Prevalence of Vitamin B12 deficiency in dementia was 7.5%. It was associated with macrocytosis, shorter duration and more severe dementia. There was a significant improvement in median MMSE score at 6 weeks and 12 weeks following Vitamin B12 supplementation.
While the relationship between nutrition and physical well-being is well established, that between nutrition and brain function still remains
uncertain. This study attempts an approach to the investigation of the association between the quality of nutrition and the cognitive and emotional aspects of human behaviour. The developmental and
educational skills of students who had participated in a health education intervention programme were evaluated. The evaluation was carried out by their teachers, using an academic performance scale.
Performance scores and school grades were correlated with haematological and anthropometric indices, dietary intake and performance on a physical fitness scale. The findings indicated that
consumption of dairy products, vegetables and fruits was associated with improvements in some cognitive abilities. Vitamins B12 and A, and calcium and proteins appear to play a role. The association observed between physical activity and high scores on the academic performance scale is of special interest. Girls scored higher than boys on this scale,
and pupils with higher scores in the scale had greater body weight and recorded higher intakes of vegetables, fruits and vitamin B12 than pupils with lower scores. These findings are in accordance with those of other studies and suggest that the quality of nutrition correlates not just with physical wellbeing but also with cognitive performance. This association should be further investigated. In view of the possible negative consequences of malnutrition and reduced physical activity on the general performance of children, prevention and intervention programmes are indicated.
Paediatriki 2004; 67:178-189 (in Greek)
BACKGROUND: Vitamin B-12 deficiency is associated with cognitive impairment in older people. However, evidence from randomized trials of the effects of vitamin B-12 supplementation on cognitive function is limited and inconclusive. OBJECTIVE: The objective was to investigate whether daily supplementation with high doses of oral vitamin B-12 alone or in combination with folic acid has any beneficial effects on cognitive function in persons aged >/=70 y with mild vitamin B-12 deficiency. DESIGN: In a double-blind, placebo-controlled trial, 195 subjects were randomly assigned to receive 1000 microg vitamin B-12, 1000 microg vitamin B-12 + 400 microg folic acid, or placebo for 24 wk. Vitamin B-12 status was assessed on the basis of methylmalonic acid, total homocysteine (tHcy), and holotranscobalamin (holoTC) concentrations before and after 12 and 24 wk of treatment. Cognitive function was assessed before and after 24 wk of treatment with the use of an extensive neuropsychologic test battery that included the domains of attention, construction, sensomotor speed, memory, and executive function. RESULTS: Vitamin B-12 status did not change significantly after treatment in the placebo group; however, oral vitamin B-12 supplementation corrected mild vitamin B-12 deficiency. Vitamin B-12 + folic acid supplementation increased red blood cell folate concentrations and decreased tHcy concentrations by 36%. Improvement in memory function was greater in the placebo group than in the group who received vitamin B-12 alone (P = 0.0036). Neither supplementation with vitamin B-12 alone nor that in combination with folic acid was accompanied by any improvement in other cognitive domains. CONCLUSION: Oral supplementation with vitamin B-12 alone or in combination with folic acid for 24 wk does not improve cognitive function.
The biosynthesis of B12, involving up to 30 different enzyme-mediated steps, only occurs in bacteria. Thus, most eukaryotes require an external source of B12, and yet the vitamin appears to have only two functions in eukaryotes: as a cofactor for the enzymes methionine synthase and methylmalonylCoA mutase. These two functions are crucial for normal health in humans, and in particular, the formation of methionine is essential for providing methyl groups for over 100 methylation processes. Interference with the methionine synthase reaction not only depletes the body of methyl groups but also leads to the accumulation of homocysteine, a risk factor for many diseases. The syndrome pernicious anemia, characterized by lack of intrinsic factor, leads to a severe, sometimes fatal form of B12 deficiency. However, there is no sharp cutoff for B12 deficiency; rather, there is a continuous inverse relationship between serum B12 and a variety of undesirable outcomes, including neural tube defects, stroke, and dementia. The brain is particularly vulnerable; in children, inadequate B12 stunts brain and intellectual development. Suboptimal B12 status (serum B12 <300pmol/L) is very common, occurring in 30%-60% of the population, in particular in pregnant women and in less-developed countries. Thus, many tens of millions of people in the world may suffer harm from having a poor B12 status. Public health steps are urgently needed to correct this inadequacy.
Das Demenzsyndrom ist durch die progrediente Entwicklung vielfältiger kognitiver und psychopathologischer Defizite charakterisiert, wobei neben einer Merkfähigkeits - und Gedächtnisstörung weitere kognitive Einbußen (»Werkzeugstörungen «) vorhanden sein müssen: Hierzu zählen z. B. Orien tierungs-, Aufmerksamkeits- und Konzentrationsstörungen, Aphasie, Apraxie, Agnosie, Alexie, Akalkulie, Visuo - konstruktion oder eine Beeinträchtigung der Exekutivfunktionen (Planen, Organi sieren, Abstrahieren). Im Vergleich zur noch z. T. verbreiteten deutschsprachigen Tradition, in der der Demenzbegriff ausschließlich auf schwere fortgeschrittene Zustände intellektuellen Abbaus angewendet wurde, ist die moderne Definition erheblich weiter gefasst (American Psychiatric Association 1994). Die Störung kann reversibel oder irreversibel sein, muss aber das Gedächtnis betreffen und darf nicht mit einer qualitativen Bewusstseinsstörung einhergehen. Das Ausmaß der kognitiven Defizite muss zu einer individuell bedeutsamen Beeinträchtigung der Alltagsbewältigung führen und eine Verschlechterung gegenüber einem zuvor höheren Leistungsniveau darstellen.
Neurodegenerative disorders commonly increase in incidence with advancing age. These disorders broadly can be cognitive decline, such as Alzheimer's disease, vascular dementia, and Parkinson's disease; and physical decline, which may also include these disorders. Cognitive performance and nutritional status are important indications of general health and functional status in elderly persons. Nutrition and cognition are interrelated. Nutrition surveys of the elderly often indicate increased risk of malnutrition, most often subclinical deficiencies, which can impair cognition and mood. Impaired cognition and depression, in turn, decrease appetite. This chapter addresses the interrelationship of nutrition and cognition. In the broadest sense, the primary objective is to review the evidence for nutritional components as potential risk factors for cognitive decline, Alzheimer's disease, and Parkinson's disease. It also include animal studies, pathological comparisons, retrospective case-control studies, cross-sectional studies, and longitudinal studies. Evidence from clinical trials for use of specific nutritional therapies for Alzheimer's disease and Parkinson's disease is described. Finally, nutritional management issues specific for Alzheimer's disease and Parkinson's disease is examined in the chapter.
Vitamin B12 deficiency can be associated with neurological impairments and mental changes. This chapter discusses the role of vitamin B12 deficiency in the development of various neuropsychiatric symptoms such as delirium, mood disorders, psychosis, and Alzheimer's dementia. In addition, there are cases published in the literature of patients with vitamin B12 deficiency who present with frontotemporal dementia-like behavioral and dysexecutive symptoms and are reversible after treatment with vitamin B12. These mental changes may be attributed to a frontal-subcortical dysfunction secondary to different functional and structural brain damages induced by vitamin B12, folate, or homocysteine abnormal status. Further studies are needed to better identify the clinical profile of such reversible forms of dementia and the role of vitamin B12 in the underlying pathophysiological mechanisms.
Understanding the cognitive aspects of neurological disorders is essential to manage effectively patients suffering from these conditions. This book begins by outlining the various cognitive domains and how these can be tested, before covering in depth the cognitive deficits seen in prototypical neurodegenerative cognitive disorders (Alzheimer's disease, frontotemporal dementias, Huntington's disease, prionoses) and other common neurological disorders that may be complicated by cognitive impairment (stroke, multiple sclerosis, Parkinson's disease, brain tumours). This second edition has been completely revised and updated, with new material added throughout, including two new chapters: 'Sleep-Related Disorders' and 'Psychiatric Disorders in the Cognitive Function Clinic'. This an essential reference for all neurologists, not just for those with an interest in cognitive disorders. General physicians and specialists who deal with endocrine, metabolic, vascular or infective disorders that may compromise cognitive function, and allied health professionals who work with cognitively impaired patients, will also find this text useful.
Vitamin B12 (cobalamin) deficiency in the older adult occurs frequently and has the potential for serious neurological and hematological complications. Because of a myriad of discreet clinical manifestations, this disorder is often unrecognized by providers. The purpose of this article is to increase awareness of cobalamin deficiency, its causes, clinical manifestations, diagnostic work-up, and management. As primary providers, nurse practitioners should have a high degree of suspicion for at-risk populations. With early identification and treatment, cobalamin anemia has an excellent prognosis with a normal lifespan.
Among 141 consecutive patients with neuro-psychiatric abnormalities due to cobalamin deficiency, we found that 40 (28 percent) had no anemia or macrocytosis. The hematocrit was normal in 34, the mean cell volume was normal in 25, and both tests were normal in 19. Characteristic features in such patients included paresthesia, sensory loss, ataxia, dementia, and psychiatric disorders; longstanding neurologic symptoms without anemia; normal white-cell and platelet counts and serum bilirubin and lactate dehydrogenase levels; and markedly elevated serum concentrations of methylmalonic acid and total homocysteine. Serum cobalamin levels were above 150 pmol per liter (200 pg per milliliter) in 2 patients, between 75 and 150 pmol per liter (100 and 200 pg per milliliter) in 16, and below 75 pmol per liter (100 pg per milliliter) in only 22. Except for one patient who died during the first week of treatment, every patient in this group benefited from cobalamin therapy. Responses included improvement in neuropsychiatric abnormalities (39 of 39), improvement (often within the normal range) in one or more hematologic findings (36 of 39), and a decrease of more than 50 percent in levels of serum methylmalonic acid, total homocysteine, or both (31 of 31). We conclude that neuropsychiatric disorders due to cobalamin deficiency occur commonly in the absence of anemia or an elevated mean cell volume and that measurements of serum methylmalonic acid and total homocysteine both before and after treatment are useful in the diagnosis of these patients.
Purpose:
Patients with cobalamin (vitamin B12) deficiency usually lack many of the classic features of severe megaloblastic anemia; because of the low diagnostic specificity of decreased serum cobalamin levels, demonstrating the deficiency unequivocally is often difficult. We examined the sensitivity of measuring serum concentrations of methylmalonic acid and total homocysteine for diagnosing patients with clear-cut cobalamin deficiency and compared the results with those of patients with clear-cut folate deficiency.
Patients and methods:
Serum metabolites were measured for all patients seen from 1982 to 1989 at two university hospitals who met the criteria for cobalamin and folate deficiency states and for such patients seen from 1968 to 1981 from whom stored sera were available. In all, 406 patients had 434 episodes of cobalamin deficiency and 119 patients had 123 episodes of folate deficiency. Criteria for deficiency states included serum vitamin levels, hematologic and neurologic findings, and responses to therapy. Responses were documented in 97% of cobalamin-deficient patients and 76% of folate-deficient patients. Metabolite levels were measured by modified techniques using capillary-gas chromatography and mass spectrometry.
Results:
Most of the cobalamin-deficient patients had underlying pernicious anemia; two thirds were blacks or Latinos. Hematocrits were normal in 28% and mean cell volumes in 17%. Of the 434 episodes of cobalamin deficiency, 98.4% of serum methylmalonic acid levels and 95.9% of serum homocysteine levels were elevated (greater than 3 standard deviations above the mean in normal subjects). Only one patient had normal levels of both metabolites. Serum homocysteine levels were increased in 91% of the 123 episodes of folate deficiency. Methylmalonic acid was elevated in 12.2% of the folate-deficient patients; in all but one, the elevation was attributable to renal insufficiency or hypovolemia.
Conclusions:
For the cobalamin-deficient patients, measuring serum metabolite concentrations proved to be a highly sensitive test of deficiency. We conclude that normal levels of both methylmalonic acid and total homocysteine rule out clinically significant cobalamin deficiency with virtual certainty.
Routine determination of serum vitamin B12 levels is generally recommended as part of the screening of demented patients, based on the notion that vitamin B12 deficiency is one of the causes of reversible dementia. We studied the effects of vitamin B12 replacement therapy in a prospective longitudinal study at a memory clinic, with special emphasis on assessment of severity of dementia: not only cognitive deterioration, but also disability in the activities of daily life, behavioural problems, and the burden experienced by the caregiver were examined using instruments of proven validity. In a series of 170 consecutive patients with dementia, subnormal serum vitamin B12 levels were found in 26 cases (15%); all but one fulfilled diagnostic criteria for possible Alzheimer's disease. Cobalamin supplementation was given to all patients and the effect was evaluated after 6 months. When the size and pattern of individual change scores, and the mean change scores on all instruments were taken into account, functioning after replacement therapy was not improved. When change scores of treated patients were compared with those of patients with Alzheimer's disease (n = 69), vitamin B12 replacement did not result in slowing of the progression of dementia. Contrary to widely accepted beliefs, subnormal serum vitamin B12 levels are not a (quantitatively) important cause of reversible dementia.
Dementia has a reversible cause in some cases, and these should be diagnosed without over-investigating the many patients with irreversible disease. We prospectively studied the prevalence of reversible dementia in a memory clinic, determined the added value of investigations compared with clinical examination and assessed the outcome of treatment of potentially reversible causes by measuring (1) cognition, (2) disability in daily functioning, (3) behavioural changes and (4) caregiver burden. Two hundred patients aged 65 years and over were examined, using the CAMDEX-N. If they were demented, the probable cause was diagnosed clinically and confirmed or excluded by a standard set of investigations, which were done in all patients. Of the patients, 170 (mean age 79.2 years) were demented; 31 were treated for potentially reversible causes. At follow-up after 6 months, no patients showed complete reversal of dementia. Five patients improved on clinical impression, but only one on clinical measurement. Thirty patients were cognitively impaired, but not demented; seven were treated. Judged clinically, three patients improved, but on assessment only one did so; she recovered completely. Blood tests often produced diagnostic results that were not expected clinically, but electroencephalography and computed tomography of the brain did not. None of the investigations had an effect on outcome of dementia after treatment. We conclude that in elderly patients referred to a memory clinic, the prevalence of reversible dementia is of the order of 1%, if outcome after treatment is assessed by a standardized measurement. We recommend blood tests in all patients, to detect not only metabolic causes of dementia but also co-morbidity possibly worsening the dementia. Other investigations can be performed on clinical indication. Clinical evaluation remains the mainstay of diagnosis in dementia.
A case is reported of a 14 month old boy with severe dietary vitamin B-12 deficiency caused by his mother's vegan diet. Clinical, electroencephalography (EEG), and haematological findings are described. Cranial magnetic resonance imaging (MRI) showed severe frontal and frontoparietal cranial atrophy. Vitamin B-12 supplements led to a rapid improvement of haematological and neurological symptoms. Serum vitamin B-12 and urinary methylmalonate excretion were normal 10 days after treatment began. After six weeks, EEG was normal and cranial MRI after 10 weeks showed complete disappearance of all structural abnormalities. Cognitive and language development, however, remained seriously retarded at the age of 2 years. It is concluded that infantile vitamin B-12 deficiency induced by maternal vegan diets may cause lasting neurodisability even though vitamin B-12 supplementation leads to rapid resolution of cerebral atrophy and electroencephalographic abnormality.
Objective: To determine the prevalence of reversible dementia and to assess the added value of investigations for its management. Design: Prospective. Setting: Academic Medical Center, Amsterdam, the Netherlands. Methods: 200 consecutive patients of 65 and over, referred for suspected dementia to the memory clinic by general practitioners were examined; 170 (mean age: 79 years) met diagnostic criteria for dementia. The probable cause of dementia was diagnosed clinically, its severity was assessed clinimetrically, and the indications for investigations were documented. Complete investigations were then performed in all patients, and the diagnosis alter investigations was compared with the clinical diagnosis. Potentially reversible causes were treated. Outcome of treatment after 6 months was assessed clinimetrically, with regard to cognition, disability in daily functioning, behavioural changes, and caregiver burden. The added value of investigations was judged by their effects on diagnosis, treatment and outcome. Results. Potentially reversible causes of dementia were diagnosed in 33 of 170 patients; 31 patients were treated (2 had died), notably for vitamin B 12 deficiency. Complete reversal occurred in none of these patients. 5 patients improved on clinical impression, but only 1 on clinimetric assessment. Blood tests often had clinically unexpected results, with treatment implications, but chest radiographs, ECGs, EEGs and CT scans of the brain did not. None of the investigations had effect on the outcome. Conclusions. The prevalence of reversible dementia is 0.6% (95% confidence interval: 0-3%) in elderly patients with dementia referred to a memory clinic. We recommend blood tests in all patients with dementia; other investigations can be performed on clinical indication.
To examine the effects of cobalamin repletion on cognition in elderly subjects with low serum cobalamin and evidence of cognitive dysfunction.
Time series data collected in an open trial of parenteral cobalamin therapy.
Outpatient geriatric assessment centers, inpatient geropsychiatry unit, and tertiary care university hospital.
Twenty-two subjects with low serum cobalamin (less than 150 pmol/L) and evidence of cognitive dysfunction were entered consecutively over an 8-month period of time. Eighteen subjects completed the study.
Subjects received 1000 micrograms of cyanocobalamin intramuscularly daily for 1 week, then weekly for 1 month, then monthly thereafter for a minimum of six months. OUTPATIENT MEASURE: The Mattis Dementia Rating Scale (DRS) was administered both before and at least 6 months after full cobalamin replacement therapy. The hypothesis that cognitive improvement was dependent on the duration of cognitive symptoms was formulated a posteriori.
After a minimum of 6 months of cobalamin therapy, 11 of 18 patients showed cognitive improvement. There was a striking correlation between duration of cognitive symptoms and response to therapy. Patients symptomatic for less than 12 months gained an average of twenty points on the DRS (paired t test P = 0.0076), whereas patients symptomatic greater than 12 months lost an average of three points (paired t test P = .34). Two patients symptomatic for only 3 months normalized their DRS scores, gaining 31 and 28 points, respectively.
There may be a time-limited window of opportunity for effective intervention in patients with cognitive dysfunction and low serum cobalamin.
Thirty-two studies (2889 subjects) that investigated the prevalence of the causes of dementia were critically reviewed. Particular attention was paid to potential and actual reversibility. Although dementia manifests itself primarily in old age (particularly age 75 and older), the mean age of patients for the studies that reported age data (56%) was 72.3 years. Twenty-five studies originated from secondary or tertiary centers, and four were community-based. Dementias consisted of Alzheimer disease, 56.8%; multi-infarct, 13.3%; depression, 4.5%; alcoholic, 4.2%; and drugs, 1.5%. No single other cause contributed more than 1.6% of the cases. Potentially reversible causes made up 13.2% of all cases. However, the more important question of whether patients with potentially reversible causes were followed and reversal actually seen was not always examined. In 11 studies (34%) that provided follow-up, 11% of dementias resolved, either partially (8%) or fully (3%). The commonest reversible causes were drugs, 28.2%; depression, 26.2%; and metabolic, 15.5%. Due to the presence of various biases (selection, lack of "blinded" investigators, and others) in the surveyed works, it is probable that the true incidence of reversible dementias in the community is even lower than that reported. Research implications as well as a conservative approach to the workup of a new case of dementia are offered.
Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
We set out to investigate the possible beneficial effects on cognitive function of demented patients with cobalamin deficiency after cobalamin replacement. A total of 181 consecutive, demented (DSM-III or DSM-III-R criteria and score below 24 on the Mini-Mental State Examination [MMSE]) outpatients (mean age 77.5 years) were prospectively evaluated and had their vitamin B12 level measured by radioimmunoassay. The frequency of vitamin B12 deficiency (less than 200 pg/mliter) was 25% (46 patients). Treatment outcome was obtained in 19 patients (19 of 46). Despite cobalamin replacement, 16 of 19 patients persisted in showing progressive decline during follow-up visits (3 to 24 months). The nonresponse to vitamin B12 replacement in most cases seems to reflect the presence of associated irreversible dementia or a follow-up of shorter duration in a few patients. All of the patients who showed some improvement (MMSE returned to normal values) had mild dementia with a history of less than 2 years. Thus, screening for B12 deficiency should be considered in patients with recent onset of mild mental status changes.
Cobalamin levels are frequently low in patients with dementia, but it is unclear if they represent definable deficiency and what the mechanisms are. Therefore, patients being evaluated for dementia who had low cobalamin levels but no obvious evidence of deficiency were studied hematologically, neurologically and with metabolic tests and were re-evaluated after cobalamin treatment. Abnormalities suggestive of or diagnostic for deficiency were documented in most of the 16 demented and nondemented patients. Metabolic results: 50% of patients tested had abnormal deoxyuridine suppression and 44% had increased serum methylmalonic acid and/or homocysteine levels; these test results correlated with each other. Neurologic results: 73% of patients had clinical abnormalities, primarily mild neuropathies, not attributable to other causes, 75% had electroencephalographic abnormalities, 77% had abnormal visual evoked potentials and 33% had abnormal somatosensory potentials. Metabolic and neurologic dysfunction were present together or absent together in all but 2 cases. Cobalamin therapy improved 50-100% of the various types of abnormalities, although it did not improve cognitive function in the 13 demented patients. Food-cobalamin malabsorption was found in 60% of the patients. Despite the absence of megaloblastic anemia and rarity of traditional malabsorption of free cobalamin, low cobalamin levels in demented patients frequently represent mild cobalamin deficiency and are often associated with food-cobalamin malabsorption. Perhaps most importantly, this is accompanied not only by metabolic changes but by evidence of mild neurologic dysfunction. Their frequent reversibility by cobalamin confirms that these defects indeed arise from cobalamin deficiency. Although the long-standing dementia does not improve, treating such patients with cobalamin has other concrete benefits.
Recent evidence suggests that letter and semantic category verbal fluency tasks may use different component processes of a distributed word retrieval system. We hypothesized that the retrieval of words that begin with the same letter places greater demands on frontal lobe mediated strategic search processes than on temporal lobe mediated semantic knowledge. Conversely, generation of words from the same semantic category places greater demands on semantic knowledge than on strategic search. This hypothesis was tested by requiring subjects to generate lists of words to letter and semantic cues alone and while performing an interference task. A motor sequencing task (developed by Moscovitch, Neuropsychology of Memory, pp. 5-22, 1992) was used to activate frontal regions and an object decision task was used to activate posterior temporal cortex. In support of the hypothesis, letter fluency was reduced to a greater extent by concurrent performance of the motor sequencing task than by the object decision task. The opposite interference pattern was found for semantic category fluency.
To determine whether low serum B12 levels are associated with an increased incidence of dementing illness.
Longitudinal cohort study, 5-year follow-up.
Volunteer cohort of 410 nondemented ambulatory subjects aged 75 to 85 years.
Annual serum B12 determinations and neuropsychological assessments including the Blessed Test of Information, Memory and Concentration (BIMC) and the Fuld Object Memory Evaluation (FOME). If subject met criteria for a major cognitive change (as defined by an increase of 4 or more points on the BIMC), a work-up that included CT, EEG, and neurologic assessment was performed. Clinical diagnoses were made according to established criteria.
Mean serum B12 level of entire sample was 558 pg/mL. Twenty-two subjects had low B12 levels defined as values < 150 pg/mL. Three of these 22 subjects (13.6%) became demented, compared with 57 of 388 subjects (14.7%) with higher levels. The incidence of Alzheimer disease among the low B12 group was 4.5% compared with 7.5% in the higher B12 group. The mean B12 level at time of diagnosis in subjects who did develop Alzheimer disease was 551 pg/mL. There was no evidence of hematologic disorder among the 22 subjects with low B12. Of the 3 low B12 subjects who did become demented, none responded to monthly B12 injections.
A low B12 level may not be a risk factor for dementia in general or Alzheimer disease in particular.
The influence of vitamin B12 on the activity of methionine adenosyltransferase (MAT) in postmortem brains of patients with senile dementia of the Alzheimer's type (SDAT) was investigated. In samples of cortex gyrus frontalis from SDAT patients with normal and low levels of serum B12, MAT Vmax was significantly increased by 25% and 19%, respectively. MAT Vmax from a SDAT group chronically treated with B12 was similar to controls. In contrast to cortex gyrus frontalis, no significant alterations were seen in MAT activity in nucleus caudatus. This study provides evidence that SDAT is associated with significant alterations in transmethylation mechanisms in specific regions of the brain. The relationship between blood levels of B12 and the actual status of this vitamin in the brain influencing the rates of synthesis of both methionine and SAM may, however, be far more complex and cannot be directly clarified on the basis of the present human brain results.
To determine the clinical significance of subnormal serum vitamin B12 concentration in older people by comparing the hematological, neurological, and biochemical findings in patients with subnormal serum B12 with a control group with normal B12 levels.
Clinical and laboratory assessment of hospital patients selected to represent a wide range of serum B12 levels.
Patients in the medical wards of two hospitals, one a general hospital and the other a geriatric hospital.
Ninety-four older patients, 43 with subnormal (< 150 pmol/L) and 51 with normal serum B12 concentrations.
Mini-Mental State Examination, neurological score, full blood examination, mean neutrophil lobe count; serum B12, holotranscobalamin II, total homocysteine, folate, creatinine and gastrin red folate; parietal cell antibodies, intrinsic factor antibodies.
Of all the measurements, only mean neutrophil lobe count and mean serum total homocysteine were significantly different in the low serum B12 compared with the control group. There was a significant correlation between serum B12 and homocysteine levels. Eighty-eight percent of patients in the test group compared with 76% in the control group showed at least one of the following; elevated serum total homocysteine, neutrophil hypersegmentation, or elevated MCV. This overlap was much reduced when patients with borderline values for serum B12 (150-250 pmol/L) were included in the low B12 group. Most of the older subjects had little or no B12 on transcobalamin II, irrespective of the serum B12 level.
Almost 90% of older patients with serum B12 < 150 pmol/L show evidence of tissue vitamin B12 deficiency. Deficiency becomes manifest in older patients at relatively higher concentrations of serum B12 than in younger subjects, possibly because of lower levels of holotranscobalamin II in the older patients.
Vitamin B12 de®ciency and dementia
- U G Cunha
- F L Rocha
- J M Peixoto
- M F Motto
- M T Barbosa
Cunha, U. G., Rocha, F. L., Peixoto, J. M., Motto, M. F.
and Barbosa, M. T. (1995) Vitamin B12 de®ciency and
dementia. Int. J. Geriatr. Psychiat. 7, 85±88.
Kendrick Cognitive Tests for the Elderly
- D Kendrick
- Windsor Nfer-Nelson
Kendrick, D. (1985) Kendrick Cognitive Tests for the
Elderly. NFER-NELSON, Windsor.
Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)
American Psychiatric Association (1994) Diagnostic and
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