J Nutr Health Aging

HOMOCYSTEINE AND MILD COGNITIVE IMPAIRMENT: ARE THESE THE TOOLS FOR EARLY INTERVENTION IN THE DEMENTIA SPECTRUM? Z. ANSARI Corresponding author: Dr. Zarrin Ansari, Department of Medical Services, Cipla Limited, Cipla House, Peninsula Business Park, Ganpatrao Kadam Marg, Lower Parel, Mumbai 400 013, Maharashtra, India, Phone: +91 9819131436, [email protected]; [email protected]

Abstract: Dementia, being a neurodegenerative disease, has devastating consequences not just for the ailing but also for the carers as it has a tremendous negative impact on the quality of life. The pathophysiology of dementia commences far earlier than its diagnosis. Mild cognitive impairment (MCI) is a stage prior to definite dementia. The progression from MCI to dementia is insidious with no definite demarcation, thus making diagnosis clinically difficult at an early stage. This paper attempts to throw light on the epidemiology, risk factors and the aetiopathogenesis of MCI. It further attempts to elaborate on the rate of conversion of MCI to definite dementia and the factors influencing the same. Many established as well as probable, modifiable as well as non-modifiable risk factors influence the progress of MCI to definite dementia. Homocysteine, a sulphur containing amino-acid has been identified as a probable risk factor for the dementia spectrum. Various existing clinical evidences and biological plausibility towards probable link between homocysteine and dementia are discussed in this paper. B vitamin mediated homocysteine reduction and cognitive outcomes demonstrate mixed results. This review attempts to evaluate hyperhomocysteinaemia and MCI as a brain risk marker and assess their potential for future research with a view to attempt early intervention. Key words: Mild cognitive impairment, dementia, hyperhomocysteinaemia, B vitamins, early intervention.

Introduction Cognition is a vast word encompassing all aspects of knowing. It includes awareness, reasoning, language, memory, judgement and various other aspects of intelligence. Mild cognitive impairment (MCI) is an intermediate pathological condition between normal and definite dementia. MCI is an evolving concept and is described as cognitive decline, which is proportionately greater to the patient’s age and educational background. Many terms have been used to describe the pre-dementia stage, viz. age-associated memory impairment (AAMI), age-associated cognitive decline (AACD) and cognitive impairment no dementia (CIND), with each having its own operational definition. An International Working Group defined MCI as evidence of decline over time on objective cognitive tasks and/or preserved basic activities of daily living/ minimal impairment in complex instrumental functions. For the diagnosis of MCI, the patient must not meet the criteria for the dementia syndrome (1-3). MCI has been broadly classified into two subtypes, viz. amnestic MCI (aMCI) and non-amnestic, based upon the involvement of memory function. Further, MCI is also classified based on the involvement of single domain and multiple domains of cognition, viz. language, executive function and visuo-spatial skills, with or without memory impairment. The subtypes have prognostic value with different outcomes, depending upon the involvement of the memory function (4). The aim of this paper is to throw light on the epidemiology, risk factors and the aetiopathogenesis of MCI. There are several established as well as probable, modifiable as well as nonReceived December 1, 2014 Accepted for publication January 21, 2015

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modifiable risk factors influencing the progression of MCI to definite dementia. Homocysteine, a sulphur containing aminoacid has been identified as an important factor influencing dementia progression. This paper attempts to evaluate the biological plausibility and clinical evidences available towards the same. Also, evaluated is the debatable link between B vitamin mediated homocysteine reduction and cognitive outcomes. Search strategy and selection criteria References for this review were identified by searches of Pubmed and Cochrane Library and references from relevant articles. The search terms ‘mild cognitive impairment’, ‘MCI’, ‘dementia’, ‘homocysteine’ and ‘B vitamins’ were used. The search was restricted to the English language only. The final reference list was generated on the basis of relevance to the topics covered in this review. Epidemiology of MCI A systematic review evaluating nine epidemiology studies for MCI stated the incidence rate to be 1.7–22.6% of the study population at risk. The incidence rates of MCI varied between 8.5 and 76.8 per 1,000 person-years. The incidence varied depending upon the diagnostic inclusion and exclusion criteria such as education and age of the sample population, with higher age being associated with a higher incidence of MCI. The incidence also varied depending upon the MCI subtypes. The incidence of amnestic MCI subtypes ranged between 9.9 and 40.6 per 1,000 persons-year, and the incidence of non-amnestic

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HOMOCYSTEINE, MCI: ARE THESE THE TOOLS FOR EARLY INTERVENTION IN THE DEMENTIA SPECTRUM? MCI subtypes was 28 and 36.3 per 1,000 (5). Another systematic review of 35 population-based observational studies stated the prevalence rates depending upon various operational definitions of cognitive impairment (AAMI, 3.6–38.4%; CIND, 5.1–35.9%; MCI, 3–42%; aMCI, 0.5–31.9%). The incidence rates calculated from the 13 population-based studies ranged from 8.5 to 25.9 per 1,000 person-years for aMCI and 21.5 to 71.3 per 1,000 person-years for MCI (6). Progression of MCI to definite dementia MCI is an established risk factor for the development of definite dementia. The transition from MCI to dementia is gradual and, thus, identifying the demarcations between normal, MCI and early dementia can be clinically challenging. A longitudinal 5-year follow-up study involving more than 75 patients from a community dwelling stated that in 10–15% of individuals with MCI, it evolved into Alzheimer’s disease (AD) each year. In contrast, a control group of 500 healthy individuals followed-up for 10 years had an MCI/AD conversion rate of 1–2% per year (7, 8). In a longitudinal study, 1,045 dementia-free individuals aged 75 years and above were observed for 6 years. The total lifetime conversion rate to dementia in individuals with MCI was 60–65%. The study demonstrated a non-linear progression towards dementia unlike the other studies. The proportion of participants with MCI who developed dementia was highest during the first 18 months of observation (between 14% and 23%). At further follow-up, the progression rate reduced to about 10 % per year (9). A naturalistic, longitudinal, observational study of 211 individuals with MCI and 587 without any cognitive impairment demonstrated that at 4.5 years, 34% of individuals with MCI developed AD versus only 7% of individuals without cognitive impairment. The study demonstrated that MCI patients were 3.2 times more likely to develop AD versus those without cognitive impairment (10). Twenty-one individuals with isolated memory loss from a cohort of 811 individuals with cognitive complaints were observed for a mean of 48 months versus a comparison group with newly identified cognitive complaints without dementia or isolated memory loss who were followed-up for a mean of 31 months. During follow-up, 10 patients (48%) who initially had isolated memory loss became demented versus 18% in the comparator group. Thus, individuals with early memory impairment are more likely to convert to dementia as compared to those with no memory complaints in patients with cognitive impairment (11). Aetio-Pathophysiology and risk factors The aetiology of MCI/dementia can range from degenerative to vascular to metabolic, traumatic and psychiatric causes. Extensive research has implicated that the pathophysiology 2

of MCI includes cholinergic dysfunction, white-matter lesions, cerebral infarction, extracellular amyloid deposition and neurofibrillary tangle formation. Risk factors for MCI and definite dementia can be divided into modifiable and non-modifiable. However, the pathogenesis of the dementia spectrum is multifactorial and is an outcome of the interaction of both modifiable and non-modifiable risk factors. Hereditary risk factors such as APOE ε4 allele status, amyloid precursor protein gene mutation and advancing age are amongst the nonmodifiable risk factors for the dementia spectrum (12-15) The cerebrovascular risk factors are under-represented in the pathogenesis of cognitive impairments. Cerebrovascular factors, viz. hypertension, diabetes mellitus, cerebral microbleeds and cerebral infarctions are found to be causally associated with the dementia spectrum (16-18). The aforementioned factors are ‘relatively modifiable’ and it is known that after a particular stage in their pathogenesis, they remain unchanged and persistent. Mixed dementia is an increasingly popular concept defined as a co-existence of Alzheimer’s pathology and vascular pathology, leading to the dementia spectrum. It is a well-known fact that cerebrovascular pathology and MCI are prevalent in the elderly population and progresses as age advances (19). A brain imaging study was done in four groups of patients, viz. 10 patients with aMCI, 11 with mild AD, 17 with moderate AD, and 15 with severe AD. Both MCI and AD patients had whitematter lesions in the periventricular and subcortical region, which correlated significantly with advancing age and severity of dementia (20). A community dwelling sample of 3301 individuals (>65 years of age) underwent MRI scanning for white-matter lesions. White-matter findings were significantly associated with age, silent stroke, hypertension, FEV1 (forced expiratory volume in 1 second) income and impaired cognitive function (21). In the Rotterdam Study, 111 subjects from the general population aged 65–85 years were studied for white-matter lesions, classic cardiovascular factors, thrombogenic risk factors and cognitive functions. Twenty-seven percent of subjects had white matter lesions and the prevalence and severity increased with age. The authors stated that whitematter lesions tended to be associated with lower scores on tests of cognitive function and were significantly associated with subjective mental decline. It was also stated that classic cardiovascular risk factors, as well as thrombogenic factors, were associated with white-matter lesions and that these lesions may be related to cognitive function (22). Homocysteine as a modifiable risk factor: Clinical evidence Homocysteine is a sulphur-containing amino acid formed during the metabolism of methionine, an essential amino acid in the methylation cycle. Vitamin B6 and vitamin B12 serve as cofactors for the enzymes, whereas folate forms a substrate during methylation. Deficiency of B vitamins and

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THE JOURNAL OF NUTRITION, HEALTH & AGING© folate can result in high levels of homocysteine (23, 24). Homocysteine has been implicated as a risk factor for cerebrovascular and cardiovascular pathology. It has been reported that homocysteine serves as an independent risk factor for recurrent stroke (25). A meta-analysis concluded that lowering homocysteine concentrations by 3 µmol/l from current levels (achievable by increasing folic acid intake) would reduce the risk of ischaemic heart disease by 16% (11 –20%), deep vein thrombosis by 25% (8–38%), and stroke by 24% (15–33%) (26). The association of homocysteine and cognitive impairment has been demonstrated in various studies previously published (27). A study investigated the connection between homocysteine levels and the development of AD in patients with MCI. The analyses included 136 men and women in the ratio of 1:1. Within a period of 3 years, 26% of men and 36% of women converted to AD. The total percentage of men and women converting to AD was 31%. There was a statistically significant difference between the conversion rates in individuals with high versus low homocysteine levels. Forty-five percent of women with homocysteine >16 µmol/L converted to AD, whereas, 21% of women with homocysteine 20 µmol/L developed AD, whereas, none of the men with homocysteine levels below 17 µmol/L converted to AD. The study concluded that there is a possible protective effect of low/normal homocysteine levels on dementia conversion in MCI patients (28). A total of 1,092 subjects without dementia from the Framingham study were followed-up for 8 years. Dementia developed in 111 subjects, including 83 who were given a diagnosis of AD. Hyperhomocysteinaemia (plasma homocysteine >14 µmol per litre) was correspondingly associated with an increased risk of dementia and AD. An increase in the plasma homocysteine level by 5 µmol per litre increased the risk of AD by 40%. With the plasma homocysteine level >14 µmol per litre, the risk of AD nearly doubled. The authors commented, “The magnitude of this effect is similar to the magnitude of the increases in the risks of death from cardiovascular causes and stroke associated with a similar increment in the plasma homocysteine level, which have been previously described in the Frahmingham cohort” (29). A study in a Korean population of 1,215 elderly subjects (aged 60–85 years) demonstrated that mean plasma homocysteine concentrations were significantly higher in elderly subjects with MCI (17.6 ± 7.4 µmol/L) than in the elderly with normal cognition (15.7±4.8 µmol/L). The difference was statistically significant. Subjects with hyperhomocysteinaemia (>15 µmol per litre) had a higher prevalence of MCI than individuals with homocysteine within normal levels, the risk being 2 fold greater in the Korean population (30). Homocysteine-predicted cognitive scores and rate of cognitive, as measured by the MMSE (Mini Mental Status

Examinination) and ADAS (Alzheimer’s Disease Assessment Scale) Cognitive Subscale, declined independent of age, sex, education, renal function, B vitamins status, smoking and hypertension in 32 healthy elderly individuals when followedup for 5 years. In one subject with the second highest baseline homocysteine levels, probable AD had developed at follow-up. The authors concluded that homocysteine is an independent predictor of cognitive decline in healthy elderly individuals and it appears to exert the maximal effect on spatial copying skills (31). Three twenty one ageing men from the Veterans Affairs Normative Aging Study were followed up for 3 years to assess the changes in cognitive measure and the influence of baseline homocysteine, folate, vitamin B12, and B6. High homocysteine was associated with a decline in recall memory. Folate was protective against decline in constructional praxis and verbal fluency. The authors concluded that low B vitamins and high homocysteine concentrations predict cognitive decline (32). Homocysteine as a modifiable risk factor: Biological plausibility Homocysteine has been postulated to impair cognition by various vascular and/or degenerative mechanisms. The vascular mechanisms described are endothelial damage, platelet activation, endothelial-leucocyte interactions and oxidative modification of low-density lipoproteins. These factors are responsible for oxidative stress-mediated cellular toxicity. A pivotal mechanism is via causing atherosclerosis and/or microvascular damage, leading to microinfarcts and microbleeds (33, 34). Healthy older individuals have reported central brain atrophy relating to homocysteine levels in the blood, suggesting direct and indirect mechanisms associated with homocysteine and cerebral damage. Stroke patients have demonstrated white matter hyperintensities associated with plasma homocysteine. Regression analysis have shown that homocysteine effect on cognition was possibly mediated through stroke number and volume (35). Homocysteine is known to be toxic to neurons by various mechanisms. It may exert its effect by nitric oxide-mediated direct toxicity. Homocysteine is an endogenous glutamatereceptor agonist that is prone to act on the N-methyl-Daspartate (NMDA) receptor subtype. Homocysteic acid, which is an oxidative product of homocysteine, is produced by neuronal cells in response to excitatory stimulus. Excitation of the NMDA receptors results in calcium influx. Excess of calcium influx results in neuronal toxicity and resultant apoptosis and death of the neuronal cell (36). Apart from NMDA-mediated cytotoxicity, homocysteine stimulates the cells by activating group I metabotrophic glutamate receptors, resulting in a deleterious cascade of reaction (37). Homocysteine can itself undergo auto-oxidation, thus resulting in the production of reactive oxygen species that raise the oxidative stress, thereby leading to direct toxicity (38). Interactions between homocysteine and factors such as 3

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HOMOCYSTEINE, MCI: ARE THESE THE TOOLS FOR EARLY INTERVENTION IN THE DEMENTIA SPECTRUM? the ApoE ε4 genotype, an established risk factor for the development of AD, have been reviewed in previous publications (39). A cohort of 911 dementia- and strokefree elderly was stratified into an ApoE ε4 genotype and no-ApoE ε4 genotype. Plasma homocysteine was inversely correlated to cognitive performance in both the ApoE ε4 and no-ApoE ε4 genotypes, though the magnitude of association was higher for the ApoE ε4 genotype. When adjusted for cardiovascular disease risk factor and B vitamins, the higher magnitude of associations between plasma homocysteine and cognitive performance within the ApoE ε4 genotype persisted, but the association of homocysteine and cognitive performance was attenuated and no longer significant in the no-ApoE ε4 genotype (40). The study implicated that the impairment of cognition due to hyperhomocysteinaemia could be worsened in people with the ApoE genotype. Plasma beta-amyloid protein (Aβ) levels have been positively correlated to homocysteine levels in patients with neurodegenerative diseases such as AD, Parkinson’s disease and MCI. Homocysteine is known to exacerbate the beta-amyloid pathology, tau pathology, and cognitive deficit in preclinical models of AD (41, 42). As a marker of direct toxicity, plasma homocysteine levels have demonstrated a significant association with hippocampal volume even after controlling other risk factors, viz. the degree of global cerebral beta-amyloid deposition, vascular burden, age, gender, education and the APOE ε4 genotype (43).

High homocysteine levels at baseline (> 11 µmol/L) correlated with higher atrophy rate, however, was decelerated by B vitamins (45). The study by Jager et al. demonstrated a significant decrease in the decline of cognitive and clinical outcomes in the B vitamins treatment arm versus the placebo arm of people with MCI, particularly in those with elevated homocysteine levels. The mean plasma total homocysteine was 30% lower in patients treated with B vitamins as compared to placebo. There was stabilization of executive functioning as compared to placebo. On specific cognitive domain analysis, there was significant improvement in global cognition, episodic memory and semantic memory in patients with homocysteine levels >11.3 µmol/L (46). Results from a middle-European cohort of the Vienna Transdanube Aging Study (VITA) supports the administration of folate and vitamin B12 for one year in 141 MCI persons (>75 years of age) with respect to conversion to dementia. After 5 years of follow-up, 83 patients with MCI were investigated. Serum levels of folate and vitamin B12 were 116% and 19% higher, respectively, in those who reportedly took supplementary B vitamins. Homocysteine levels were significantly lower by 27% as compared to baseline; this was designated to the intake of vitamins. Conversion rate to dementia at 5 years was 20% in people who took both vitamin B12 and folate, whereas the conversion rate amongst non-users was almost 63%. Though baseline homocysteine levels were not significantly associated with conversion to dementia, higher serum level of homocysteine at baseline predicted higher rates of global brain atrophy at 5 years of follow-up. Higher rates of folate at baseline predicted lower conversion rates to dementia and lower atrophy of medial temporal lobes (47). In the FACIT trial, the effect of 3-year folic acid supplementation on cognitive function in older adults was assessed in a randomized, double-blind, controlled method. Serum folate concentrations was increased by 576% and plasma homocysteine concentrations decreased by 26% in participants taking folic acid compared with those taking placebo. Folic acid supplementation significantly improved information processing speed, memory and sensorimotor speed versus placebo (48). Increase in the albumin ratio indicating BBB dysfunction is an important pathophysiological marker of vascular dementia. In another trial, vitamin B12-B6-folate treatment demonstrated improvement in the function of the blood-brain barrier (BBB) in patients with mild cognitive impairment and hyperhomocysteinaemia. The patients demonstrated improved albumin ratio, which suggests tightening of the BBB (49, 50). The use of B vitamins for cognitive improvement has never been free of controversy. Various trials and meta-analysis have demonstrated negative or equivocal results. A meta-analysis combining the data of from 11 trials in 22,000 participants reported no significant effect of homocysteine-lowering due to B vitamins on individual cognitive or global functioning (51).

B Vitamins-Mediated homocysteine reduction and cognitive outcomes Analysis of 1160 adult survivors from the original Framingham Heart Study cohort demonstrated that inadequate plasma concentration of one or more B vitamins contributed to 67% of cases of high homocysteine (23). There have been studies supporting as well as refuting the concept of B vitamins-mediated prevention of cognitive deterioration in patients with MCI. The VITACOG study evaluated whether supplementation of high-dose vitamins that lower the homocysteine level can slow the rate of brain atrophy in elderly (>70 years of age) people with MCI. The study randomized 168 participants to an active group and a placebo group. The active group was treated with folic acid (0.8 mg/day), vitamin B12 (0.5 mg/day) and vitamin B6 (20 mg/day) for 24 months. There was a difference of 32% in the homocysteine levels of the active treatment group versus the placebo group, with placebo being on the higher side. The rate of atrophy was significantly lesser by 30% in the active treatment group versus the placebo group. The reduction in the rate of brain atrophy was highest (by 53%) in those patients with the highest tertiles of homocysteine (>13 µmol/L) (44). Another morphologic study demonstrated that high dose of B vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) decelerated the shrinkage of AD specific grey matter region including the median temporal lobe, over a period of 2 years. 4

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THE JOURNAL OF NUTRITION, HEALTH & AGING© In the VITATOP (VITAmins TO Prevent Stroke) trial, daily supplementation with folic acid and B vitamins in cognitively unimpaired patients with previous stroke or transient ischaemic attack lowered mean homocysteine levels but had no effect on the incidence of cognitive impairment as measured by the MMSE scale during a median of 2.8 years (52). A total of 409 participants with mild-to-moderate AD were randomly assigned with daily high-dose supplements of folate 5 mg, vitamin B6 25 mg and vitamin B12 1 mg versus identical placebo. This regimen did not demonstrate slowing of cognitive decline in patients with established AD (53). A recently published multicentre, double-blind trial randomized 2,919 people (>65 years) with normal cognition and homocysteine levels between 12 and 50 µmol/L to receive B vitamins and placebo. In the intention-to-treat analysis, both treatment groups improved performance on episodic memory and executive function after 2 years, but no effect of B-vitamin treatment was observed. The MMSE score decreased slightly in the B vitamin group than in the placebo. The difference though slight was statistically significant. The authors attributed this difference to chance (54).

(52, 54). Most importantly, long-term interventions are required to capture gradual changes associated with cognitive decline. Thus, short-term studies are unlikely to demonstrate benefits. The threshold level of homocysteine has played a vital role in B vitamin interventional trials, with positive responses demonstrated at higher homocysteine levels (>11.3 and 13 µmol/L) (44, 45). Studies not demarcating homocysteine levels are unlikely to capture the threshold effects of the same (5254). There is a probability that homocysteine reduction aided by B vitamins can serve as a potential intervention for the prevention of dementia progression. This is an attractive aspect for future evaluation. This possibility can raise further pragmatic questions such as whether homocysteine measurement should be incorporated in the routine cerebrovascular clinical tools for the outcome of MCI/ dementia, what should be the likely duration of B vitamins intervention, cost-effectiveness, and the post-intervention follow-up. Conflict of interest: Dr. Zarrin Ansari is an employee of Cipla Limited. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

Discussion The onset of dementia is insidious and the pathophysiology is multifactorial. It could be neurodegenerative changes in the ageing brain, already made vulnerable by genetic factors and accelerated by environmental factors. The transition from MCI to definite dementia does not have any demarcations and, thus, the diagnosis at a clinically inconspicuous stage may be missed. Recognizing the patient at the stage of MCI could serve as a window of opportunity for therapeutic intervention (1-22). The evidences available establish a probable link between homocysteine levels and cognitive impairment (23-32). Whether, homocysteine can serve as a biomarker and a likely predictor of dementia needs to be evaluated further in welldesigned clinical trials. B vitamins-mediated reduction in homocysteine and consequent improvement in cognition is an issue that has long been in the grey zone since, in several published clinical trials, the influence seen has been positive as well as negative (45-54). The results of the trials must be interpreted cautiously as there are numerous factors responsible for the equivocal response of B vitamins for cognitive improvement. The trial was not designed to measure cognitive improvement as primary outcome (52, 54). Insensitive scales do not measure domain specific improvements, viz. executive functioning, speed processing, constructional praxis, fine motor speed, verbal memory, episodic and semantic memory, thereby, yielding negative results for global domains (51, 52, 54). Trials performed in countries with folic acid fortification program are likely to yield equivocal results. The inclusion criteria of patients either being normal or having definite dementia influences the results of the studies, with patients with no cognitive impairment unlikely to show any positive findings

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Homocysteine and Mild Cognitive Impairment: Are These the Tools for Early Intervention in the Dementia Spectrum?

Dementia, being a neurodegenerative disease, has devastating consequences not just for the ailing but also for the carers as it has a tremendous negat...
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