International Psychogeriatrics (2012), 24:4, 541–556 C
International Psychogeriatric Association 2012
Cognitive impairment and vitamin B12: a review
Eileen Moore,1Alastair Mander,2David Ames,3Ross Carne,4Kerrie Sanders5
and David Watters6
1Department of Psychiatry, The University of Melbourne, Department of Surgery, The Geelong Hospital, Barwon Health, Geelong, Victor ia, Australia
2Barwon Health, Geelong, Victoria, Australia
3National Ageing Research Institute (NARI), The University of Melbourne, Royal Melbourne Hospital, Melbourne, Victoria, Australia
4Geelong Clinical School, Deakin University, Department of Neurosciences, The Geelong Hospital, Barwon Health, Geelong, Victoria, Australia
5NorthWest Academic Centre, The University of Melbourne, Department of Medicine, Western Health, St Albans, Victoria, Australia
6Department of Surgery, Deakin University, The Geelong Hospital, Barwon Health, Geelong, Victoria, Australia
Background: This review examines the associations between low vitamin B12 levels, neurodegenerative disease,
and cognitive impairment. The potential impact of comorbidities and medications associated with vitamin
B12 derangements were also investigated. In addition, we reviewed the evidence as to whether vitamin B12
therapy is efﬁcacious for cognitive impairment and dementia.
Methods: A systematic literature search identiﬁed 43 studies investigating the association of vitamin B12 and
cognitive impairment or dementia. Seventeen studies reported on the efﬁcacy of vitamin B12 therapy for these
Results: Vitamin B12 levels in the subclinical low-normal range (<250 ρmol/L) are associated with Alzheimer’s
disease, vascular dementia, and Parkinson’s disease. Vegetarianism and metformin use contribute to depressed
vitamin B12 levels and may independently increase the risk for cognitive impairment. Vitamin B12 deﬁciency
(<150 ρmol/L) is associated with cognitive impairment. Vitamin B12 supplements administered orally or
parenterally at high dose (1 mg daily) were effective in correcting biochemical deﬁciency, but improved
cognition only in patients with pre-existing vitamin B12 deﬁciency (serum vitamin B12 levels <150 ρmol/L
or serum homocysteine levels >19.9 μmol/L).
Conclusion: Low serum vitamin B12 levels are associated with neurodegenerative disease and cognitive
impairment. There is a small subset of dementias that are reversible with vitamin B12 therapy and this
treatment is inexpensive and safe. Vitamin B12 therapy does not improve cognition in patients without pre-
existing deﬁciency. There is a need for large, well-resourced clinical trials to close the gaps in our current
understanding of the nature of the associations of vitamin B12 insufﬁciency and neurodegenerative disease.
Key words: dementia, Alzheimer’s disease (AD), cognitive disorders, molecular biology, aging
Dementia is an umbrella term used to describe
over 100 conditions, of which Alzheimer’s disease
(AD) is the most common. Alzheimer’s Disease
International estimated that there were over 35
million people with dementia worldwide in 2010
(Wimo and Prince, 2010). This number is predicted
to double every 20 years (Ferri et al., 2005) placing
Correspondence should be addressed to: Eileen Mary Moore, Depar tment of
Surgery, Barwon Health, The Geelong Hospital, PO Box 281, Geelong,
Victoria 3220, Australia. Phone: +61 352267899; Fax: +61 352267019. Email:
firstname.lastname@example.org, email@example.com. Re-
ceived 4 Jul 2011; revision requested 29 Aug 2011; revised version received 2
Oct 2011; accepted 7 Nov 2011.
enormous pressure on healthcare resources. Yet,
dementia is not a normal part of aging so there is
considerable interest in preventing or delaying the
onset of this syndrome.
The criteria for diagnosing AD, which affects
between 60% and 80% of those with dementia
(Alzheimer’s Association, 2011), was ﬁrst proposed
in 1984 by the National Institute of Neurolo-
gical and Communicative Disorders and Stroke
(NINCDS) and the Alzheimer’s Disease and
Related Disorders Association (ADRDA). Memory,
language, orientation, problem solving, perceptual
skills, attention, and functional abilities may all be
affected in AD according to the NINCDS-ADRDA
criteria. Without any cure, the aim of the current
treatment is palliative maintenance of cognition to
542 E. M. Moore et al.
limit the severity of the resultant disability on the
patient and the burden on their caregiver.
Petersen described a clinically distinct patient
subpopulation with “mild cognitive impairment”
(MCI) (Petersen et al., 1999) which experience
memory complaints beyond those expected for their
age (amnestic MCI) or other cognitive deﬁcits
(single nonmemory and multidomain MCI). Each
of the MCI subtypes have recently been shown to
accompany a loss of functional ability (Ames et al.,
2010). MCI cases convert to AD at an increased
rate of up to 15% per year, whereas conversion to
AD is just 1% in those aged over 65 years. There-
fore, MCI may be an early disease stage where inter-
vention to prevent or delay dementia may be most
Vitamin B12 metabolism
Vitamin B12 is a term used to describe a group
of molecules having in common a corrin ring
structure and central cobalt atom. This vitamin
is a cofactor in two reactions, namely (1) the
regeneration of methionine (required in methylation
and DNA synthesis) from homocysteine; and (2)
the rearrangement of methylmalonic acid (MMA),
an organic acid which has neurotoxic properties in
cell culture (Okun et al., 2002), to succinyl-CoA (an
intermediate in the citric acid cycle).
Vitamin B12 storage and distribution
More than 80% of serum vitamin B12 is stored
bound to the glycoprotein haptocorrin (also known
as transcobalamin-I), a blood transport protein that
is available only to storage liver cells. Less than
20% of serum vitamin B12 is stored bound to
transcobalamin-II (TC-II), which is available to
all cells of the body that undergo DNA synthesis.
Holotranscobalamin (B12:TC-II) has a very short
half-life of just six minutes in circulation; thus
holotranscobalamin levels are an early indicator of
vitamin B12 deﬁciency (Herbert, 1994).
A diet in which as little as 0.1 μg vitamin B12
per day is absorbed is sufﬁcient to prevent the
onset of traditional signs of vitamin B12 deﬁciency,
namely megaloblastic anemia and degeneration of
the spinal cord. A diet meeting the recommended
dietary allowance (RDA) in Australia of 2.4 μg
for an adult of either gender allows for signiﬁcant
stores of vitamin B12 in the liver and that
bound to haptocorrin in circulation. Enterohepatic
recirculation allows for vitamin B12 to be released
into the bile from the liver and reabsorbed at the
distal ileum. On reabsorption, vitamin B12 binds
TC-II for redistribution to the other tissues of the
body. Absorption of vitamin B12 at the distal ileum
is dependent upon its coupling to the intrinsic factor
released by the parietal cells in the stomach.
Risk factors for vitamin B12 deﬁciency
Those experiencing pernicious anemia (an auto-
immune reaction to either the parietal cells or
intrinsic factor) go on to develop vitamin B12
deﬁciency through malabsorption if untreated.
Patients having surgical alteration of the distal
ileum, Crohn’s disease, and using metformin
are also at an increased risk for malabsorption.
Herbert (1994) estimates that deﬁciency could
take as long as 20–30 years to develop in
persons having normal absorption/reabsorption and
suddenly ceasing to include substantial amounts of
vitamin B12 in their diet during adulthood. This
is due to the large amount of vitamin B12 that
can be stored in the body and recycled through
enterohepatic reabsorption. Deﬁciency could
develop within 1–3 years in those experiencing
Prevalence of vitamin B12 deﬁciency
Vitamin B12 deﬁciency has been deﬁned as serum
vitamin B12 levels below a clinical cut-off falling
in the range of 100–150 ρmol/L (McLean et al.,
2008). McLean et al. (2008) also deﬁned a “high
threshold” for vitamin B12 insufﬁciency at between
200 and 250 ρmol/L; which was used in a
quarter of the 127 studies that these researchers
Vitamin B12 deﬁciency is common in school-
age children, pregnant women, and the elderly but
is not associated with geographical location or level
of economic development. Prevalence of deﬁciency
may be as high as 49% in India, which is possibly
related to widespread vegetarianism. In Finland,
6.1% of community-dwelling over-65-year olds are
deﬁcient (Loikas et al., 2007); 7.8% are deﬁcient in
Israel (Figlin et al., 2003); and 15.3% are deﬁcient
in Canada (Garcia et al., 2002). In China, 19.7% of
over-60-year olds are deﬁcient (Wang et al., 2009)
and up to 24.8% of 74–80-year olds living in The
Netherlands may be deﬁcient (van Asselt et al.,
Subclinical low-normal serum vitamin B12 levels
(150–250 ρmol/L) fall between the lower reference
value and the “high threshold”. The traditional
signs of vitamin B12 deﬁciency are not commonly
reported with subclinical low-normal vitamin B12
levels. Nonetheless, there is considerable interest
in investigating whether subclinical low-normal
vitamin B12 levels contribute to cognitive decline.
Cognitive impairment and vitamin B12: a review 543
Vitamin B12 deﬁciency and
Deﬁciency of vitamin B12 has long been implicated
in the pathogenesis of megaloblastic anemia and
subacute combined degeneration of the spinal
cord (Lanska, 2009). Commercial preparations of
vitamin B12 replaced concentrated liver extracts
in the 1950s for correcting pernicious anemia and
were effective in preventing further degeneration
of the spinal cord and cognitive decline in almost
all of 36 cases (Brewerton and Asher, 1952).
Cognitive decline, neuropathy, myelopathy, and
sensory neuropathy have also been associated with
deﬁciency (Aaron et al., 2005; Gadoth et al., 2006).
Elevated serum or urine homocysteine or MMA
levels are markers for vitamin B12 deﬁciency.
Hyperhomocysteinemia has been associated with
cardiovascular disease (Redeen et al., 2009) and
Alzheimer’s disease (Annerbo et al., 2009; Siuda
et al., 2009). A postulated mechanism of disease
may also be through overstimulation of the N-
methyl-D-aspartate (NMDA) receptor; causing
neuronal cell death through an inﬂux of calcium
ions and oxidative stress (Lipton et al., 1997).
Methylmalonic acid may have a direct neurotoxic
affect as an organic acid causing dysfunctional
myelination (Okun et al., 2002). Therefore, vitamin
B12 insufﬁciency, leading to elevated homocysteine
and MMA levels, may possibly be a preventable
cause of neurodegenerative disease.
If low vitamin B12 levels contribute to dementia,
there may be an opportunity for treatment or
prophylaxis of “at risk” groups in earlier decades.
This review will explore the role of vitamin B12
insufﬁciency in cognitive impairment and dementia
by identifying studies in the literature that address
the following questions:
1. Is vitamin B12 associated with neurodegenerative
2. Is a low or low-normal vitamin B12 level associated
with cognitive impairment?
3. What medical conditions or treatments are
associated with vitamin B12 derangements and
4. Can vitamin B12 treatment reverse or arrest
cognitive impairment or dementia?
A search of Medline (ISI), PsychINFO (CSA), and
PubMed databases was undertaken using the key
words: “(vitamin B12 AND cognit∗) OR (vitamin
B12 AND dementia)” in March 2011. This search
returned 460 items in Medline (ISI), 683 items
in PsychINFO (CSA), and 783 items in PubMed.
These items were initially screened by title and
year for articles that potentially addressed the
research questions and that were published after
1995. This cut-off was applied because clinical
deﬁnitions and laboratory methodologies change
over time; however, articles published prior to 1995
were also included for historical reference. For
the purpose of this review, vitamin B12 deﬁciency
was deﬁned as a serum vitamin B12 measurement
<150 ρmol/L, whereas a subclinical low-normal
vitamin B12 level was deﬁned as falling in the range
Articles not reporting original research were
screened out at this initial stage. Case reports
(n=6), observational/case-control studies (n=43),
intervention studies (n=8), placebo-controlled
studies (n=9), meta-analysis/literature reviews (n=
8), in vitro/cell culture and studies in animal models
(n=4), and instructional/clinical handbooks (n=2)
were retained if written in English (n=78)orifan
English translation was readily available (n=2).
Studies relying on food frequency question-
naires/nutrient intake reports, rather than meas-
urement of biochemical markers, were excluded
(n=9). Articles reporting on studies and clinical
trials were scrutinized for relevance, use of
protocols, and clinical deﬁnitions for cognitive
impairment, dementia, and vitamin B12 deﬁciency.
Fourteen intervention studies were excluded for the
•intervention involving a vitamin B12 supplement
in combination with commercial or experimental
antidementia drugs (n=2),
•the supplement used or the length of the
intervention or follow-up periods were not
•treatment and control or placebo groups were
poorly matched with respect to age or baseline
vitamin B12 or homocysteine levels, or cognitive
test scores (n=3),
•the sample size was too small to see an effect
•intervention studies with folate and vitamin B12
were included due to their similar biochemical
pathways, whereas combination therapies with
other nutrients or “nutriceuticals” were excluded
Studies that were of a similar type and addressed
the same research question were grouped for
discussion, allowing for duplication. Forty-three
studies were identiﬁed investigating the association
of vitamin B12 and cognitive impairment or
dementia. Seventeen intervention studies reported
on the efﬁcacy of vitamin B12 therapy.
Is vitamin B12 associated with
Most observational studies investigating the associ-
ation of vitamin B12 levels with neurodegenerative
544 E. M. Moore et al.
Table 1. Is vitamin B12 associated with Alzheimer’s disease?
(ρmol/L) FINDINGS p-VA LU E
Prevalent Alzheimer’s disease
(Malaguarnera et al., 2004)
Italy, aged 55–92 years
22 392 ±65.32 24b438.6 ±61.62 <0.021
Prevalent Alzheimer’s disease
(Clarke et al., 1998) England, aged
76a215 ±79 108c253 ±100 <0.05
Prevalent Alzheimer’s disease
(Koseoglu and Karaman, 2007)
Turkey, aged 69–88 years
51 280.6 ±20.86 40d389.7 ±20.86 <0.001
Incident Alzheimer’s disease
(Wang et al., 2001) e
Sweden, aged >75 years
60 <250 310 >250 Twofold increased risk (95% CI:
1.2–4.1, p-value <0.05) of
incident AD over 3 years
Incident dementia (Kim et al.,
2008a) fSouth Korea,
aged >65 years
45 372.6 ±164.7 473 381.5 ±147.7 Risk of developing dementia was
not signiﬁcantly different (p-value
0.483) after two years
aAD conﬁrmed by histology at autopsy.
bHealthy controls, matched by age, level of education, and nutritional and socioeconomic status.
cHealthy controls, comparable by age, gender, and smoking status.
dHealthy controls, comparable by age and nutritional status.
eCommunity-dwelling, healthy volunteers aged 75 years and above.
fCommunity-dwelling, healthy volunteers aged 65 years and above.
disease have compared AD patients to healthy
controls (Table 1) because AD accounts for
between 60%–80% of all reported dementia cases
(Alzheimer’s Association, 2011).
Serum vitamin B12 levels <250 ρmol/L were
associated with a twofold increased risk for incident
AD within three years in those aged 75 years
andoverinSweden(Wanget al., 2001). Vitamin
B12 levels were also signiﬁcantly lower in AD
patients compared with healthy controls in 69–88-
year olds living in Turkey (Koseoglu and Karaman,
2007); and in over-55-year olds living in Italy
(Malaguarnera et al., 2004) and in Oxford, UK
(Clarke et al., 1998). This association was not
conﬁrmed in a large study in over-65-year olds living
in South Korea (Kim et al., 2008a). It is noteworthy
that vitamin B12 levels associated with AD were in
the subclinical low-normal range in four of the ﬁve
The association of non-Alzheimer-type
dementias with low-normal vitamin B12
The association of neurodegenerative disease with
subclinical low-normal vitamin B12 levels is not
conﬁned to AD. Mean serum vitamin B12 levels
were similarly low but within the reference range
in vascular dementia patients (169 ±5.36 ρmol/L,
versus healthy controls 389.7 ±20.86 ρmol/L;
p-value <0.001) (Koseoglu and Karaman, 2007)
and in patients with Parkinson’s disease (216 ±
66.8 ρmol/L, versus neurological controls excluding
dementia patients, 283.5 ±114.4 ρmol/L; p-value
<0.05) (Triantafyllou et al., 2008).
Serum vitamin B12 levels were not different
between epileptic and non-epileptic patients
(Gorgone et al., 2009), nor in autistic versus
non-autistic children (Pasca et al., 2008). This
review has not identiﬁed any studies of vitamin
B12 levels in Huntington’s disease, frontotemporal
dementia (FTD), or dementia with Lewy bodies.
Subclinical low-normal serum vitamin B12 levels
(<308 ρmol/L) were associated with a faster rate of
brain volume loss in one study of 107 community-
dwelling elderly (p-value 0.003) (Vogiatzoglou et al.,
2008). A large study of 1,102 over-60-year olds
also revealed an association between vitamin B12
deﬁciency (<148 ρmol/L) and white matter lesions
(p-value 0.001) (de Lau et al., 2009).
Vitamin B12 deﬁciency precedes
We identiﬁed just one longitudinal study in which
a large sample (n=1,648) was followed over an
extended time (ten years); their data conﬁrmed that
vitamin B12 deﬁciency (<150 ρmol/L) preceded
Cognitive impairment and vitamin B12: a review 545
a decline in cognition as measured by the Mini-
Mental State Examination (MMSE) in those aged
65 years and over (Clarke et al., 2007). This
study does not demonstrate that vitamin B12
deﬁciency caused cognitive decline; possibly those
experiencing vitamin B12 deﬁciency had a faster
rate of cognitive decline compared to those not
Is a low or low-normal vitamin B12 level
associated with mild cognitive impairment?
Siuda et al. (2009) compared 55 cases of MCI
(Petersen criteria) with 44 age-, gender-, and
education-matched healthy controls; they found
that MCI patients had a lower mean serum vitamin
B12 level (338.35 ±213.8 ρmol/L versus 396.79 ±
122.3 ρmol/L; p-value 0.0012) (Siuda et al., 2009).
No other studies were identiﬁed in which vitamin
B12 levels were compared between MCI cases and
Vitamin B12 deﬁciency and cognitive
impairment in AD
In one study, low serum vitamin B12 levels <147.6
ρmol/L were associated with lower MMSE scores
in AD patients (14.7 ±7.3 versus 16.9 ±5.7,
n=643; p-value <0.01) (Whyte et al., 2002), albeit
the patients with low serum vitamin B12 levels were
also older (p-value 0.01).
Stuerenburg et al. (2004) also report an
association between cognitive impairment in AD
and low serum vitamin B12 levels. In their study, the
MMSE scores of 24 AD patients in the bottom tenth
percentile for vitamin B12 level (<136 ρmol/L;
MMSE 15.7 ±6.1) were signiﬁcantly lower than
MMSE scores for the 24 AD patients in the
upper tenth percentile for vitamin B12 levels
(>441 ρmol/L; MMSE 20.0 ±4.6; p-value <0.05).
Neither vitamin B12 level nor MMSE score were
associated with age in the latter study.
Vitamin B12 deﬁciency and cognitive
impairment is not conﬁned to Alzheimer’s
The association between cognitive impairment and
low serum vitamin B12 levels is not conﬁned to
AD. In one study, lower serum vitamin B12 levels
were found in 51 cognitively impaired (MMSE
<26) Parkinson’s disease patients compared with 60
non-impaired Parkinson’s disease patients (203.0 ±
90.3 ρmol/L versus 227.4 ±114.4 ρmol/L;
p-value <0.05) (Triantafyllou et al., 2008).
In a second study, 830 community-dwelling
participants aged 75 years and older were screened
for cognitive impairment (MMSE <22) and serum
vitamin B12 levels. Serum vitamin B12 levels in the
lower quartile (<157 ρmol/L) were associated with
a twofold increased risk of cognitive impairment
when compared to vitamin B12 levels in the
upper quartile (>275 ρmol/L; 95% CI: 1.11–
4.27) (Hin et al., 2006). These ﬁndings contradict
those of a longitudinal study of 499 over-70-
year olds, in which vitamin B12 levels were
neither associated with cognitive impairment at
baseline (measured by standardized cognitive
performance tests assessing memory, language,
conceptualization, and visuospatial ability) nor with
increased risk of developing dementia over a seven-
year period (Kado et al., 2005).
Vitamin B12 deﬁciency, high serum folate,
and cognitive impairment
A large US survey of cognitive impairment and
vitamin B12 levels in 1,301 community-dwelling
volunteers aged 60 years and older found that
participants with low serum vitamin B12 levels
(<148 ρmol/L) and elevated folate levels (>59
nmol/L) were four times more likely to experience
cognitive impairment (OR 4.3; 95% CI: 2.3–8.0)
than individuals with normal levels of vitamin
B12 and folate (Selhub et al., 2009). The latent
period of effect could not be determined from
this observational study. Such an association was
not conﬁrmed in a second study of comparable
size (n=1,535) and age distribution (Miller et al.,
One possible reason for the discrepancy in
results is that the Wechsler Adult Intelligence
Scale (WAIS – third edition) was used to detect
cognitive impairment in the Selhub et al. (2009)
study, whereas the MMSE was used in the Miller
study. Yet, in their original publication of the
MMSE, Folstein et al. (1975) demonstrated that the
MMSE and WAIS correlated well with respect to
measuring cognitive performance in a mixed patient
population, including dementia and psychiatric
patients. Any underlying difference between the two
instruments to detect cognitive impairment in the
general population, may explain the differing ﬁnd-
ings of Selhub et al. (2009) and Miller et al. (2009).
What medical conditions or treatments are
associated with vitamin B12 derangements
The prevalence of vitamin B12 deﬁciency increases
with age and is associated with a number of
conditions and treatments (Table 2). The main
causes of vitamin B12 deﬁciency are (1) poor
dietary intake (as in vegetarianism), (2) poor
absorption (occurring in achlorhydria, pernicious
anemia, Helicobacter pylori (H. pylori) infection,
546 E. M. Moore et al.
Table 2. Causes of vitamin B12 deﬁciency
AT RISK GROUPS
CAUSE OF VITAMIN B12
PREVALENCE OF VITAMIN B12
Achlorhydria (Andres et al., 2004) Inadequate release from food 20% of those aged above 65 years
Vegetarianism (Hokin and Butler,
Inadequate dietary intake 53% of lacto-ovo-vegetarians
Crohn’s disease (Oostenbrug et al.,
Disease or resection of the distal ileum
causing poor absorption
41.9% of patients having undergone
H.pylori infection (Kaptan et al.,
Gastritis affecting the parietal cells or
bacterial absorption of the vitamin
40% of patients having gastritis with
Metformin use (Adams et al., 1983) Malabsorption at the distal ileum due to
10%–30% of metformin users
Pernicious anemia (Andres et al.,
Malabsorption due to an autoimmune
reaction against intrinsic factor or the
15% of those aged over 65 years who
have vitamin B12 deﬁciency
Pregnancy >28 days (Ray et al.,
Hemodilution of serum vitamin B12 in
10.1% of women after 28 days pregnancy
Genetic predisposition (Huemer
et al., 2006)
Aberrant proteins involved in the
absorption, distribution, cellular
uptake, chemical re-arrangement, or
Prevalence of MTHFR 677TT
polymorphism was estimated at 10.4%
in Austrian children and adolescents
Note. There are many studies conﬁrming each cause of vitamin B12 deﬁciency. This table gives a substantive reference for each cause
Crohn’s disease, and metformin use), and (3) poor
distribution (genetic predisposition for aberrant
proteins that are inefﬁcient in transport or cellular
uptake of vitamin B12).
Vitamin B12 deﬁciency and
hyperhomocysteinemia in older age
Older age is a risk factor for neurodegenerative
disease (Profenno et al., 2009) with the risk of onset
of dementia approximately doubling each ﬁve years
after the age of 65 (Jorm et al., 1987; Di Carlo et al.,
2002). Vitamin B12 deﬁciency is also age-associated
and the conditions giving rise to deﬁciency also
increase with age, such as achlorhydria, Crohn’s
disease, pernicious anemia, and diabetes requiring
treatment with metformin.
There is also the further risk that diet deteriorates
with age; for instance, those living alone may
be less able to cook and poor teeth may also
lead to less consumption of meat. These factors
may lead to a higher risk for vitamin B12
deﬁciency and hyperhomocysteinemia. Further to
this, Serot et al. (2005) found that homocysteine
levels in cerebrospinal ﬂuid (CSF) increased with
age, independently of vitamin B12 status in 121
The Conselice Study of 1,016 over-65-year
olds living in the Italian community found that
elevated homocysteine levels (mean 14.5 μmol/L)
were associated with poorer cognitive performance
(MMSE scores 24–25 versus MMSE >28), whereas
no association between cognition and vitamin B12
levels was identiﬁed in this sample of patients
without dementia (Ravaglia et al., 2003).
The Main–Syracuse Longitudinal Study
(MSLS) similarly found that cognitive performance
in a neuropsychological battery of tests (including
visuospatial organization, scanning and tracking,
working memory, and verbal memory) was
positively correlated with vitamin B12 level and
inversely correlated with homocysteine level in 812
over-60-year olds (Elias et al., 2006).
A study in 2,096 dementia-free participants of
the Framingham Offspring Study also found an
inverse relationship between cognitive performance
and homocysteine levels, and this association was
conﬁned to those aged 60 years and over (Elias
et al., 2005). Similarly, the Northern Manhattan
Study enrolling 1,822 over-65-year olds and 1,049
under-65-year olds also found that MMSE scores
were inversely correlated with homocysteine levels
and positively correlated with vitamin B12 measure-
ments only in those aged over 65 years (Wright et al.,
There is a correlation in those aged 60 years
and over between poor cognitive performance
and elevated homocysteine levels, of which
vitamin B12 insufﬁciency is a cause. Vitamin
B12 levels are also positively correlated with
measures of cognition in some, but not all,
studies. Randomized controlled trials investigating
the efﬁcacy of vitamin B12 replacement therapy to
correct hyperhomocysteinemia and reverse or arrest
Cognitive impairment and vitamin B12: a review 547
cognitive decline in the elderly are warranted. The
duration of intervention required to adequately test
the efﬁcacy of vitamin B12 replacement therapy in
this role is difﬁcult to estimate and intervention
would need to commence before the onset of
irreversible cognitive changes.
Neurological complications of metformin use
Peripheral neuropathy is a condition common
to both diabetes and vitamin B12 deﬁciency.
Bell (2010) reported metformin-induced peripheral
neuropathy associated with vitamin B12 deﬁciency
in a 69-year-old diabetic patient of six years. In
a prospective case-control study of 122 diabetics,
metformin use for more than six months was
associated with both low serum vitamin B12
levels and peripheral neuropathy (Wile and Toth,
In cell culture, therapeutic levels of metformin
induced overexpression of the beta-site amyloid
precursor protein-cleaving enzyme 1 (BACE1)
(Chen et al., 2009). BACE1 is a component of β-
secretase, which initiates cleavage of the amyloid
precursor protein (APP) to its pathogenic form.
Pathogenic Aβpeptide may then aggregate and
deposit as amyloid plaques, which are found in
the brains of AD patients at autopsy. Metformin
use may accelerate the formation of amyloid
plaques through this mechanism. Also, in a mouse
model, BACE1-regulated myelination of nerve cells
(Willem et al., 2006) and so upregulation of its
expression, as may occur during metformin use,
may also induce dysfunctional myelination.
Can vitamin B12 treatment reverse or arrest
cognitive impairment or dementia?
Potentially reversible dementias account for only
9% of all cases; in fact, in a comprehensive meta-
analysis, only 0.6% of all dementias partially or
fully resolved (Clarﬁeld, 2003). One study found
that 25% of 181 patients meeting Diagnostic and
Statistical Manual of Mental Disorders (DSM-III
or DSM-IV) criteria for dementia were vitamin
B12 deﬁcient (with serum levels <147.6 ρmol/L).
Nineteen deﬁcient patients were followed up after
commencing vitamin B12 therapy alone, only
three of whom showed improvement of MMSE
scores to normal levels (>24) (Cunha et al., 1995).
Concordant with the ﬁndings of Clarﬁeld (2003),
only a small number of dementias were reversible
with vitamin B12 therapy, possibly because
supplements were commenced in responding
patients at an early stage before the onset of
irreversible neurodegenerative disease.
Is timing or stage of disease important for
Martin et al. (1992) found that vitamin B12 therapy
was signiﬁcantly more beneﬁcial for vitamin B12
deﬁcient patients showing cognitive dysfunction for
less than one year (gaining 24 points on the Mattis
Dementia Rating Scale, MDRS); than patients
experiencing cognitive dysfunction for more than
one year (losing three points on the MDRS; p-value
Abyad (2002) also demonstrated a time-limited
window of opportunity for successful treatment
with vitamin B12 in 56 nursing home residents
and outpatients showing cognitive dysfunction and
vitamin B12 levels <300 ρmol/L. Patients showing
neurological symptoms for less than 12 months
gained an average of six points on MMSE score
(p-value 0.0065) with six patients symptomatic
for less than six months normalizing their
MMSE score. Patients symptomatic for more than
12 months also gained an average of four points on
their MMSE score; however, this change was not
signiﬁcant (Abyad, 2002).
In single case reports, vitamin B12 treatment has
been reported to correct or alleviate schizophrenia
(Kuo et al., 2009), subacute combined degeneration
with sensory dysfunction (Puntambekar et al.,
2009), peripheral neuropathy (Bell, 2010), cere-
bellar ataxia (Gochard et al., 2009), extrapyridimal
symptoms (Akdal et al., 2008; Dogan et al., 2009),
and personality, emotional, and behavioral changes
associated with frontotemporal hypoperfusion
(Akdal et al., 2008).
Placebo-controlled trials for reversing
In each of these cases, the successful outcome
of using vitamin B12 supplements occurred when
vitamin B12 deﬁciency was detected or highly
suspected. Vitamin B12 therapy for reversing
cognitive impairment has been attempted without
success in only a small number of placebo-
controlled trials identiﬁed in this review. Of these,
only two trials had sufﬁcient numbers to detect any
effect (Table 3).
Homocysteine, a marker for vitamin B12
deﬁciency, was measured in three of the six placebo-
controlled studies. In advanced kidney disease
patients, Brady et al. (2009) found that while the
vitamin B12 intervention reduced homocysteine
levels by 26% there was no beneﬁt to cognition.
Similarly, Aisen et al. (2008) reported lowering
homocysteine levels with vitamin B12 therapy,
yet ADAS-Cog scores did not improve in AD
patients. Stott et al. (2005) also reported lowering
homocysteine levels in patients with ischemic heart
548 E. M. Moore et al.
Table 3. Can vitamin B12 treatment arrest or reverse cognitive impairment or dementia?
INDICATION B12 INTERVENTION nTREATMENT nPLACEBO
MCIa(Lehmann et al., 2003) 1 mg tablet twice daily for
over 110 days
30 35 MMSEbNo difference in MMSE
MCIa(van Uffelen et al., 2008) 0.4 mg tablet daily for
78 74 MMSE; Neuropsychiatric
No difference in MMSE. DSST
improved in women
Advanced chronic kidney disease
(CKD) (Brady et al., 2009)
2 mg tablet daily for
339 320 Telephone interview for
cognitive status (TICm)
Hcyelevels decreased by 26% from
baseline. No difference in TICm
scores between groups
Non-impaired elderly, mean age
84.9 years (Seal et al., 2002)
10 μg (low-dose) or
50 μg (high-dose) tablet
daily for one month
10 low dose/10
11 MMSE Hcyelevels did not decrease
signiﬁcantly from baseline. No
difference in MMSE scores between
Patients over-65-year olds having
ischemic heart disease (Stott et al.,
400 μg tablet daily for
23 24 Telephone interview for
cognitive status (TICm)
No difference in TICm scores between
Patients with mild-to-moderate
Alzheimer’s disease (MMSE scores
14–26) (Aisen et al., 2008)
1 mg tablet daily for
202 138 ADAS-CogdHcy levels reduced in treatment group
but ADAS-Cog scores did not
aMild cognitive impairment (MCI) diagnosed by clinical consensus (Petersen criteria).
bMini-Mental State Examination (MMSE).
cIncluding memory by the Auditory Verbal Learning Test (AVLT), executive function by the Verbal Fluency Test (VFT), information processing speed by the Digit Symbol Substitution Test
(DSST), and attention by the Abridged Stroop Color Word Test (SCWT-A).
dCognitive section of the Alzheimer’s Disease Assessment Scale (ADAS).
Cognitive impairment and vitamin B12: a review 549
disease but with no improvement in cognition
on commencing vitamin B12 therapy. The latter
placebo-controlled trial was conducted over just 12
weeks, which may be too short a time period to
detect differences in changes to cognition between
placebo and treatment groups. In another study,
vitamin B12 therapy neither lowered homocysteine
levels nor improved MMSE scores (Seal et al. 2002),
albeit using a lower dose vitamin B12 intervention
than the previous two studies and for a short period
of just one month.
In cases of deﬁciency, intervention should
be commenced at a sufﬁciently high dose and
continued over an adequate period to correct the
biochemical deﬁciency. Doses of up to 50μg daily
taken orally for one month were inadequate to
decrease homocysteine levels in the study by Seal
et al. (2002), whereas doses in excess of 1 mg
daily for 18 months did lower homocysteine levels
in the three other studies. Restoring biochemical
status to within the higher normal range may be
essential to preventing further cognitive decline
and other adverse outcomes associated with
hyperhomocysteinemia, such as cardiovascular
disease, despite the fact that cognition was not
shown to improve on commencing vitamin B12
Depression has been associated with low vitamin
B12 levels in later life (Kim et al., 2008b) and may
also affect cognitive test scores. Studies in which
an association between cognitive test scores and
vitamin B12 levels are investigated are susceptible
to confounding if participants having depression
are not identiﬁed. Of the six studies described in
Table 3, only the study by Brady and colleagues
evaluated depression in their participants and this
was achieved via the Global Depression Scale
(GDS). There is a need for more robust studies
in which participants are screened for depression
and the risk of confounding with depression
is reduced. This can be achieved by excluding
participants identiﬁed as depressed or by adjusting
statistical analyses to include depression as a
Only one of six placebo-controlled trials reported
a beneﬁt for vitamin B12 treatment, other than
a reduction of homocysteine levels. Vitamin B12
treatment was reported to improve attention and
information processing speed in women (van
Uffelen et al., 2008); no other differences between
treatment and control groups were reported.
Intervention studies in neurological patients
presenting with vitamin B12 deﬁciency
None of the placebo-controlled studies selected
for patients that were vitamin B12 deﬁcient at
baseline, the very group that would be expected
to beneﬁt the most from vitamin B12 treatment.
Selecting only patients presenting with vitamin
B12 deﬁciency might yield more positive ﬁndings;
however, withholding treatment from vitamin B12
deﬁcient patients would be unethical. Four studies
were identiﬁed in this review in which vitamin B12
treatment was evaluated in neurological patients
presenting with deﬁciency (Table 4).
Improvement in cognitive test scores was
seen in vitamin B12 deﬁcient patients who
were either mildly cognitively impaired (Kalita
and Misra, 2008) or who were more severely
cognitively impaired (Aaron et al., 2005). Vitamin
B12 therapy was equally beneﬁcial in both groups,
yielding moderate improvements in cognition when
measured by the MMSE. Cognitive test scores
failed to improve in one of the four studies
which included AD patients with relatively higher
vitamin B12 levels (up to 200 ρmol/L) at baseline.
Depression in study participants was assessed only
in the study by Kalita and Misra (by clinical
assessment) of the four studies described in Table 4.
The possibility of depression confounding cognitive
test scores and low serum vitamin B12 levels cannot
be ruled out in these studies.
Each study investigated megadoses of up to 1 mg
of vitamin B12 daily. This review has not identiﬁed
any studies in vitamin B12 deﬁcient patients
followed for more than ten months. One limitation
common to these and other studies is that it
is not possible to estimate the latent period of
exposure to low vitamin B12 levels before the
onset of symptoms. Vitamin B12 deﬁciency over a
prolonged period of time may result in irreversible
neurological complications which may not resolve
on commencing replacement therapy.
Intervention studies in non-impaired
individuals with low vitamin B12 levels
This review identiﬁed just two studies in which
vitamin B12 therapy, prescribed to improve
cognition or prevent cognitive decline, was
evaluated in vitamin B12 deﬁcient but otherwise
healthy volunteers. In one study, participants were
enrolled who did not have a history of dementia,
had a MMSE score >19 at enrolment and had a
vitamin B12 level between 100 and 200 ρmol/L.
All participants received either 1 mg vitamin
B12 (n=54), 1 mg vitamin B12 and 0.4 mg
folate (n=51), or a placebo (n=57) orally for
24 weeks. A comprehensive neuropsychological
workup including the MMSE and the WAIS, failed
to detect any beneﬁt from using vitamin B12
with or without folate. In this study, participants
550 E. M. Moore et al.
Table 4. Vitamin B12 treatment in neurologic patients with vitamin B12 deﬁciency
INDICATION B12 INTERVENTION nTREATMENT
Consecutive patients admitted with
vitamin B12 deﬁciency-related
neuropathy within three years
(Aaron et al., 2005)
1 mg tablet daily for seven days,
then 1 mg tablet per week for
63 patients with vitamin B12
MMSE MMSE improved (17.9 ±6.4
versus 15.5 ±7.5; p-value 0.01)
Patients with organic dementia –
including dementia of the
Alzheimer type, vascular
dementia, and frontotemporal
dementia (Nilsson et al., 2001)
1 mg tablet daily for two months 17 patients with HHcyb/11
patients without HHcyb
MMSE SKTcMMSE and SKT scores improved
in HHcy patients; no differences
detected in other patients
Patients having vitamin B12
syndromes (Kalita and Misra,
1 mg injection daily for 10 days,
then 1 mg injection weekly for
one month, then 1 mg injection
monthly for three months
32 neurological patients with
vitamin B12 deﬁciencyd
MMSE Cognitive evoked
MMSE improved (29.68 ±1.19
versus 28.16 ±2.98; p-value
0.006). Cognitive evoked
potential improved (p-value
Alzheimer’s disease patientse
(Kwok et al., 2008)
1 mg injection three times in the
ﬁrst week, then 1 mg tablet
weekly for three weeks, then 1 mg
injection monthly for nine months
30 patients with serum
vitamin B12 levels
MMSE (Chinese version)
MMSE and MDRS did not
improve after 10 weeks of treatment
aSerum vitamin B12 level <147.5 ρmol/L.
bHyperhomocysteinemia, serum homocysteine levels >19.9 μmol/L.
cShort memory and language test.
dSerum vitamin B12 level <155 ρmol/L.
eNational Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria.
fMattis Dementia Rating Scale.
Cognitive impairment and vitamin B12: a review 551
were assessed using the GDS. Depression was
investigated as a covariate (Eussen et al., 2006).
The second study enrolled 16 community-
dwelling individuals with vitamin B12 deﬁciency
(<150 ρmol/L) and no history of cognitive
deﬁcit. Participants were given a water injection
intramuscularly for four weeks followed by 1
mg injection of vitamin B12 weekly for four
weeks and then monthly for four months. MMSE
scores remained unchanged after the vitamin B12
intervention, conﬁrming the results from Eussen
et al. (2006), though in a much smaller sample of
relatively short duration. Verbal Word Learning test
scores did improve signiﬁcantly in this small study;
however, the authors could not rule out a practice
effect and did not screen for depression (van Asselt
et al., 2001).
Placebo-controlled studies to improve
cognition in functional vitamin B12 deﬁciency
Functional vitamin B12 deﬁciency is detected by
elevated homocysteine or MMA levels. Functional
deﬁciency arises as a result of either genetic predis-
position for aberrant proteins involved in vitamin
B12 biochemical pathways (Tanaka et al., 2009)
or exposure to nitrous oxide, inactivating the me-
thionine synthetase-vitamin B12 complex (Myles
et al., 2008). This review identiﬁed two placebo-
controlled studies that enrolled patients having
elevated homocysteine or MMA levels at baseline.
In one study, 253 healthy participants without
dementia and aged 65 years and over having
elevated homocysteine levels (>13 μmol/L) were
randomized to two groups. Half were required to
take a daily B-vitamin tablet including vitamin B12
(500 μg), folate, and pyridoxine (n=126), and half
received a placebo tablet. The treatment group did
not improve in MMSE score after two years of
treatment (McMahon et al., 2006).
In a second study of 140 participants with
elevated MMA levels (>0.4 μmol/L), half received
1 mg vitamin B12 by injection and half received
isotonic saline weekly for four weeks. Neuro-
psychiatric workup included MMSE and the
Cambridge Cognitive Examination (CAMCOG) at
baseline and after three months (Hvas et al., 2004).
Cognitive test scores were inversely associated with
age and improved in both treatment and placebo
groups; hence any beneﬁt of vitamin B12 therapy in
improving cognition may be due to a placebo effect
in this study.
The studies identiﬁed in this review present
a body of evidence showing that a subclinical
low-normal serum vitamin B12 level up to
250 ρmol/L is associated with AD, vascular
dementia, and Parkinson’s disease. Vitamin B12
deﬁciency (<150 ρmol/L) is associated with
cognitive impairment. Vitamin B12 deﬁciency may
precede cognitive impairment, but there is currently
insufﬁcient evidence to determine whether a
low vitamin B12 level is causative in the onset
or progression of neurodegenerative disease and
cognitive impairment. The duration of any cause
and effect between low vitamin B12 levels and
neurological pathology remains to be established.
An association between neurodegenerative disease
and subclinical low-normal serum vitamin B12
levels (up to 250 ρmol/L) is evident, meriting
increased monitoring and treatment for vitamin B12
insufﬁciency in elderly patients.
A need for better-resourced studies following
patients over a longer period
Having established the association of vitamin B12
insufﬁciency with neurodegenerative disease, the
challenge is to discern the direction, if any, of
causation. Most neurological impairments present
a slow, progressive course (Josephs et al., 2009) and
vitamin B12 levels may take a number of years
to deplete (Herbert, 1988). Studies investigating
causation would need to continue over an extended
period of time.
Low serum vitamin B12 levels may play a role
in the pathogenesis of neurodegenerative disease;
however, it is equally plausible that neurological
impairment may lead to poor nutrition and hence to
inadequate dietary intake. Also, any association may
simply be coincident or the factors predisposing
patients for neurodegenerative disease may simply
also expose the patient to a higher risk of vitamin
B12 deﬁciency, for example, poor nutrition. Further
intervention studies in large samples followed over
an extended period of time are required. This
will allow for further investigation of the role, if
any, of vitamin B12 in the onset or progression
of neurodegenerative disease, as well as the latent
period of effect of vitamin B12 insufﬁciency before
cognitive deﬁcits are evident.
A need for studies with more robust measures
The MMSE (Folstein et al., 1975) remains the
most highly utilized screening tool for cognitive
impairment in primary care. Consequently, almost
all of the studies included in this review detect
cognitive impairment by a low MMSE score and
report on changes in cognition by MMSE score;
despite the availability of alternative, more robust
instruments for measuring cognition. The majority
552 E. M. Moore et al.
of studies identiﬁed in this review utilized MMSE
score as a measure of cognition, largely without
adjusting for age and education, or screening
patients for depression or delirium.
Notably only two placebo-controlled studies
reviewed included a comprehensive neuropsychi-
atric workup. Future studies would beneﬁt from
more comprehensive instruments for measuring
cognition, such as the Alzheimer’s Disease
Assessment Scale – Cognitive section (ADAS-Cog)
or CAMCOG. Other instruments may be less
affected by differences between the groups with
respect to age or education than the MMSE. These
may provide greater sensitivity for detecting changes
in cognition over time or between groups.
Depression has been associated with low serum
vitamin B12 levels in those aged over 65 years
(Kim et al., 2008b) and may also affect performance
on cognitive tests. Yet, few studies investigated
this possible confounder in their participants.
Future studies investigating the association between
vitamin B12 levels and cognitive impairment would
beneﬁt from more robust study designs which either
exclude participants who are identiﬁed as having
depression or that include depression as a covariate
in statistical analyses.
Patients who may beneﬁt from vitamin B12
Petersen et al. (1999) estimated that the annual
rate of conversion from MCI to AD was between
10% and 15%, whereas only 1%–2% of the normal
population convert to AD each year. Cognition in
MCI patients, measured by the MMSE, did not
improve with vitamin B12 therapy in two placebo-
controlled trials yet mean serum vitamin B12 levels
were lower in MCI patients. This may signal that
low vitamin B12 levels contribute to this early
disease stage; that MCI patients are less able to
meet their dietary requirements; or that the factors
that predispose the patient to MCI also lead to poor
vitamin B12 status. The MMSE may also be a poor
choice for measuring change in cognition in MCI
patients. In any event, vitamin B12 therapy may be
beneﬁcial for patients presenting with MCI.
Few studies were identiﬁed that investigated
whether concurrent conditions and treatments
giving rise to vitamin B12 deﬁciency serve
to exacerbate neurological complications. Older
patients (over the age of 75 years), vegetarians
(consuming a high folate, low vitamin B12 diet),
and metformin users (not using insulin) are at
increased risk for vitamin B12 deﬁciency. This alone
may modify their risk for cognitive impairment and
neurodegenerative disease, therefore warranting
more studies that speciﬁcally investigate cognitive
impairment and neurodegenerative disease in these
patient populations. Additional monitoring of
vitamin B12 levels and supplement therapy are
warranted in such potentially high-risk groups.
One criticism of mandatory or voluntary
fortiﬁcation of foods with folate is that this may
mask vitamin B12 deﬁciency in a segment of
the population that would otherwise experience
traditional signs of deﬁciency, such as megaloblastic
anemia, and that would otherwise be treated earlier.
This same argument extends to the need to monitor
serum vitamin B12 levels for those receiving folate
Improving vitamin status in the elderly through
the provision of supplements or nutrient-dense
foods, which include vitamin B12 and folate,
may be of beneﬁt. However, in older age, CSF
homocysteine levels become independent of serum
vitamin B12 levels so it may be that no amount
of treatment will reverse the biochemical deﬁciency
or prevent the ensuing neurological complications
of hyperhomocysteinemia. Randomized controlled
trials are required to investigate whether oral or
parenteral vitamin B12 treatment adequately alters
the CSF levels of homocysteine and MMA in the
Measures of cognition improved marginally in
three of four intervention studies that were carried
out in vitamin B12 deﬁcient neurological patients.
Vitamin B12 therapy did not improve cognition
in non-cognitively impaired individuals with low
vitamin B12 levels, nor in those experiencing
functional vitamin B12 deﬁciency. Also, there is
no evidence that patients with normal vitamin B12
levels (>250 ρmol/L) would beneﬁt from vitamin
This review did not assess the efﬁcacy of vitamin
B12 in improving cognition in combination therapy
with other supplements (other than folate, with
which it shares a biochemical role in regenerating
methionine) or medications used when treating
cognitive changes. Only two studies of this type were
found and more are required to identify whether
there is a role for vitamin B12 therapy alongside
pharmaceutical agents to prevent further cognitive
decline in the patient.
There is a lack of clinical data on neuro-
degenerative disease and long-term metformin
use despite its long market history (outside of
North America) and early association with vitamin
B12 deﬁciency (Tomkin, 1972; Bauman et al.,
2000). Diabetics using metformin presenting in
older age with neurological impairments may
beneﬁt from vitamin B12 supplements (to correct
vitamin deﬁciency). Calcium supplements were
also shown to reverse the drug interaction
preventing vitamin absorption (Bauman et al.,
Cognitive impairment and vitamin B12: a review 553
2000); and insulin therapy was found to correct
the metformin-induced overexpression of BACE1
in cell culture (Chen et al., 2009). There is
a need for large studies in diabetic populations
to identify whether metformin use increases the
risk for neurodegenerative diseases and cognitive
impairment, and whether this effect is ameliorated
with vitamin B12 therapy.
High folate and low vitamin B12 levels may be
associated with cognitive impairment
The ﬁnding of an association between low serum
vitamin B12 levels and high folate levels with
cognitive impairment in one study raises concern, as
mandatory folate fortiﬁcation (of wheat products)
was ﬁrst introduced in Australia in 1994 and
was later introduced in the USA and Canada in
1998. Folate fortiﬁcation of foods was introduced
to prevent neural tube defects and is now
being practiced in over 19 countries. Comparing
postfortiﬁcation era (1999–2000) vitamin levels in
a large segment of the US population to pre-
fortiﬁcation era (1988–1994) values, Pfeiffer et al.
(2005) found that the prevalence of high serum
folate levels (>45.3 nmol/L) increased from 7%
to 38% in over-60-year olds (Pfeiffer et al., 2005),
exposing a signiﬁcant segment of the population to
high folate levels for over a decade.
Vitamin B12 is neuroprotective; a high intake of
folate may drive the distribution of vitamin B12
toward overutilization in the cytosol/methionine
regeneration pathway, possibly disrupting the
supply of vitamin B12 and its neuroprotective
effect. An older vegetarian population may present
an adequate sample in which to further test the
hypothesis that high folate in the setting of low levels
of serum vitamin B12 contributes to an increased
risk of cognitive impairment. The vegetarian diet
likely leads to a low vitamin B12 intake, alongside
consumption of folate-rich foods. Large studies
in diverse populations where folate fortiﬁcation of
foods is not widespread are required.
Conﬂict of interest
D. Ames is a former editor of International
Description of authors’ roles
D. Watters, D. Ames, A. Mander, and R. Carne
wrote the research questions and assisted in writing
the paper. E. Moore searched the journal databases
and wrote the paper. A. Mander, D. Watters, and
D. Ames provided further papers for inclusion.
K. M. Sanders assisted in writing the paper.
We would like to acknowledge the valuable
support provided by The University of Melbourne,
Deakin University, and Barwon Health for research
assistance and electronic resources provided to
complete this review of the literature.
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