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Biokemistri
Nigerian Society for Experimental Biology
ISSN: 0795-8080
Vol. 23, Num. 3, 2011, pp. 118-123
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Biokemistri, Vol. 23, No. 3, Dec, 2011, pp. 118-123
Original Article
Dyslipidemia,
altered erythrocyte fatty acids and selenium are associated with dementia in
elderly Nigerians
Olubunmi G. Ayelagbe1*,
Emmanuel O. Agbedana2, Adesola Ogunniyi3, Amelechi J. Onuegbu4
1Department
of Chemical Pathology and
4Department of Biomedical Sciences,
College of Health Sciences, Ladoke Akintola University of Technology, Osogbo,
Nigeria;
2Department of Chemical Pathology and
3Department
of Medicine, College of Health Sciences, University of Ibadan, Nigeria
*Corresponding
author: Olubunmi Ayelagbe; E-mail: olabung1@yahoo.com, Phone: +234 8065615202
Received: 14 November 2011
Code Number: bk11016
ABSTRACT
Dyslipidemia,
reduced omega-3 and -6 fatty acids and antioxidative nutrients are modulatory
risk factors associated with dementia. Diet, genetics and environment
interact with nutritional metabolism and susceptibility to neurodegeneration.
This study investigated the relationship between erythrocyte fatty acids and
selected antioxidant nutrients in elderly Nigerians with vascular dementia
(VD) and Alzheimer’s disease (AD). Forty VD (69.03±8.19 years) twenty AD
(71.06±5.0 years) and forty control (67.5±6.8 years) subjects were studied.
Anthropometric indices, blood pressure (BP) and body mass index (BMI) were
measured in all subjects. Venous blood sample was drawn from all subjects and
erythrocytes separated for the determination of fatty acids. Plasma lipids,
selenium and vitamin E levels were also measured. There were no differences
in BMI, weight and height among the three groups except for systolic BP that
was lower in VD (148.3±41.8mmHg) than AD (156±36mmHg). Docosahexanoic acid
and eicosapentanoic acid were lower in VD (6.3±2.2 and 2.0±1.6% total fatty
acids [TFA]) and AD (5.4±3.1 and 3.0±1.7 %TFA) respectively than in controls
(8.9±3.8 and 6.0±4.7%TFA). No variation was recorded in linolenic and
arachidonic acids. Significant increases in triglycerides, LDL-cholesterol
and decreased HDL-cholesterol were observed in both VD and AD when compared
to controls (p<0.05 in all cases). Plasma selenium levels were
significantly decreased in VD and AD than in controls. Eicosapentanoic and
linolenic acids concentrations were negatively correlated with plasma total
cholesterol. Low levels of erythrocyte omega-3 fatty acids and plasma
selenium concentrations are associated with occurrence of vascular dementia
and Alzheimer’s disease in elderly Nigerians.
KEYWORDS: Antioxidants; Docosahexanoic
acid; Eicosapentanoic acid; Lipoproteins
INTRODUCTION
Low dietary intake and plasma concentration of
omega-3 polyunsaturated fatty acids (PUFA) are associated with cognitive
decline and dementia risk1. The etiology of sporadic Alzheimers
disease (AD) is multifactorial. In Yorubas of African descent, it was observed
that age, genetic variations, cultural, lifestyle and environmental factors
like habitual diet may play important roles in the neurological disorder 2,
3. It was hypothesized that very long chain omega-3 PUFA as present in
fish oil could be responsible for interindividual variation in the rate of
decline cognitive performance over time in the general elderly population4.
Kalmijn et al.5 reported that increased docosahexanoic acid (DHA)
intake was protective of cognitive decline and that low concentration of DHA
was found in brain tissue of persons with AD.
Brain cholesterol alters the degradation of amyloid
precursor protein, which contributes to the pathogenesis of AD. Some workers
suggested that reduced cellular cholesterol levels promote tau phosphorylation
in neurons, inhibit dendrite outgrowth and synaptogenesis, and induce
neurodegeneration6. The gene coding for the low-density lipoprotein
receptor-related protein gene, which is the ApoE receptor and resides on
chromosome 12, may be associated with the expression of late-onset AD7.
Lipoproteins are targets for oxidation. It was
reported that cholesterol oxidation in the brain is of relevance in
pathogenesis of vascular dementia (VD) cases with mixed pathology 8.
Long chain PUFAs in brain include both omega-3 (e.g DHA, 22:6n-3) and omega-6
(e.g arachidonic acid (AA), 20:6n-6) PUFAs. They are prone to free radical
attack and hydrogen abstraction leading to oxidative damage 9.
Oxidative damage in the form of lipid peroxidation is known to play a
significant role in pathogenesis of neurodegeneration in AD 10.
Laboratory studies show that markers of oxidative damage are elevated in early
AD11 and this is associated with lower plasma antioxidant levels11.
When there is a weakening of antioxidant defence or
excessive production of free radicals, a state of oxidative stress occurs, if
uncontrolled, these free radicals damage different biological targets such as
lipids 12. Lipophilic antioxidants such as vitamin E is
neuroprotective, essential for normal brain function, accumulates in the brain
and decrease peroxidation of brain lipids in animal models 13,14.
Evidence suggests that decreased levels of antioxidant vitamins lead to higher
susceptibility to oxidative stress and a higher grade of lowdensity
lipoprotein (LDL) cholesterol oxidation as found in VD patients6.
Epidemiological studies support antioxidant intake as a means of reducing AD
risk from oxidative damage.15, 16
In humans, selenium deficiency has been implicated in
etiology of cardiovascular disease and conditions in which oxidative stress and
inflammation are prominent features 17. Selenium deficiency also
interferes with normal conversion of alpha-linolenic acid (ALA) to
eicosapentanoic acid (EPA) and DHA leading to increased omega 6: omega 3 PUFA
ratios 18. Glutathione peroxidase (a selenium containing enzyme) and
vitamin E inactivates the damaging effects of intermediates of lipofuscin
metabolism 19. Lipofuscin is formed by reactions of hydrogen
peroxide with PUFA resulting in formation of organic free radicals which could
damage neuronal DNA. This may have a direct toxic effect on brain cells 19.
This study is aimed at studying the relationship between omega-3, -6 fatty
acids and selected antioxidant nutrients in elderly Nigerians with vascular
dementia (VD) and Alzheimers disease in comparison to controls.
MATERIALS AND METHODS
Study
population
One hundred subjects (60 males, 40 females; mean age:
65.6±6.71 years) were enrolled in this study. These comprised of:
- Forty patients (24 males, 16 females; 69.03±8.19 years) attending the Neurology
clinic at the Medical Outpatient Unit of the University College Hospital,
Ibadan were diagnosed as suffering from vascular dementia using the National
Institute of Neurological Disorders and Stroke (NINDS) criteria which includes
incidence of cerebrovascular disease with or without history of stroke, onset
of dementia within 3 months following a recognized stroke and abrupt or
fluctuating deterioration in cognitive functions 20. Diagnosis by
the Consultant Neurologist also included taking a medical history, performing a
physical and neurological examination, and administering a neuropsychological
battery using Mini-Mental State Examination (MMSE).
- Twenty patients (9 males, 11 females: mean age: 71.06 ±5.0 years) suffering
from Alzheimers disease were diagnosed using the National Institute of
Neurological and Cognitive Disorders (NINCD) and Stroke/Alzheimers Disease and
Related Disorders Association (ADRDA) criteria. These include: dementia
established by examination and objective testing, deficits in 2 or more
cognitive areas, progressive worsening of memory and other cognitive functions,
onset between ages 40 and 90 years and establishment of absence of systemic
disorders or other brain diseases 21.
- Forty apparently healthy subjects (27 males, 13 females; mean age: 67.5 ± 6.83
years) who had no report of endocrine diseases, diabetes mellitus,
hyperlipidemia or hypertension and had not used any medications or drugs
influencing fat metabolism during the last 3 months before commencement of the
study were selected as controls.
Each participant underwent an interview with the aid
of a structured questionnaire of general health and detailed dietary habits
using a food frequency questionnaire followed by a standard assessment of
alcohol and fish consumption during the preceding 3 months. All the subjects
gave their informed consent prior to participation in the study. The study was
approved by the University of Ibadan / University College Hospital Ethical
Review Committee. Inclusion criteria: Patients with VD and AD and
that are over 60 years old. Exclusion criteria: Individuals that use
psychotropic drugs or consume alcohol on a regular basis, and also individuals
below 60 years old; Unwillingness to participate in the study.
Blood
sample collection
Blood sample (10 ml) was drawn by venipuncture after
10-14 hours fast and was carefully dispensed into ethylenediaminetetraacetic
acid (EDTA)-containing bottles. Samples were immediately placed on ice before
centrifugation. Whole blood was centrifuged at 4OC for 10 min at
2500rpm; the plasma was immediately separated from erythrocytes, and then
freshly frozen under nitrogen at -800C, not later than 30 min after
puncture.The erythrocytes were washed four times at 4OC and
centrifuged at 2500rpm for 10min. The plasma and buffy coat were removed after
centrifugation. This procedure was done twice, leaving a substantially
hemoglobin-free pellet of erythrocyte membranes, which was resuspended in twice
its volume of phosphate buffer saline and stored at -70OC until
analyzed for fatty acids. The separated plasma sample was used for α-tocopherol,
selenium and lipid analysis.
Plasma
lipids and fatty acid analysis
Plasma total cholesterol (TC), triglycerides (TG),
and high-density lipoprotein (HDL) cholesterol were quantified by commercially
available enzymatic kits (Boehringer Mannheim, Mannheim, Germany). LDL-
cholesterol was calculated using the Friedewald formular (LDL-C: TC - TG/5 -
HDL-C). Erythrocyte fatty acids were determined using the method of Pandey et
al 44 . Fatty acid methyl esters (FAMEs) were prepared by
methylating free fatty acids with methanol sulphuric acid. High Performance
Liquid Chromatography was carried out using Waters 616/626 LC chromatograph
equipped with Waters 501 pump solvent programmer and Waters UV detector.
Absorbance was measured @ 300nm. A 90cm x 0.64cm: bondapak C18 column was used
with acetonitrite (8:20v/v) as eluent at a flow rate of 0.50ml/min. FAMEs were
identified by comparison with internal standard (C17:0). Peak retention times
for total fatty acids (TFA) were identified by injecting known standards. FAMEs
from C12:0 through C22:6 were expressed as percent TFA. Precision of fatty
acids measurement was determined by repeat analysis of a pooled plasma sample;
1 pooled plasma sample was assayed for every 20 samples.
Measurement
of α-tocopherol
and selenium
α-Tocopherol was
determined as a major form of vitamin E in plasma and was quantified by
reversed-phase high-performance liquid chromatography (HPLC) with
electrochemical detection as previously described 22.
Plasma selenium was estimated using atomic absorption spectrophotometry.
Statistical
analysis
Lipid levels, erythrocyte fatty acids content and
other potential risk factors were compared among VD, AD and non-demented subjects
using SPSS version 14.0. Data are reported as mean ± standard deviation (SD).
Means were compared by analysis of variance; Chi-square test was used for
categorical data while the relationships between variables were determined
using Pearson correlation coefficient. Statistical significance was defined as
p < 0.05.
Other
measurements
Anthropometric indices were measured which included
weight in light clothing with shoes off using analogue bathroom scale, and
height using standiometre. Body mass index (BMI) was computed as weight
(kg)/height (m2). Subjects were considered as smokers (current or
past) at the time of blood sampling. Percentage alcohol intake was considered
as ≥ 2 drinks per day (1 drink was defined as 13ml alcohol). High blood
pressure was defined as systolic blood pressure (BP) ≥140mmHg or a
diastolic BP ≥ 80mmHg 23. Subjects with high BP by this
definition or those taking antihypertensive medication such as β-blockers,
calcium antagonists or diuretics were considered hypertensive 24.
Results
General characteristics of patients and controls are
displayed in Table 1. No significant differences in age, BMI and diastolic
blood pressure were seen in VD and AD patients but increase in systolic BP was
significant in AD compared with VD patients. The percentage consumption of fish
in VD and AD was similar and higher than controls. Approximately 62.5% of VD
and 25% of AD patients were hypertensive.
TABLE 1 General
characteristic of VD, AD and control subjects
Parameters |
VD (n=40) |
AD (n=20) |
Control
(n=40) |
BMI(kg/m2) |
26.4±3.4 |
26.1±2.6 |
25.9±2.7 |
Smoking
(Y/N) |
9/31 |
2/18 |
1/38 |
Hypertension
(Y/N) |
25/15 |
5/15 |
0/40 |
Alcohol
intake (%) |
23 |
22 |
18 |
Fish
intake (%)* |
20 |
20 |
25 |
SBP(mmHg) |
148.3±41.8 |
156±36.0 |
141±24.2 |
DBP(mmHg) |
85.3±20.9 |
89±18.0 |
81±15.1 |
MMSE
Score |
12.3±2.2 |
12.0±3.4 |
26.1±2.2§ |
*1mg/d
= 1.05 fish servings/week 25; p<0.05 vs VD and AD;
§ p<0.05 vs VD and AD. SBP systolic blood pressure; DBP
diastolic blood pressure |
From Table 2, differences in mean plasma TG, LDL-C and
HDL-C in all patients were significant compared to control. In contrast, there
was no significant change in the mean plasma total cholesterol in the patients
and control group. In VD patients, mean values of TG and LDL-C were
significantly higher and HDL-C lower (p<0.05 in all cases) than in AD. The
mean percentage contributions of n-6 PUFAs: AA and linolenic acid (LA) showed
minimal variations between the dementia subtypes and control subjects. Mean
contributions of DHA and EPA were significantly lower in the patients than the
values in controls. When patients with VD and AD as well as control subjects
were compared according to their mean values of plasma vitamin E and selenium,
plasma selenium concentration was higher in patients compared to controls but
changes in vitamin E among the different groups were not significant (Table 3).
TABLE 2 Plasma lipids and
erythrocyte fatty acids contents in VD, AD and control subjects
|
VD (n=40)
|
AD (n=20)
|
Control (n=40)
|
TC
(mmol/l)
|
4.3±28.4
|
4.0±27.2
|
3.54±26.2
|
TG
(mmol/l)
|
3.24±41.9
|
2.85±36.1
|
1.80± 26.3*
|
HDL-C
(mmol/l)
|
1.03 ± 20.4
|
1.40 ±14.8
|
1.60 ± 14.9**
|
LDL-C
(mmol/l)
|
2.80±32.4
|
2.21 ±20.2
|
1.58 ± 21.1**
|
TFA
(mmol/l)
|
37±2.9
|
35.1±3.1
|
39.2±2.7
|
AA
(% TFA)
|
13.6±2.4
|
14.0±2.3
|
14.3 ±3.5
|
LA
(% TFA)
|
10.1±2.5
|
10.3±2.4
|
8.1 ± 3.3
|
DHA
(% TFA)
|
6.3±2.2
|
5.4±3.1
|
8.9 ± 3.8#
|
EPA
(% TFA)
|
2.0±1.6
|
3.0±1.7
|
6.0 ± 4.7#
|
*p<0.05 vs VD
and AD, **p=0.000 vs VD and AD, # p=0.002 vs VD and AD.
|
In order to ascertain possible relationships among
the biochemical parameters analyzed in both dementia subtypes with the
exclusion of control subjects, Pearson correlation coefficient showed that in
VD patients, consistent positive correlations were present between triglyceride
and total cholesterol, LDL cholesterol and total cholesterol and LDL
cholesterol and triglyceride. On the other hand, there were negative
correlations between EPA and total cholesterol and LA and total cholesterol
(Table 4). In AD patients, there were no significant correlations among the
parameters analyzed (data not shown).
Discussion
The primary purpose of the present study was to
identify possible relations between the expression of specific putative
atherogenic risk modulating factors, antioxidative nutrients and the incidence
of dementia in this community. In the present study the patients were a mixed
population of elderly male and female adults suffering from either vascular
dementia or Alzheimers disease. Lifestyle factors including habitual diet,
cigarette smoking and alcohol intake are believed to be major contributors to
the development of VD and AD. The findings in this study showed that a larger
percentage of VD (29%) and AD (11.1%) patients were either current smokers or
had smoked before when compared with control subjects (2.6%). In a review of
risk factors and post stroke dementia by Pasquier et al 26, it was
postulated that cigarette smoking was a common risk factor for both Alzheimers
and vascular disease.
TABLE 3 Plasma
selenium and vitamin E levels in all subjects
|
VD (n=40)
|
AD (n=20)
|
Control (n=40)
|
Selenium
(µmol/l)
|
1.39±0.7*
|
1.48±0.57*
|
2.06±0.53
|
Vitamin
E (µmol/l)
|
1.63±0.74
|
1.73±0.86
|
1.78±0.68
|
*significantly
different from controls
|
This study showed that increased triglyceride, LDL-
cholesterol and decreased HDL-cholesterol concentrations in plasma were
associated with incidence of VD. In addition, total cholesterol concentration
appeared to be elevated in VD and AD patients compared with control subjects.
These findings also suggest that hypertriglyceridemia and elevated LDL-
cholesterol may be among the intermediary mechanisms linking hyperlipidemia to
VD. This observation is in agreement with some studies 8,27 and at
variance with others 28. A previous study suggested that elevated
serum lipids may enhance atherogenesis of the extracranial and intracranial
arteries causing an increase in blood viscosity which in turn decreases
cerebral perfusion and impair cognitive performance 29.
To operationalize the diagnosis of dementia for this
study, we developed a composite variable with a positive diagnosis when both a
clinical diagnosis of dementia or one of its types were documented and the
patient had a MMSE score less than 24. This cutoff has been shown to improve
diagnostic accuracy 30. Covariates included age, gender, smoking,
alcohol intake, blood pressure, medical diagnosis (stroke, hypertension and
depression), family history of dementia or AD, cholesterol level, LDL-
cholesterol, HDL-cholesterol and triglyceride. Both of the dementia groups were
similar in BMI, alcohol intake, fish consumption and MMSE score. A limitation
of this study is the accuracy of the diagnosis of dementia. However, the high
rate of concordance between clinical diagnosis and cognitive testing result
suggest accuracy of dementia diagnosis.
The systolic blood pressure was significantly higher
in AD and VD patients than in controls while the change in diastolic blood
pressure was not significant. It is noteworthy that the blood pressure values
for AD and VD patients (156/89 and 148/85 respectively) were higher than the
cut-off value of 140/85mmHg for diagnosis of hypertension 23. In
their study on association of cognitive function with high blood pressure,
hypertension and high pulse rate in persons aged 60 years and older, Obisesan
et al 31 reported that optimal blood pressure (120/80mmHg) was
associated with best cognitive performance and that at age 70 years and older,
high blood pressure, hypertension and uncontrolled blood pressure were
independently associated with poorer cognitive function than normal blood
pressure. It is therefore suggested that optimal control of blood pressure may
be useful in preventing neurocognitive loss in the aging population. The causal
role of vascular risk factors in different types of dementia has been linked to
sclerosis of small cerebral arteries and arterioles which is considered to be
responsible for diffuse periventricular white matter abnormalities, which play
an important role in the development of VD 6. It was hypothesized
that high concentrations of LDL-cholesterol and low levels of HDL-cholesterol
are independent risk factors for coronary heart disease and carotid artery
atherosclerosis 32; this in turn may lead to cognitive impairment
through cerebral hypoperfusion or embolism 33. HDL-cholesterol
particles have also been reported to play a role in the removal of excess
cholesterol from the brain by interaction with ApoE and heparan sulfate
proteoglycans in the subendothelial space of cerebral microvessels and this
mechanism has been linked to low incidence of small-vessel disease 34.
TABLE 4 Correlation coefficient
matrix of parameters in VD and AD
Variables
|
TC
|
TG
|
LDL-C
|
EPA
|
LA
|
TC
|
NS
|
0.395*
|
0.333*
|
-0.353*
|
-0.333*
|
LDL-C
|
NS
|
0.458**
|
NS
|
NS
|
NS
|
EPA
|
-0.353*
|
NS
|
NS
|
NS
|
NS
|
TG
|
0.395*
|
NS
|
0.458
|
NS
|
NS
|
LA
|
-0.333*
|
NS
|
NS
|
NS
|
NS
|
*significant
@ p<0.05 level, **p<0.01; NS not significant
|
There is increasing scientific interest in the
hypothesis that very-long-chain n-3 PUFAs, as present in fish or fish oil and
supplements rich in n-3 fatty acids are beneficial for the maintenance of
cognitive performance in adults. This hypothesis is corroborated by the pattern
of erythrocyte fatty acid changes in this study which shows that the percentage
of DHA and EPA, were significantly decreased in VD and AD patients compared to
control subjects. Several observational studies, conducted among older adults
reported that participants in those studies with high erythrocyte levels of
eicosapentanoic acid and docosahexanoic acid - which are the most abundant n-3
PUFAs in erythrocyte - had a lower risk of experiencing cognitive decline 24,
35. However others have reported no such associations 15,
36. Some of these studies also evaluated the association between
fish consumption and cognitive performance and reported a lower incidence of AD
37 or a trend toward a lower risk of cognitive decline 38
with increasing fish intake. In the present study the average percentage fish
intake in patients with the dementia subtypes was slightly higher than the
control subjects. It could be possible that these control subjects represent a
population of people with relatively unhealthy dietary habits, such as
inadequate consumption of diets rich in n-3 PUFAs.
There were no significant differences in erythrocyte
levels of DHA and EPA in vascular dementia as compared to those in Alzheimers
disease patients probably suggesting a possible relationship between n-3 PUFAs
and low cognitive function irrespective of the subtypes of dementia. This is
more likely as both VD and AD patients studied scored less than 24 points on
the MMSE scale. Dietary n-3 PUFAs had been shown to improve brain functioning
in animal studies and it was hypothesized that dietary intake of n-3 fatty
acids and weekly consumption of fish may reduce the risk of incident
Alzheimers disease 37. Nevertheless, the findings in this present
study are in line with earlier report by Heude et al 24 which showed
that lower proportions of n-3 PUFAs in erythrocytes are associated with a
higher risk of cognitive decline. Hence, there is the possibility that a more
detailed cognitive assessment in a larger population may show significant
associations in fish consumption and cognitive impairment in this community.
A suggested mechanism for the cardio-protective
effect of n-3 fatty acids focused on their influence on eicosanoid metabolism,
inflammation, beta oxidation, endothelial dysfunction, cytokine growth factors,
and gene expression of adhesion molecules 39. Cerebrovascular
disease might play a role in vascular dementia 34,6. N-3 fatty acids
are also neuroprotective by suppressing the synthesis and release of
interleukins and TNF-alpha (which is neurotoxic) and modulation of
hypothalamic-pituitary-adrenal anti-inflammatory responses in the nervous
system 39.This shows a close association between the central nervous
system and dietary n-3 fatty acids. High concentrations of DHA and EPA are
associated with cardiovascular benefit. Trials showed reductions in
cardiovascular events of 19-45% in subjects receiving n-3 fatty acid
supplementation containing EPA and DHA. Patients with hypertriglyceridemia can
also benefit from treatment with 3-4g daily intake of DHA and EPA 40.
Previous literature from this community emphasized or studied the incidence and
risk factors of VD and AD. With this study, erythrocyte PUFAs, total plasma
lipid profile, selenium and vitamin E were all determined in the two groups of
neurodegenerative disorders. Low level of plasma selenium was a constant
feature in VD and AD patients but not in control subjects.
Although the slight decrease in plasma values of
vitamin E observed in patients in comparison with controls in this study was
not significantly different, low levels of this vitamin may still undoubtedly
play an important role in the occurrence of these neurodegenerative disorders.
Several studies found that low intake and reduced serum vitamin E was associated
with higher risks of AD and vascular dementia 41,42 and that
Alzheimer disease patients on vitamin E supplement survived longer than those
not getting supplements 43. It could be deduced from results
obtained in this study that vitamin E is unlikely to be responsible for the
severity and progression of VD and AD among Nigerian Africans when compared
with the white populations of the developed countries 41,42.
Results from this case-control study showed that low
levels of omega-3 fatty acids and selenium were strongly associated with the
occurrence of dementia in the elderly Nigerian population among whom there is
lack of awareness on the benefits of adequate consumption of fatty cold water
fish that are rich sources of eicosapentanoic and docosahexanoic acids known to
alleviate neurodegeneration. A prospective study investigating the effect of
omega-3 fatty acids and antioxidant vitamins on pathogenesis of dementia in the
elderly would shed more light on the observed associations.
Acknowledgements The authors appreciate the technical
assistance and cooperation of the staff of the Ibadan Dementia Project,
University College Hospital, Ibadan, Nigeria.
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