Atherosclerosis 210 (2010) 542547

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Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Serum low-density lipoprotein cholesterol level is strong risk factor for acquired
color vision impairment in young to middle-aged Japanese men:
The Okubo Color Study Report 2
Takuhei Shoji a,e, , Yutaka Sakurai b , Hiroki Sato c , Etsuo Chihara d ,
Masahiro Ishida e , Kazuyuki Omae a
a

Department of Preventive Medicine and Public Health, School of Medicine, Keio University, Tokyo, Japan
Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Saitama, Japan
c
Department of Medical Informatics, National Defense Medical College, Tokorozawa, Saitama, Japan
d
Sensho-kai Eye Institute, Uji, Kyoto, Japan
e
Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan
b

a r t i c l e

i n f o

Article history:
Received 26 July 2009
Received in revised form 11 October 2009
Accepted 13 November 2009
Available online 1 December 2009
Keywords:
Acquired color vision impairment
Prevalence
Low-density lipoprotein cholesterol
Cardiovascular risk factors

a b s t r a c t
Objective: To investigate associations between blood low-density lipoprotein cholesterol (LDL-C) levels
and the prevalence of acquired color vision impairment (ACVI) in middle-aged Japanese men.
Methods: Participants in this cross-sectional study underwent color vision testing, ophthalmic examination, a standardized interview and examination of venous blood samples. Ishihara plates, a Lanthony
15-hue desaturated panel, and Standard pseudoisochromatic Plates part 2 were used to examine color
vision ability. The FarnsworthMunsell 100-hue test was performed to dene ACVI. Smoking status and
alcohol intake were recorded during the interview. We performed logistic regression analysis adjusted
for age, LDL-C level, systemic hypertension, diabetes, cataract, glaucoma, overweight, smoking status,
and alcohol intake. Adjusted odds ratios for four LDL-C levels were calculated.
Results: A total of 1042 men were enrolled, 872 participants were eligible for the study, and 31 subjects
were diagnosed with ACVI. As compared to the lowest LDL-C category level (<100 mg/dl), the crude OR of
ACVI was 3.85 (95% condence interval [CI], 1.2411.00) for the 2nd highest category (130159 mg/dl),
and 4.84 (95% CI, 1.4216.43) for the highest level (160 mg/dl). The multiple-adjusted ORs were 2.91
(95% CI, 0.879.70) for the 2nd highest category and 3.81 (95% CI, 1.0314.05) for the highest level. Tests
for trend were signicant (P < 0.05) in both analyses.
Conclusions: These ndings suggested that the prevalence of ACVI is higher among middle-aged Japanese
men with elevated LDL-C levels. These changes might be related to deteriorated neurologic function
associated with lipid metabolite abnormalities.
2009 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Population studies have reported consistently that increased
low-density lipoprotein cholesterol (LDL-C) is a strong and independent risk factor for cardiovascular diseases [1]. Evidence also
suggests a relation between lipids and vascular changes involving
the brain in dementia [2]. Recent experimental and clinical reports
have discussed in depth the link between late-onset neurodegenerative diseases and the asymptomatic atherosclerosis, or the blood
cholesterol or glycemia levels that occur during mid-life [26].

Corresponding author at: Department of Preventive Medicine and Public Health,

School of Medicine, Keio University, 35, Shinanomachi, Shinjyuku-ku, Tokyo 1608582, Japan. Tel.: +81 3 5363 3758; fax: +81 3 3359 3686.
E-mail address: t-shoji@yg7.so-net.ne.jp (T. Shoji).
0021-9150/$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.atherosclerosis.2009.11.039

The deterioration of the color vision discrimination ability,

which is referred to as acquired color vision impairment (ACVI),
is generally believed to be an early indicator of various neurotoxic and neurodegenerative diseases [7,8]. However, because
ACVI is a secondary feature of a variety of pathological states,
there are few studies that have reported on the impact of cardiovascular risk factors or life style factors on ACVI [715].
In addition, even though these risk factors may inuence the
color vision function via several different mechanisms, at the
present time, these relationships have yet to be fully understood.
The Okubo Color Study has focused attention on the impact of
cardiovascular risk factors on color vision function in male subjects
in the Japanese Self Defense Force (JSDF). The primary aim of the
current study was to investigate these relationships with crosssectional multivariable analysis.

T. Shoji et al. / Atherosclerosis 210 (2010) 542547

2. Subjects and methods

2.1. Study population and design
The Okubo Color Study evaluated the relationship between color
vision function, especially ACVI, and ophthalmic disease, cardiovascular risk factors, and lifestyle factors. The study was reviewed
by the National Defense Medical College (NDMC) Ethics Board to
ensure that it met the ethical guidelines, with all subjects providing written informed consent in accordance with the Helsinki
Declaration prior to their participation in the study. The detailed
design of the current study has been previously described [16].
Briey, this study was a large-sample prevalence survey of color
vision impairment among male ofcials aged 2060 years who
were on active duty in the JSDF, Okubo Garrison, Kyoto, Japan. All
subjects underwent an annual health examination between April
2005 and March 2006 at the Okubo Garrison. The authors used
structured questionnaires, personal physical records, along with
conducting detailed interviews in order to collect information on
current and past diseases, medication use, and lifestyle characteristics in all of the subjects. Subsequently, all participants underwent
color vision testing, measurement of visual acuity (VA), slit-lamp
biomicroscopic examination, measurement of intraocular pressure
using non-contact applanation tonometry, and fundus examination. Venous blood samples were also collected from all subjects.
The VA was measured using a Landolt ring chart (with refractive
correction, if any) at a distance of 5 m. Ishihara pseudoisochromatic
plates (Kanehara Shuppan Co. Ltd., Tokyo, Japan), the Lanthony
15-hue desaturated panel (D-15 DS) plates (Luneau, Paris, France),
and the Standard pseudoisochromatic plates part 2 (SPP2; IgakuShoin, Tokyo, Japan) were used to perform color testing. Color
fundus photographs were obtained using a fundus camera system (Canon, CR-45NM, Tokyo, Japan) with an angle of 30 . Venous
blood was drawn after an overnight fast in order to measure the
fasting plasma glucose, total cholesterol (TC), triglyceride (TG), lowdensity lipoprotein cholesterol (LDL-C), high-density lipoprotein
cholesterol (HDL-C), uric acid (UA), and hemoglobin A1c (HbA1c).
All examiners and photograph readers were masked to all other
information on the subject including vision, referring diagnosis,
systemic status and life style characteristics.

2.2. Measurements and denitions

2.2.1. Examination color testing
The Ishihara pseudoisochromatic plates 121 (38-plate edition)
were used to identify red-green color sense anomaly. Subjects with
more than four errors were classied as having failed the test [7].
The D-15 DS was used to supplement standard D-15 testing to
diagnose milder congenital anomalies or ACVI [8]. Subjects with
more than one major crossing were classied as having failed [7,10].
The SPP2 test was designed especially to detect ACVI and also
can be used to identify a blue-yellow color sense abnormality.
Subjects with more than one blue-yellow error were classied as
having failed the test. Missing the 2 on Plate 3 was not considered
a failure [7,10].
The FarnsworthMunsell (FM) 100-hue test was performed
according to the standard technique [7]. Color discrimination was
tested monocularly at a distance of 30 cm with the subjective near
refraction placed in a trial frame. Subjects with scores worse than
the 95th percentile described by Verriest et al. [17] were diagnosed
with ACVI.
Subjects were inspected binocularly with the Ishihara plates and
monocularly with D-15 DS, SPP2, and the FM 100-hue test, with
the right eye tested before the left eye.

543

2.2.2. Cardiovascular risk factor denition

In accordance with the guidelines, the LDL-C level was categorized as less than 100 mg/dl, equal to or exceeding 100 mg/dl
but less than 130 mg/dl, equal to or exceeding 130 mg/dl but
less than 160 mg/dl, or equal to or exceeding 160 mg/dl [1]. Systemic hypertension was dened as a systolic/diastolic pressure of
140/90 mmHg or more at the time of examination or a history of a
diagnosis of hypertension and current use of medication for hypertension [1]. Diabetes was dened as a previous history of diabetes
treated with either insulin, oral hypoglycemic agents, or diet. Newly
diagnosed diabetes was dened as no previous medical history of
diabetes in the presence of an elevated fasting plasma glucose level
of 126 mg/dl or more at the time of the examination [18].
2.2.3. Smoking and drinking status
Subjects were categorized as those who had never smoked and
current and past smokers. Current and past smokers were dened
as current or past habitual smokers who had smoked for at least 1
year. Subjects who had been smoking for less than 1 year were not
considered to be smokers. Cigarette smokers were classied into
two groups, namely, light smokers with 19 or fewer median packyears of smoking and heavy smokers with 19 or more pack-years
of smoking.
Classication of alcohol consumption was based on the frequency of alcohol consumption (daily, weekly, monthly, or less
often).
2.2.4. Overweight
The body mass index (BMI), a standard measure dened as the
weight in kilograms divided by the square of the height in meters,
was categorized as less than 25 or 25 or higher, with the cutoff
point chosen as a criterion for obesity because it corresponds to
the standard indicator for overweight in an Asian population [19].
2.2.5. Cataract grading
Ophthalmologists used a slit-lamp examination to grade the
cataract level, which was based on Lens Opacity Classication System III (LOCS III) [20] standard color photographs and the Wilmer
Classication [21]. We dened the presence of a nuclear cataract as
at least one eye with a nuclear opacity of grade 3.0 or higher on the
LOCS III. Cortical cataract and posterior subcapsular cataract were
considered present with at least a grade 2 and grade 1 or higher on
the Wilmer Classication, respectively.
2.2.6. Glaucoma denition
Subjects were recruited for visual eld evaluation if the intraocular pressure was more than 20 mmHg, or if the color fundus
photography showed abnormality ndings, which included glaucomatous optic disc appearance and nerve ber layer defect. Visual
eld testing was performed with static perimetric analysis using a
Humphrey Field Analyzer, 30-2 SITA Standard Program (Humphrey
Instruments, Inc., San Leandro, CA, USA) or the Octopus 301 fullthreshold G1 program ver. 2.04, Interzeag, Schlieren, Switzerland).
The nal diagnosis of glaucoma was based on optic disc appearance, intraocular pressure, and the results of visual eld testing
and the clinical records, which included physical records and questionnaires.
2.2.7. Age-related macular degeneration (AMD) grading
Each color fundus photograph was graded based on a comparison with standard photographs according to the Rotterdam Study
[22] and classied as normal, early age-related maculopathy (stages
2 or 3), or AMD.

544

T. Shoji et al. / Atherosclerosis 210 (2010) 542547

Fig. 1. Schematic diagram of the Okubo Color Study and diagnosis of ACVI.

2.3. Inclusion and exclusion criteria

The study criteria are summarized in Fig. 1. The inclusion criteria included a best-corrected VA of at least 0.7 on the decimal
VA chart (73 subjects were excluded). Subjects were excluded who
had undergone cataract or retinal surgery and any corneal or retinal disease, including AMD, central serous chorioretinitis, diabetic
retinopathy, and any retinal or vitreous hemorrhage (6 subjects
were excluded). Considering the possibility of the side effects on
color vision, subjects currently taking or those who had taken a
systemic medication such as digitalis glycoside, antiepileptic drugs,
antimalaria drugs, and antituberculosis drugs [9,10] were excluded
(4 subjects were excluded). Moreover, 75 subjects were excluded
who failed testing with the Ishihara plates, had a pattern typical of congenital deutan or protan defect on testing with SPP2 or
D-15 DS, or had a history of congenital color vision impairment
(CCVI) in their medical history records, in which the results of color
testing had been recorded on enlistment. In questionable cases,
anomaloscopy was used. Subjects who failed testing with either
the SPP-2 or D-15 DS were classied as ACVI suspects and performed the 100-hue test bilaterally. Twelve subjects who declined
the denition test also were excluded. Subjects exceeding the age-

specic limit score of Verriest et al. [17] were diagnosed as having

ACVI.

2.4. Statistical analysis

Data were expressed as the mean the standard deviation (SD)
or median with the interquartile range as appropriate. Variables
were compared with the unpaired t-test for normal distributed
variables or the Wilcoxon rank sum test for non-normal distributed
variables between ACVI and normal subjects. Multiple logistic
regression analysis was performed to examine the relationship
between LDL cholesterol and ACVI. The model was adjusted with
risk factors including age, smoking, drinking, and overweight, and
diagnosed hypertension, diabetes, cataract, and glaucoma. Odds
ratios (ORs) with 95% condence intervals (95% CI) are presented.
Individuals, rather than eyes, were the unit of analysis because the
right and left eyes were not examined independently. A participant
was considered to have CCVI or ACVI when it occurred in either eye.
A P-value less than 0.05 indicated a statistically signicant difference. All statistical analyses were performed using SAS version 9.1
software (SAS Institute, Inc., Cary, NC, U.S.A.).

T. Shoji et al. / Atherosclerosis 210 (2010) 542547

545

Table 1
Baseline characteristics of 872 eligible subjects.
Acquired color vision impairment

Age (yr)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
LDL cholesterol (mg/dl)
HDL cholesterol (mg/dl)
Triglycerides (mg/dl)
Fasting blood glucose (mg/dl)
Height (cm)
Weight (kg)
BMI (kg/m2 )

P-value

Yes (N = 31)

No (N = 841)

40.7 8.2
129 (115, 140)
80 (72, 93)
141.8 34.8
65.2 18.1
101.7 60.3
94 (89, 100)
169.5 7.1
70.8 9.7
24.6 2.7

37.8 8.6
120 (111, 131)
75 (66, 83)
120.6 32.6
63.7 14.8
104.5 71.8
90 (85, 96)
170.3 5.8
68.5 9.0
23.6 2.7

0.063
0.024
0.014
<0.001
0.572
0.832
0.020
0.489
0.172
0.051

Plusminus values are means SD. Alternatively, in case of skewed distributions, data are medians (25th percentile, 75th percentile). Baseline characteristics were compared
with the unpaired t-test for normal distributed variables or by the Wilcoxon rank sum test for non-normal distributed variables between ACVI and no ACVI. Abbreviations:
LDL, low-density lipoprotein; HDL, high-density lipoprotein; BMI, body mass index and ACVI, acquired color vision impairment.

3. Results

for the age and BMI. There was no signicant difference between
the groups for HDL-C, triglycerides, height and weight.

3.1. Baseline characteristics of the study participants

The study included 1042 out of a total of 1152 subjects, for
an overall response rate of 90.5%. Of the 1042 enrolled subjects,
a total of 872 (83.7%) fullled the inclusion criteria (Fig. 1). Of
these subjects, 31 were diagnosed with ACVI. Table 1 presents
the characteristics according to whether or not the participants
were diagnosed with ACVI. Subjects with ACVI were more likely to
have higher systolic blood pressure, diastolic blood pressure, LDLC, and fasting plasma glucose. Marginal differences were observed

3.2. Relation between parameters of cardiovascular risk factor

and ACVI prevalence
Table 2 shows the distributions of risk factors in the groups
with and without ACVI and the rude and adjusted ORs with 95%
CI for subjects with ACVI compared with no ACVI. Compared with
the reference LDL-C category (less than 100 mg/dl), the crude and
multiple-adjusted OR for the highest LDL-C level (160 mg/dl)
was 4.84 (95% CI, 1.4216.43), and 3.81 (95% CI, 1.0314.05),

Table 2
Risk factors for acquired color vision impairment.
Risk factors

ACVI (N = 31)

No ACVI (N = 841)

Crude ORs (95%CI)

LDL cholesterol
<100
100129
130159
160
P for Trend

P-value

4
6
13
8

237
306
200
98

1.00
1.16 (0.324.16)
3.85 (1.2411.00)
4.84 (1.4216.43)

Age, years
<40
40

9
22

403
438

1.00
0.45 (0.200.98)

0.044

1.00
0.68 (0.271.71)

0.411

Hypertension
No
Yes

22
9

740
101

1.00
3.00 (1.346.69)

0.007

1.00
1.84 (0.764.48)

0.180

Diabetes
No
Yes

27
4

826
15

1.00
8.16 (2.5426.22)

<0.001

1.00
7.76 (1.9830.39)

0.003

Cataract
No
Yes

30
1

831
10

1.00
2.77 (0.3422.34)

0.339

1.00
1.07 (0.0912.97)

0.959

Glaucoma
No
Yes

29
2

826
15

1.00
3.80 (0.8317.39)

0.086

1.00
2.99 (0.5516.28)

0.205

Overweight
No
Yes

17
14

606
235

1.00
2.12 (1.034.38)

0.041

1.00
1.40 (0.633.11)

0.415

Smoking
Never
Light
Heavy

16
6
9

319
263
259

1.00
0.46 (0.181.18)
0.69 (0.301.60)

0.193
0.949

1.00
0.64 (0.241.76)
0.44 (0.181.09)

0.960
0.200

Drinking
Monthly or less
Weekly
Daily

9
12
10

264
341
236

1.00
1.03 (0.432.49)
1.24 (0.503.11)

0.838
0.608

1.00
1.31 (0.503.41)
1.45 (0.533.92)

0.832
0.571

0.080
0.042
0.014
0.001

Adusted ORs (95%CI)

1.00
0.93 (0.253.49)
2.91 (0.879.70)
3.81 (1.0314.05)

P-value

0.075
0.106
0.032
0.007

Abbreviations: ACVI, acquired color vision impairment and LDL, low-density lipoprotein (mg/dl). The multiple-adjusted ORs were adjusted for age, smoking, drinking,
overweight (dened by body mass index), diagnosed hypertension, diabetes, cataract, and glaucoma. overweight; Yes; (BMI>25.0) and no (BMI 25.0).

546

T. Shoji et al. / Atherosclerosis 210 (2010) 542547

respectively. Tests for trend were signicant in multiple-adjusted

regression analysis (P = 0.007), which indicated a signicant positive correlation between the elevated LDL-C levels and the
prevalence of ACVI. The crude OR was also signicant in subjects
with diagnosed hypertension, diabetes, and those who were obese.
The adjusted OR in subjects with diagnosed diabetes was 7.76 (95%
CI, 1.9830.39), which was signicant (P = 0.003). Multiple logistic
regression analysis did not identify correlations between ACVI and
diagnosed hypertension, obesity, cataract, or glaucoma.
4. Discussion
Results of the current study demonstrate that there is a signicant relationship between the blood LDL-C level and the prevalence
of ACVI. In addition, the multiple logistic regression analysis results
suggest that the blood LDL-C is an independent risk factor for ACVI.
Furthermore, the multiple logistic regression analyses also indicated there was a signicant trend for an increased risk of ACVI
risk associated with higher LDL-C blood levels. This nding suggests that there might be a doseresponse relationship between
the increased risk of ACVI and increased LDL-C level.
To the best of our knowledge, few reports documented the relationship between ACVI and blood LDL-C levels. Although one other
study [23] has suggested there might be a relationship between
an increased risk of ACVI and increased hypercholesterolemia, this
previous study has a poorer reliability than our current study due
to the small sample size and the use of an unauthorized method
for evaluating the color vision. In our study, we found 31 ACVI subjects out of the 872 enrolled participants. In contrast to the previous
study, we evaluated the ACVI by using the gold standards for ACVI
diagnosis [7], the FM 100-hue test and the criteria of Verriest et
al. [17].
The etiology of ACVI is multifactorial, which includes prereceptoral, receptoral, and post-receptoral mechanisms [7]. ACVI
has been demonstrated to occur in a variety of patient populations
in association with ocular diseases (senile cataract, age-related
macular degeneration [AMD], cone degenerations, optic neuritis,
and glaucoma), use of certain medications (antiepileptic drugs,
anti-malarial drugs, and antituberculosis drugs), and various chemical substances (solvent mixtures, styrene, perchloroethylene,
toluene, carbon disulphide, and ethanol) [710]. While it is difcult to elucidate the effects of these factors on the pathology of
ACVI [7], strict differential diagnosis criteria between ACVI and
no ACVI and the multivariable analysis adjusted for the reported
risk factors [1115] supports the verity of our current results.
The lack of association between ACVI and ocular diseases such
as cataract and glaucoma is most likely because of the exclusion
of the severe cases due to the deterioration in visual acuity. The
results were unchanged if all cataract and glaucoma patients were
excluded from the analysis (table not shown). We were able to conrm that diabetes without signicant retinopathy is also a strong
risk factor for ACVI, which is in agreement with previous ndings reported in the Early Treatment Diabetic Retinopathy Study
[11].
The current results would indicate that increased LDL-C is able
to cause morphologic and functional changes in the retina and the
higher visual pathways due to atherosclerotic or other effects on
the ocular capillaries or ocular neurons [7,8]. Although the detailed
mechanism remains unclear, there are several possible mechanisms that may account for our ndings. Recently, Alcala et al.
reported nding a signicant positive correlation between the LDLC level and the deterioration in the visual eld [24]. These results
suggest that a rise in cholesterol plasma concentration might negatively modify the function of the neuron entrusted with vision.
Animal studies have shown that lipid metabolism dysfunction
can induce ultrastructural changes in the retinal cells, increase

the intraneural immunoreactivity of Amyloid beta-peptide (Ab)

[6], and signicantly reduce cell numbers in the retinal layers
[25]. Moreover, electrophysiologic studies have shown there is an
impairment of the visual pathways in hypercholesterolemic mice
[25,26]. These studies suggest that blood cholesterol might play an
important role in the deterioration of the retinal or higher visual
function, which are consistent with current results.
There is growing evidence that cholesterol is linked to the development of neurodegenerative disease, in particular, Alzheimers
disease (AD) [26]. It has also been proposed that vascular factors
might have a toxic effect on the microvasculature of susceptible
brain regions [2]. Evidence has been reported that suggests there
is axonal degeneration in the optic nerve in AD, with a marked
decreased in the number of ganglion cells [27]. Thus, an alternative hypothesis is that ACVI due to hyperlipemia may be linked
to early subclinical neurological symptoms in the late-onset neurodegenerative diseases. Electrophysiologic studies support the
notion that the visual pathways in patients with AD are impaired
as compared to those found in patients without AD [28]. Pathological and intravascular ultrasound studies of young adults have
demonstrated that histological evidence of neurobrillary tangle
formation can be seen starting from 40 to 50 years prior to the
onset of dementia [1]. These pathological ndings are not contrary
to our results, as the deterioration of color discrimination ability has
long been recognized as an impairment that can precede the onset
of clinically detectable changes [69]. Nevertheless, these relationships still have to be considered to be hypothetical [28] due to the
long latency that is associated with their incidence.
There are several limitations that should be kept in mind with
regard to our current results. First, even though our ndings suggest that there is a relationship between the LDL-C levels and
the prevalence of ACVI, the etiology and the detailed mechanisms
have yet to be clearly elucidated. A second limitation is related to
design of the current study. Cross-sectional studies are not able
to determine the long-term changes in the LDL-C levels and the
associated time points for the incidence of ACVI. Therefore, in
order to assess the causal relationship between the LDL-C levels
and the incidence of ACVI, a longitudinal approach needs to be
employed. A nal limitation is that since the study population consisted entirely of middle-aged healthy Japanese males, this might
restrict the external validity of the current study. Woo and Lee have
reported that differences in macular pigmentation between Caucasians and Asians can cause substantial differences in the results
of the FM 100-hue test [29]. However, to our knowledge, few studies have investigated the prevalence of ACVI in a large population of
middle-aged healthy Japanese males. The prevalence rate that was
determined for the 40-year age span of our subjects was approximately 4.5%, which appears to be similar to the results reported
by Verriest et al. [17]. Thus, the high participation rate (90.3%), low
amounts of missing data, use of eligibility criteria, and an approved
diagnostic method suggest our study is internally valid. To further
conrm our results, a prospective cohort study that employs a more
generalized population will need to be undertaken.
In conclusion, the ndings of this cross-sectional study indicate
that the blood LDL-C levels have a positive relationship with the
prevalence of ACVI, which is one of the indicators of neurological
symptoms. This relationship might possibly be explained by the
deterioration of the neurological function that is associated with
the abnormality of the lipid metabolites. Our current data is also
useful and important as it provides information that can be used to
further investigate many of these associations.
Conict of interest
The authors have no proprietary interest in any aspect of this
study.

T. Shoji et al. / Atherosclerosis 210 (2010) 542547

Acknowledgments
The authors wish to thank The Okubo Color Study team, in particular, K. Tanaka for subject recruitment; A. Katagiri for help in
preparing the study; K. Sintomi, Y. Usuda, T. Kanazaki, N. Nakai, Y.
Komatsu, and T. Bessho for clinical input; and the volunteers for
participating in the study. In addition, we wish to thank Ms. Lynda
Charters for her linguistic and editorial support.
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