Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment

Abstract

Concord grape juice contains polyphenol compounds, which have antioxidant and anti-inflammatory properties and influence neuronal signalling. Concord grape juice supplementation has been shown to reduce inflammation, blood pressure and vascular pathology in individuals with CVD, and consumption of such flavonoid-containing foods is associated with a reduced risk for dementia. In addition, preliminary animal data have indicated improvement in memory and motor function with grape juice supplementation, suggesting potential for cognitive benefit in ageing humans. In this initial investigation of neurocognitive effects, we enrolled twelve older adults with memory decline but not dementia in a randomised, placebo-controlled, double-blind trial with Concord grape juice supplementation for 12 weeks. We observed significant improvement in a measure of verbal learning and non-significant enhancement of verbal and spatial recall. There was no appreciable effect of the intervention on depressive symptoms and no effect on weight or waist circumference. A small increase in fasting insulin was observed for those consuming grape juice. These preliminary findings suggest that supplementation with Concord grape juice may enhance cognitive function for older adults with early memory decline and establish a basis for more comprehensive investigations to evaluate potential benefit and assess mechanisms of action.

Full text

Concord grape juice supplementation improves memory function in older
adults with mild cognitive impairment
Robert Krikorian
1
*, Tiffany A. Nash
1
, Marcelle D. Shidler
1
, Barbara Shukitt-Hale
2
and James A. Joseph
2
1
Department of Psychiatry, University of Cincinnati Academic Health Center, Cincinnati, OH, USA
2
USDA Human Nutrition Research Center on Aging and Tufts University, Boston, MA, USA
(Received 1 May 2009 – Revised 3 September 2009 – Accepted 4 September 2009 – First published online 23 December 2009)
Concord grape juice contains polyphenol compounds, which have antioxidant and anti-inflammatory properties and influence neuronal signalling.
Concord grape juice supplementation has been shown to reduce inflammation, blood pressure and vascular pathology in individuals with CVD,
and consumption of such flavonoid-containing foods is associated with a reduced risk for dementia. In addition, preliminary animal data have
indicated improvement in memory and motor function with grape juice supplementation, suggesting potential for cognitive benefit in ageing
humans. In this initial investigation of neurocognitive effects, we enrolled twelve older adults with memory decline but not dementia in a ran-
domised, placebo-controlled, double-blind trial with Concord grape juice supplementation for 12 weeks. We observed significant improvement in
a measure of verbal learning and non-significant enhancement of verbal and spatial recall. There was no appreciable effect of the intervention on
depressive symptoms and no effect on weight or waist circumference. A small increase in fasting insulin was observed for those consuming grape
juice. These preliminary findings suggest that supplementation with Concord grape juice may enhance cognitive function for older adults with
early memory decline and establish a basis for more comprehensive investigations to evaluate potential benefit and assess mechanisms of action.
Memory: Cognitive impairment: Elderly: Grape juice: Polyphenols
Worldwide dementia prevalence is almost 25 million cases
and is projected to reach more than 81 million cases by the
year 2040
(1)
. Alzheimer’s disease comprises 60 to 80 % of
cases of dementia
(2)
. The construct mild cognitive impair-
ment
(3)
identifies individuals with elevated risk for demen-
tia
(4)
, and progression from mild cognitive impairment to
Alzheimer’s disease can be as high as 10 % per year
(5)
.
Further, there are indications that even age-associated
memory impairment, originally conceptualised as benign
forgetfulness
(6,7)
, can reflect very early neurodegeneration.
Older adult samples with subjective memory complaints
who meet criteria for age-associated memory impairment
show degradation in the medial temporal lobe that is similar,
albeit not as extensive, as that observed in subjects with
mild cognitive impairment and Alzheimer’s disease
(8)
, and
longitudinal investigation has shown a trebling of risk for
those categorised as having age-associated memory impair-
ment
(9,10)
. Such findings imply that memory complaints and
associated manifestations in everyday functioning can be
meaningful indicators of neurodegeneration. Preventive inter-
ventions initiated when early memory decline is evident have
the potential to forestall progression, most likely at the final
stage when such treatment might be effective
(11)
.
Regulation of inflammation generally is reduced with
ageing
(12)
, and accelerated inflammation is implicated in
neurodegenerative disorders such as Alzheimer’s disease
(13)
.
Berry fruits contain polyphenol compounds, which have
anti-inflammatory and antioxidant properties
(14)
. Polyphenols
also induce neuroprotective effects and influence neuronal
signalling involved in memory function
(14 – 16)
, and specific
constituents of grape juice have exhibited neuroprotective
effects
(17)
.
Concord grape juice contains a variety of flavonoids and
antioxidants, among them anthocyanins and proanthocyani-
dins
(18,19)
and comparatively high levels of total phenolics
(20)
.
Information concerning flavonoid transport into the central
nervous system and absorption into brain tissue is emerging.
A number of recent studies have indicated that certain of
these compounds, in particular anthocyanins, cross the
blood–brain barrier, although specific mechanisms have not
been established
(21 – 23)
. In addition, anthocyanins have been
identified in brain regions that mediate cognition, including
the medial temporal lobe and cortex
(24)
, and hippocampal dis-
tribution has been associated with behavioural enhancement in
animal supplementation studies
(24,25)
.
Human trials have shown that short- and moderate-term
supplementation with grape juice produces benefit in individ-
uals with CVD, including increased serum antioxidant
capacity and reduced LDL oxidation
(19)
, improved endothelial
function
(26)
and reduced platelet aggregation
(27)
. Such findings
are pertinent with respect to age-related cognitive decline
because of the strong relationship between CVD and neurode-
generation
(28 – 31)
. Epidemiological studies indicate that con-
sumption of fruits and vegetables is associated with lower
risk of neurodegenerative disorders and better cognitive per-
formance in the elderly
(32 – 34)
, and these effects have been
*Corresponding author: Dr Robert Krikorian, fax þ1 513 558 0877, email robert.krikorian@uc.edu
British Journal of Nutrition (2010), 103, 730–734 doi:10.1017/S0007114509992364
qThe Authors 2009
British Journal of Nutrition

attributed to the intake of a variety of flavonoid compounds
with antioxidant and anti-inflammatory properties. Recently,
a preliminary animal study demonstrated that ingestion of
Concord grape juice for 6 – 8 weeks induced enhancement of
cognitive performance in aged rodents
(35)
.
We sought to assess the effect of supplementation with
Concord grape juice on memory performance in older adults
with early age-related memory decline in a controlled trial
as an initial assessment of potential benefit in an at-risk
sample. We also obtained data on mood, anthropometrics
and metabolic parameters.
Methods
Participants
Participants were recruited from the general community with
newspaper advertising soliciting older adults with early
memory decline but not dementia for a dietary intervention
study. We enrolled twelve participants (eight men, four
women) with acquired memory changes such as forgetfulness
and prospective memory lapses. The mean age of the entire
sample was 78·2 (SD 5·0) years and the mean educational
level was 14·1 (SD 2·9) years.
Procedure
Prospective participants were assessed with structured inter-
view instruments to determine eligibility for study inclusion.
The Academic and Medical History Questionnaire
(36)
was
used to obtain demographic information and information
regarding academic attainment, current and past medical
conditions, and medication and substance use. Those with dia-
betes, substance-abuse disorder, or diagnosed psychiatric or
neurological condition were excluded. The level of memory
impairment was determined with the Clinical Dementia
Rating
(37)
, which elicits information from the participant and
an informant (typically, spouse or adult child) about the
nature and extent of cognitive decline as manifested in activi-
ties at home and in the community. The domains memory,
orientation, problem solving, community affairs, home activi-
ties and personal care were evaluated to determine a dementia
staging classification. Scores for each domain contributed to a
global Clinical Dementia Rating classification with the
memory domain weighted most heavily. Clinical Dementia
Rating classifications include no impairment, mild decline,
and mild, moderate and severe dementia. We enrolled individ-
uals with mild decline and excluded those with Clinical
Dementia Rating classifications indicating no impairment
and those with mild, moderate and severe dementia. A sum
of boxes score also was derived
(38)
. This score represented
the arithmetic sum of the category scores across the six
domains of functioning and served to quantify level of func-
tional decline.
Seven subjects were randomly assigned to receive the
placebo beverage and five were assigned to receive 100 %
Concord grape juice. Placebo and juice were provided for
the research by Welch Foods, Inc. (Concord, MA, USA).
The placebo beverage contained no juice or natural poly-
phenol but was formulated to look and taste like grape juice
and to have the same carbohydrate composition and energy
load (3·0 kJ/ml). The intervention involved 12 weeks of
daily consumption of juice or placebo with assessments at
pre-treatment baseline and during the final week of the inter-
vention. Previous human trials examining antioxidant effects,
endothelial function and cardioprotection in healthy subjects
and those with CVD used briefer interventions, of the order
of 2–4 weeks
(17,20 – 21)
. We chose a longer intervention
period because our outcomes concerned cognitive – cerebral
function in older adults, and there are indications in pre-
clinical studies with other berry fruits that several weeks may
be required for accumulation in brain regions
(39)
. We instituted
a dosing schedule determined by body weight to maintain
daily consumption between 6 and 9 ml/kg, a range consistent
with other human grape juice trials
(17,20 – 21)
. Individuals
weighing 54 to 64 kg were prescribed 444ml/d, those weighing
between 65 and 76 kg consumed 532 ml/d, and those weighing
between 77 and 91 kg consumed 621 ml/d. Participants were
instructed to take daily quantities in equal, divided dosages
with the morning, midday and evening meals.
The primary outcomes were neurocognitive measures of
memory function administered before and after the interven-
tion. The California Verbal Learning Test
(40)
was administered
to assess verbal learning and retention, and the Spatial Paired
Associate Learning Test
(41)
was used to evaluate non-verbal
memory. The California Verbal Learning Test is a list-
learning and recall task, and the Spatial Paired Associate
Learning Test assesses memory for visual-spatial information
that is not amenable to verbal encoding. Both list-learning and
paired associate tasks have been used in the context of cogni-
tive ageing and dementia and are among the more sensitive
measures of memory decline associated with neurodegene-
ration
(42 – 44)
. We also assessed mood as a potential covariate
of the cognitive measures with the Geriatric Depression
Scale
(45)
. We performed weight and waist circumference
measures and obtained fasting blood samples for deter-
mination of serum glucose and insulin values.
Analyses of covariance were performed for each outcome
factor to isolate effects of the intervention while controlling
for individual differences
(46)
. The outcome score from the
final visit was the dependent measure and the corresponding
score from the baseline visit and the depressive symptom
score were covariate measures. We used eta squared values
to derive Cohen’s feffect size estimates, which are character-
ised as small (0·10), medium (0·25) and large (0·40)
(47)
.
Fig. 1. List acquisition performance assessing verbal learning on the
California Verbal Learning Test. Values are adjusted means, with standard
errors represented by vertical bars. Subjects consuming Concord grape juice
demonstrated significant improvement (F(1, 8) ¼5·55; P¼0·04; Cohen’s
f¼0·28).
Grape juice supplementation improves memory 731
British Journal of Nutrition

The present study was conducted according to the guide-
lines laid down in the Declaration of Helsinki and all
procedures involving human subjects were approved by the
University of Cincinnati Medical Institutional Review Board.
Written informed consent was obtained from all subjects.
Results
At pre-intervention baseline there was a modest, non-
significant difference for age between the groups (80 v. 75
years; t(10) ¼1·8; P¼0·10). There was no group difference
for educational level (13·4 v. 15·2 years; t(10) ¼1·02;
P¼0·32), index of functional impairment (Clinical Dementia
Rating sum of boxes score 1·0 v. 1·0; t(10) ¼0·0; P¼1·0),
weight (74·3 v. 79·4 kg; t(10) ¼1·04; P¼0·32) and waist
circumference (92·7 v. 96·7 cm; t(10) ¼0·81; P¼0·43).
There was a group difference for level of depressive
symptoms (Geriatric Depression Scale score 7·8 v. 3·0;
t(10) ¼2·19; P¼0·05), with greater depressive symptomology
among the placebo subjects. However, the symptom level
was not clinically elevated for either group
(48)
.
Both the juice and placebo beverage were generally well
tolerated, and there was no consistently reported adverse
effect. Discrete concerns included, for example, increased
frequency of urination associated with greater fluid
consumption and aversion to the taste of the juice or placebo
that developed over time.
As shown in Fig. 1, analysis of covariance demonstrated a
significant effect (P¼0·04) for item acquisition across learning
trials on the California Verbal Learning Test, indicating
improvement for subjects in the Concord grape juice group
relative to those receiving placebo. The effect size was mod-
erate (Cohen’s f¼0·28). Also, there were trends toward
improved performances for the grape juice subjects with
respect to delayed verbal recall (P¼0·10; Cohen’s f¼0·33)
and spatial memory (P¼0·12; Cohen’s f¼0·67), although
these were not statistically significant (Fig. 2).
There was no appreciable effect of the intervention on
depressive symptoms (adjusted Geriatric Depression Scale
scores 5·0 v. 7·2; F(1,8) ¼2·56; P¼0·14) and no effect on
weight (77·5 v. 77·8 kg, adjusted values; F(1, 8) ¼0·31;
P¼0·58) or waist circumference (94·9 v. 95·5 cm, adjusted
values; F(1, 8) ¼0·24; P¼063). Fasting glucose values were
not affected by the intervention (1011 v. 975 mg/l, adjusted
values; F(1, 8) ¼0·42; P¼0·53), but fasting insulin at
12 weeks was significantly elevated for the subjects consum-
ing grape juice (10·0 v. 13·7 mU/ml, adjusted values;
F(1, 8) ¼6·07; P¼0·03). Table 1 contains the unadjusted
mean scores for the outcome measures and shows the changes
in absolute values from the baseline to final assessment.
Discussion
In this preliminary study we sought to assess the effect of
moderate-term supplementation with 100 % Concord grape
juice on cognition in older adults with early memory decline
and found that memory function was improved with regular
grape juice consumption. To our knowledge, this is the first
controlled human trial examining neurocognitive response to
this dietary intervention, and our findings are consistent with
those of a recent animal study showing improvement in
cognitive performance with grape juice supplementation in
aged rodents
(35)
. Our data do not provide information as
to possible mechanisms leading to the beneficial effects.
However, given the existing body of research concerning
reductions of inflammatory and oxidative stress markers in
human subjects with CVD and lower risk of age-related
neurodegeneration with flavonoid consumption, these putative
mechanisms would be primary considerations.
Fig. 2. Delayed recall performance for verbal material on the California
Verbal Learning Test (F(1, 8) ¼3·37; P¼0·10; Cohen’s f¼0·35) and for
visual-spatial material on the Spatial Paired Associate task (F(1, 8) ¼3·23;
P¼0·12; Cohen’s f¼0·67). Subjects consumed either Concord grape juice
() or a placebo drink ( ). Values are adjusted means, with standard errors
represented by vertical bars.
Table 1. Unadjusted mean values for memory, mood, anthropometric and metabolic measures by group*
Placebo (n7) Concord grape juice (n5)
Baseline Final Difference Baseline Final Difference
CVLT learning 33·2 33·2 0·0 35·2 38·6 3·4
CVLT recall 5·4 5·0 20·4 6·0 7·2 1·2
S-PAL 2·4 2·0 20·4 2·8 4·5 1·7
GDS 7·8 7·2 20·6 3·0 5·0 2·0
Weight (kg) 74·3 74·9 0·6 79·4 80·4 1·0
Waist (cm) 92·7 93·0 0·3 96·7 97·5 0·8
Glucose (mg/l) 1002 999 23 915 987 72
Insulin (mU/ml) 11·9 11·1 20·8 9·6 12·6 3·0
CVLT, California Verbal Learning Test; S-PAL, Spatial Paired Associate Learning Test; GDS, Geriatric Depression Scale.
* Baseline refers to measures obtained at the pre-intervention assessment. Final refers to measures obtained during the
final week of the intervention. Difference ¼final score less baseline score.
R. Krikorian et al.732
British Journal of Nutrition

Recent preliminary data involving pharmaceutical TNF-a
inhibition have suggested that acute functional improvement
can be observed in patients with Alzheimer’s disease
(49,50)
,
indicating that suppression of a pro-inflammatory cytokine
can ameliorate mental decline even in patients with substan-
tially more advanced neurodegeneration than in our sample
of mild cognitive impairment subjects. Accordingly, consist-
ent application of a food product with anti-inflammatory
effects over a brief to moderate timeframe also might
be expected to induce cognitive– cerebral enhancement,
especially in individuals with very early neurodegeneration.
Pre-clinical data indicating absorption of anthocyanins in
brain regions mediating cognition and associations with beha-
vioural indices of cognitive function
(24,25)
also would support
the notion that the demonstrated improvement in memory abil-
ity may reflect reduced inflammation and/or enhanced neural
function in response to the intervention. While it is not yet
clear to what extent and by what mechanism berry fruit con-
stituents cross the blood– brain barrier, anthocyanins have
been identified in specific brain tissues even when not detected
in plasma
(51,52)
. And, it may be that consistent, moderate-term
consumption is necessary to achieve sufficient concentrations
in brain sites
(39)
. Further study of Concord grape juice
supplementation for greater duration with memory and inflam-
matory marker outcomes will be important. Other putative
mechanisms including reduction of oxidative stress and
enhanced neuronal signalling also merit investigation, as
these factors have been demonstrated to be important in
animal studies with blueberry supplementation
(53,54)
.
Our preliminary data indicated increased fasting insulin for
those who received grape juice in the absence of changes in
weight and waist circumference. This finding was unantici-
pated and is provocative given the matched carbohydrate
load in the placebo beverage and the fact that group
differences in metabolic parameters were not observed before
the intervention. It is possible that increased insulin secretion
was induced by constituents of the grape juice other than
sugars. There are data indicating that anthocyanins derived
from blueberries influence metabolic function, in particular
enhancing the actions of insulin
(54,55)
. It may be that similar
or related actions were induced in the present study, with con-
sistent grape juice consumption resulting in increased insulin
secretion. However, such notions are speculative, particularly
given the small scale of this preliminary trial. Certainly, this
issue warrants further investigation with respect to its reprodu-
cibility and the specific nature and basis for the effect.
The major limitation of the present study was the small
sample size, which limited power to detect differences.
However, the moderate to large effect sizes indicate that it
would be worthwhile to conduct larger trials to evaluate the
neurocognitive benefits and putative mechanisms of Concord
grape juice supplementation in pre-dementia conditions.
In view of the public health burden associated with neuro-
degeneration and Alzheimer’s disease, in particular, safe,
low-cost dietary interventions offer the possibility of inducing
substantial benefit.
Acknowledgements
Funding and material support was provided by Welch Foods,
Inc. (Concord, MA, USA).
R. K. conceived of the study and supervised the data
collection, analyses, interpretation and manuscript preparation.
T. A. N. and M. D. S. participated in data collection,
interpretation and manuscript preparation. B. S.-H. and
J. A. J. participated in manuscript preparation.
None of the authors has a financial interest in the supporting
company or the outcome of the research activity.
References
1. Ferri CP, Prince M, Brayne C, et al. (2005) Global prevalence
of dementia: a Delphi consensus study. Lancet 366, 2112–2117.
2. Alzheimer’s Association (2008) 2008 Alzheimer’s disease facts
and figures. Alzheimers Dement 4, 110–133.
3. Petersen RC (2004) Mild cognitive impairment as a diagnostic
entity. J Intern Med 256, 183–194.
4. Chertkow H, Nasreddine A, Joanette Y, et al. (2007) Mild
cognitive impairment and cognitive impairment, no dementia:
part A, concepts and diagnosis. Alzheimers Dement 3, 266 – 282.
5. Mitchell AJ & Shiri-Feshki M (2009) Rate of progression of
mild cognitive impairment to dementia – meta-analysis of 41
robust inception cohort studies. Acta Psychiatr Scand 119,
252–265.
6. Crook TH, Bartus RT, Ferris SH, et al. (1986) Age-associated
memory impairment: proposed diagnostic criteria and measures
of clinical change. Dev Neuropsychol 2, 261 –276.
7. Neilsen H, Lolk A & Kragh-Sorensen P (1998) Age-associated
memory impairment – pathological memory decline or normal
aging? Scand J Psychol 39, 33–37.
8. Goldman WP & Morris JC (2001) Evidence that age-associated
memory impairment is not a normal variant of aging. Alzheimer
Dis Assoc Disord 15, 72–79.
9. Reid LM & MacLullich AMJ (2006) Subjective memory
complaints and cognitive impairment in older people. Dement
Geriatr Cogn Disord 22, 471–485.
10. Saykin AJ, Wishart HA, Rabin LA, et al. (2006) Older adults
with cognitive complaints show brain atrophy similar to that
of amnestic MCI. Neurology 76, 834–842.
11. Cotman CW (2000) Homeostatic processes in brain aging: the
role of apoptosis, inflammation, and oxidative stress in regulat-
ing healthy neural circuitry in the aging brain. In The Aging
Mind: Opportunities in Cognitive Research, pp. 114 –143
[P Stern and L Carstensen, editors]. Washington, DC: National
Academy Press.
12. Franceschi C, Capri M, Monti D, et al. (2007) Inflammaging
and anti-inflammaging: a systematic perspective on aging and
longevity emerged from studies in humans. Mech Ageing Dev
128, 92–105.
13. Giunta B, Fernandez F, Nilolic WV, et al. (2008) Inflammaging
as a prodrome to Alzheimer’s disease. J Neuroinflammation 5,
51–65.
14. Ishige K, Schubert D & Sagar Y (2001) Flavonoids protect
neuronal cells by three different mechanisms. Free Radic Biol
Med 30, 433–446.
15. Joseph JA, Arendash G, Gordon M, et al. (2003) Blueberry
supplementation enhances signaling and prevents behavioral
deficits in an Alzheimer’s disease model. Nutr Neurosci 6,
153–162.
16. Olszanecki R, Gebska A, Kozlovski VI, et al. (2002) Flavonoids
and nitric oxide synthase. J Physiol Pharm 53, 571 –584.
17. Conte A, Pellegrini S & Tagliazucchi D (2003) Synergistic
protection of PC12 cells from b-amyloid toxicity by resveratrol
and catechin. Brain Res Bull 62, 29–38.
18. O’Byrne DJ, Devaraj S, Grundy SM, et al. (2002) Comparison
of the antioxidant effects of Concord grape juice flavonoids and
Grape juice supplementation improves memory 733
British Journal of Nutrition

a-tocopherol on markers of oxidative stress in healthy adult.
Am J Clin Nutr 76, 1367–1374.
19. Rice-Evans CA, Miller NJ & Paganga G (1996) Structure –
antioxidant activity relationships of flavonoids and phenolic
acids. Free Radic Biol Med 20, 933 –956.
20. Mullin W, Marks SC & Crozier A (2007) Evaluation of
phenolic compounds in commercial fruit juices and fruit
drinks. J Agric Food Chem 55, 3148–3157.
21. Singh M, Arseneault M, Sanderson T, et al. (2008) Challenges
for research on polyphenols from foods in Alzheimer’s disease:
bioavailability, metabolism, and cellular and molecular mechan-
isms. J Agric Food Chem 56, 4855–4873.
22. Youdim KA, Shukitt-Hale B & Joseph JA (2004) Flavonoids
and the brain: interactions at the blood –brain barrier and their
physiological effects on the central nervous system. Free
Radic Biol Med 37, 1683–1693.
23. Youdim KA, Qaiser MZ, Begley D, et al. (2004) Flavonoid
permeability across an in situ model of the blood –brain barrier.
Free Radic Biol Med 36, 592 –604.
24. Andres-Lacueva C, Shukitt-Hale B, Galli RL, et al. (2005)
Anthocyanins in aged blueberry-fed rats are found centrally
and may enhance memory. Nutr Neurosci 8, 111 –120.
25. Williams CM, El Moshen MA, Vauzour D, et al. (2008)
Blueberry-induced changes in spatial working memory correlate
with changes in hippocampal CREB phosphorylation and
brain-derived neurotrophic factor (BDNF) levels. Free Radic
Biol Med 45, 295–305.
26. Chou EJ, Keevil JG, Aeschlimann S, et al. (2001) Effect of
ingestion of purple grape juice on endothelial function in
patients with coronary heart disease. Am J Cardiol 88,
553–555.
27. Freedman JE, Parker C, Li L, et al. (2001) Select flavonoids and
whole juice from purple grapes inhibit platelet function and
enhance nitric oxide release. Circulation 103, 2792 – 2798.
28. Kalaria RN (2000) The role of cerebral ischemia in Alzheimer’s
disease. Neurobiol Aging 21, 321–330.
29. Rober AE, Garani Z, Alexandrov AV, et al. (2006) Interaction
of cardiovascular disease and neurodegeneration: transcranial
Doppler ultrasonography and Alzheimer’s disease. Neurol Res
28, 672–678.
30. Skoog I & Gustafson D (2003) Hypertension, hypertension-
clustering factors and Alzheimer’s disease. Neurol Res 25,
675–680.
31. Swan FE, Carmelli D & La Rue A (1998) Systolic blood
pressure tracking over 25 to 30 years and cognitive performance
in older adults. Stroke 29, 2334–2340.
32. Dai Q, Bornstein AR, Wu Y, et al. (2006) Fruit and vegetable
juices and Alzheimer’s disease: The Kame Project. Am J Med
119, 751–759.
33. Nurk E, Refsum H, Drevon CA, et al. (2009) Intake of
flavonoid-rich wine, tea and chocolate by elderly men and
women is associated with better cognitive test performance.
J Nutr 139, 120–127.
34. Letenneur L, Proust-Lima C, Le Gouge A, et al. (2007)
Flavonoid intake and cognitive decline over a 10-year period.
Am J Epidemiol 165, 1364–1371.
35. Shukitt-Hale B, Carey A, Simon L, et al. (2006) Effects of
Concord grape juice on cognitive and motor deficits in aging.
Nutrition 22, 295–302.
36. Krikorian R, Zimmerman ME & Fleck DE (2004) Inhibitory con-
trol in obsessive-compulsive disorder. Brain Cogn 54, 257 –259.
37. Hughes CP, Berg L, Danziger WL, et al. (1982) A new clinical
scale for the staging of dementia. Br J Psychiatry 140, 566–572.
38. Lynch CA, Walsh C, Blanco A, et al. (2006) The clinical
dementia rating sum of box score in mild dementia. Dement
Geriatr Cogn Disord 21, 40–43.
39. Willis LM, Shukitt-Hale B & Joseph JA (2009) Recent
advances in berry supplementation and age-related cognitive
decline. Cur Opin Clin Nutr Metab Care 12, 91–94.
40. Delis DC, Kramer JH, Kaplan E, et al. (2000) California
Verbal Learning Test, 2nd ed. San Antonio, TX: Psychological
Corp.
41. Krikorian R (1996) Independence of verbal and spatial paired
associate learning. Brain Cogn 32, 219–223.
42. Greenaway MC, Lacritz LH, Binegar D, et al. (2006) Patterns of
verbal memory performance in mild cognitive impairment,
Alzheimer’s disease, and normal aging. Cogn Behav Neurol
19, 79–84.
43. Fowler KS, Saling MM, Conway EL, et al. (2001) Paired
associate performance in the early detection of DAT. J Int
Neuropsychol Soc 8, 58–71.
44. Sahakian B, Downes J, Eagger S, et al. (1990) Sparing of atten-
tional relative to mnemonic function in a subgroup of patients
with dementia of the Alzheimer’s type. Neuropsychologia 28,
1197–1213.
45. Yesavage JA, Brink TL, Rose TL, et al. (1983) Development
and validation of a geriatric depresssion rating scale: a pre-
liminary report. J Psychiatr Res 17, 37–49.
46. Sheeber LB, Sorensen ED & Howe SR (1996) Data analytic tech-
niques for treatment outcome studies with pretest/posttest
measurements: an extensive primer. J Psychiatr Res 30, 185 –199.
47. Cohen J (1988) Statistical Power Analysis for the Behavioral
Sciences, 2nd ed. New York: Lawrence Erlbaum Associates.
48. Olin JT, Schneider LS, Eaton EM, et al. (1992) The Geriatric
Depression Scale and the Beck Depression Inventory as screen-
ing instruments in an older adult outpatient population. Psychol
Assess 4, 190–192.
49. Griffin WS (2008) Perispinal etanercept: potential as an
Alzheimer therapeutic. J Neuroinflammation 5,3.
50. Tobinick EL & Gross H (2008) Rapid cognitive improvement in
Alzheimer’s disease following perispinal etanercept adminis-
tration. J Neuroinflammation 5,2.
51. Shukitt-Hale B, Lau FC & Joseph JA (2008) Berry fruit
supplementation and the aging brain. J Agric Food Chem 56,
636–641.
52. Kalt W, Blumberg JB, McDonald JE, et al. (2008) Identification
of anthocyanins in the liver, eye, and brain of blueberry-fed
pigs. J Agric Food Chem 56, 705–712.
53. Casadesus G, Shukitt-Hale B, Stellwagen HM, et al. (2004)
Modulation of hippocampal plasticity and cognitive behavior
by short-term blueberry supplementation in aged rats. Nutr
Neurosci 7, 309–316.
54. Martineau LC, Couture A, Spoor D, et al. (2006) Anti-diabetic
properties of the Canadian lowbush blueberry Vaccinium
angustifolium Ait. Phytomedicine 13, 612 –623.
55. Tsuda T (2008) Regulation of adipocyte function by antho-
cyanins: possibility of preventing the metabolic syndrome.
J Agric Food Chem 56, 642 – 646.
R. Krikorian et al.734
British Journal of Nutrition