Effect of Elderberry Juice on Cognition and Inflammation in Patients With Mild Cognitive Impairment
Phase: PHASE1
Conditions: Mild Cognitive Impairment
Sponsor: University of Missouri-Columbia

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PROTOCOL 
 
1. General Information 
 
1.1 Title:  
HSIRB# 126030 5/11/2016 Version 4 
Effect of elderberry juice on cognition and inflammation in patients with mild cognitive 
impairment  
 
1.2 Sponsor:  
Mizzou Advantage 
 
1.3 Study Contact:  
Hannah M Rogers 
Doctoral Student Interdisciplinary Neuroscience Program 
hannahmrogers@mail.missouri.edu 
(573) 884-4263 
 
1.4 Investigators/Study Personnel Authorized to Obtain Consent:  
David Beversdorf, MD  
Departments of Neurology, Radiology, and Psychology 
beversdorfd@health.missouri.edu 
 
Joel Shenker, MD, PhD  
Department of Neurology 
shenkerj@health.missouri.edu 
 
John Hegarty, MA 
Interdisciplinary Neuroscience Program 
jphpn7@mail.missouri.edu 
 
 
1.5 Trial Sites: 
University of Missouri Health System 
University-Physicians Neurology Clinic 
1020 Hitt St Columbia, MO 65211 
573-882-1515 
 
University of Missouri School of Medicine 
Center for Translational Neuroscience 
Department of Radiology, M741 
One Hospital Dr Columbia, MO 65211 
573-884-5229 
 
1.6 Associated Sites:  
Nutritional Immunology Lab 

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110B Animal Science Research Center 
Division Of Animal Sciences  
Columbia, MO 65211 
 
 
Behavioral Neuroscience Lab 
340E Life Sciences Center 
Bond Life Sciences Center 
Columbia, MO 65211 
 
2. Background Information 
2.1 Name and description of the investigational product(s): 
 
Recent research has revealed potent antioxidant and anti-inflammatory effects of elderberry fruit 
preparations. Elderberries have traditionally been used for pain relief, swelling/inflammation, 
urine production, as a laxative, and as a flavoring in food. 
This is one of the botanical agents being studied by the MU Center for Botanical Interaction 
Studies as funded by P50AT006273.  
2.2 A summary of findings from studies that potentially have clinical significance and of the 
known and potential risks and benefits, if any, to human subjects: 
 
Elderberries have been shown in a number of studies to have significant anti-inflammatory and 
antioxidant effects. It is one of the richest sources of anthocyanins, and is rich in vitamins B2, C, 
folic acid, biotin, nicotinic acid, beta-carotene, B6, and pantothenic acid (1). Multiple in vitro 
studies have supported the anti-inflammatory and antioxidant effects of elderberry preparations 
(reviewed in (1)). Animal studies have also revealed significant anti-inflammatory and 
antioxidant effects (2). Population studies examining factors that may decrease the risk of 
Alzheimer’s disease, such as the Kame project, have revealed that drinking juices rich in 
polyphenols is one of the most reliable factors conveying decreased risk for Alzheimer’s disease 
(3). Studies examining the effects of individual vitamins or isolated nutritional factors have 
yielded mixed results in neurodegenerative diseases such as Alzheimer’s disease, but recent 
evidence suggests that combinations of such factors may yield synergistic benefits (4). Research 
suggests that combination therapies including multiple dietary supplements and other current 
therapies in mild dementia patients results in improvements in cognitive performance reported to 
persist out to 12-24 months (5). Therefore, with the broad range of potential neuroprotective 
agents contained in elderberry preparations, this seems an ideal agent for utilization in a pilot 
clinical trial in neurodegenerative patients such as those at risk for Alzheimer’s disease. No 
controlled trial of elderberry has ever been done previously in Alzheimer’s or MCI. 
In our previous research, we examined the sensitivity of our visuospatial problem solving task 
for detecting change in cognitive performance with treatment in MCI patients. Twenty-two 

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subjects with MCI were recruited for our study with a Clinical Dementia Rating (CDR) (22,23) 
score of 0.5, and a Folstein Mini Mental Status Examination (MMSE) (24) score of at least 24. 
At the first visit, all subjects were given the MMSE in order to assess global function across 
several domains including memory, and the Hopkins Verbal Learning Test (25) to assess verbal 
memory, as well as non-memory tasks including the Boston Naming Test (BNT) (26) (primarily 
considered as assessing language (naming)), Rey Complex Figure copying (Rey CFT) (27-29) 
(primarily considered as assessing visuospatial ability), a series of anagrams (primarily 
considered as assessing verbal and divergent cognitive flexibility) (30) (Rearrange these letters to 
form an English word: OGRF, RDWO, FALC, LANI, MHBTU, HTRSI, DSLEI, TMLAE), and 
the visuospatial problem solving battery (VPS) adapted from the “matchstick” problems (15, 31). 
As with our previous work with these types of tasks (14,30), solution latencies were recorded for 
performance on both. There was no significant difference between the two groups at baseline. 
However, at one year, the treated group performed significantly better on their change scores 
than the not treated group for the VPS task (p=0.038). Of interest, there were also trends detected 
for better change scores in the treated group for the Rey CFT, BNT, anagrams, and importantly, 
the IADL. As with previous research (13), no effect was observed on the memory task, the 
HVLT (paper in preparation). We wish to determine the potential effects of elderberry juice on 
preserving cognitive functioning in a group of people at risk for cognitive impairments in the 
future.  
2.3 Description of and justification for the route of administration, dosage, dosage regimen, and 
treatment period(s): 
 
Twenty of the subjects will be randomly assigned to receive 5 ml elderberry juice by mouth, 
diluted in 8oz of water three times daily. The juice will be obtained from River Hills Harvest. 
Twenty control subjects will receive an equal amount of a flavored liquid with no nutritional 
content as a placebo control group. The placebo liquid will match the elderberry juice closely in 
color using commercially available colorants. Subjects will be allowed to mix the juice in 8oz of 
water if the bitterness of the juice makes it unpalatable. The clinicians will be blinded as to 
group, as will be the assessor. Neetu Nair, a graduate student in Dr. Beversdorf’s lab who is 
otherwise uninvolved in the study, will keep the unblinding code in case a need arises to break 
the code for clinical purposes or preliminary data analyses. Subjects will be given sufficient juice 
at each visit to last until the next visit. They will be provided a liquid medicine measuring spoon 
and instructed to measure out 5ml per dose. Subjects and caregivers will be asked to check each 
dose on a dose log, and bring back the used juice containers at each visit to confirm that a proper 
amount has been taken, as monitored by the assessor. Subjects taking less than 75% of the 
scheduled dose will be excluded. 
After initiation of elderberry juice or control, subjects will be retested at 12 weeks, visit 2, (the 
timeframe that revealed significant effects with other anthocyanin-rich fruit preparations (33,34), 
6 months, visit 3, and (pending resubmission for second year of support) 12 months, visit 4. The 

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need for pursuing follow-up at 12 months is to maximize the sensitivity for detecting incidence 
of progression to dementia with the CDR. Additionally at visits 2, 3, and 4 subjects will also be 
assessed with the Clinical Global Impression of Change (CGIC), which is a valid and reliable 
research tool for overall assessment of salient changes in patients (39), in which the blinded 
clinician rates the degree of change in the patient from the beginning of the study. The 
subject/caregiver will be given time to ask any questions and the clinician will be sure the 
subject/caregiver understands all instructions before dispensing liquid.  
2.4 A statement that the trial will be conducted in compliance with the protocol: 
 
All researchers and clinicians taking part in this study will conduct all practices in compliance 
with this protocol, proceed under Good Clinical Practice (GCP), and follow all regulatory 
requirements outlined by University, State, and Federal agencies.   
 
2.5 Description of the population to be studied: 
 
When examining the impact of an agent that acts on inflammation and has antioxidant properties, 
targeting neuroprotection, it is important to identify and treat patients at the earliest stage. 
Therefore, we propose to investigate the effects of elderberry juice in patients with mild 
cognitive impairment, MCI. MCI is characterized by impaired memory and preserved activities 
of daily living (6,7). Patients with this diagnosis are at significantly increased risk for developing 
dementia (8-10). Most researchers propose MCI as the mildest endpoint on the spectrum of 
Alzheimer’s disease (9). With the recent advances in treatment options for Alzheimer’s disease, 
much attention has been directed at intervention at earlier stages. Recent research has focused on 
whether or not agents may delay the progression from MCI to dementia (11, 12). In addition to 
any delay in or prevention of progression, it would also be of interest to determine whether 
agents result in any cognitive benefits for MCI patients. Studies have examined to effects of 
cholinesterase inhibitors, the first type of drug on the market for Alzheimer’s disease, on 
cognition and global assessment outcomes in MCI, and have revealed effects on global 
assessment, psychomotor speed, and attention, but not on specific memory tasks (13). 
Inclusion criteria: CDR score of 0.5 and an MMSE of at least 24, as well as have no known 
sensitivity to elderberry products, or presence of any health condition that in the clinical 
experience of the investigators might impair their ability to complete the study. Recruited 
subjects will be aged 50 or more. 
Exclusion criteria: Known history of sensitivity to elderberry products. Known allergy to 
honeysuckle. Current diagnosis of diabetes. Bleeding disorder. Currently pregnant. Currently 
making changes to other drugs that might affect cognitive performance (subjects showing the 
greatest cognitive decline and other signs of Alzheimer's disease may be prescribed 
cholinesterase inhibitors as this is a standard of care for Alzheimer's disease but not 
MCI). Presence of any condition the health professional believes will impair ability to complete 

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study procedures (ex. terminal illness, comorbid major psychiatric disorders such as 
schizophrenia, or drug abuse). Potentially confounding neurodegenerative diseases (e.g. MS). 
Between Dr Shenker and Dr Beversdorf's clinics at the University of Missouri Hospital, there are 
at least 80 patients with MCI seen on an annual basis. Most of these patients have expressed a 
willingness to participate in research. We may need to enroll up to 60 subjects to obtain a 
sufficient set of 40. This project also harnesses the skills of Dr Beversdorf and Dr Shenker. Both 
have completed fellowships in Behavioral and Cognitive Neurology, resulting in special skills in 
the neurocognitive assessment of patients with memory loss. Should the need arise, we will also 
recruit from other aging clinics in the area. 
 
 
2.6 References: 
1. Vlachojannis JE, Cameron M, Chrubasik S. A systematic review on the Sambuci fructus 
effect and efficacy profiles. Phytotherapy Res 2010; 24: 1-9. 2.  
2. Bobek P, Nosalova V, Cerna S. Influence of diet containing extract of black elder 
(Sambucus nigra) on colitis in rats. Biol Bratislava 2001; 56: 643-648. 
3. Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and 
Alzheimer’s disease: The Kame Project. Am J Med 2006; 119: 751-759. 
4. Beversdorf DQ. Cognitive enhancement in the elderly. In: Janice Knoefel & Martin 
Albert, Eds. Clinical Neurology of Aging, 3rd Edition. Oxford University Press, New 
York, in press.  
5. Bragin V, Chemodanova M, Dzhafarova N, Bragin I, Czerniawski JL, and Aliev G. 
Integrated treatment approach improves cognitive function in demented and clinically 
depressed patients. Am J Alzheimers Dis Other Demen 2005; 20: 21–26. 
6. Petersen RC, Doody R, Kurz A, et al. Current concepts in mild cognitive impairment. 
Arch Neurol 2001; 58: 1985-1992.  
7. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive 
impairment: clinical characterization and outcome. Arch Neurol 1999; 56: 303-308. 
8. Bennett DA, Wilson RS, Schneider JA, et al. Natural history of mild cognitive 
impairment in older persons. Neurology 2002; 59: 198-205.  
9. Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage 
Alzheimer disease. Arch Neurol 2001; 58: 397-405. 
10. Storandt M, Grant EA, Miller JP, Morris JC. Rates of progression in mild cognitive 
impairment and early Alzheimer’s disease. Neurology 2002; 59: 1034-1041.  
11. Petersen RC, Thomas RG, Grundman M, Bennet D, Doody R, Ferris S, Galasko D, Jin S, 
Kaye J, Levey A, Pfeiffer E, Sano M, van Dyck CH, Thal LJ, for the Alzheimer’s 
Disease Cooperative Study Group. Vitamin E and donepezil for the treatment of mild 
cognitive impairment. New Engl J Med 2005; 35: 2379-2388.  
12. Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, 
Cummings J, del Ser T, Inzitari D, Orgogaza J-M, Sauer H, Scheltens P, Scarpini E, 
Herrmann N, Farlow M, Potkin S, Charles HC, Fox NC, Lane R. Effect of rivastigmine 
on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment: the 

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InDDEx study. Lancet Neurol 2007; 6: 501-512.  
13. Salloway S, Ferris S, Kluger A, Goldman R, Griesing T, Kumar D, Richardson S. 
Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled 
trial. Neurology 2004; 63: 651-657.  
14. Beversdorf DQ, Ferguson JLW, Hillier A, Sharma UK, Nagaraja HN, Bornstein RA, 
Scharre DW. Cogn Behav Neurol 2005; 20: 44-47.  
15. Miller LA, Tippett LJ. Effects of focal brain lesions on visual problem-solving. 
Neuropsychologia 1996; 34: 387-398.  
16. Albert MS. Cognitive and neurobiological markers of early Alzheimer’s disease. Proc 
Natl Acad Sci 1996; 93: 12547-12551.  
17. Vilkki J. Cognitive flexibility and mental programming after closed heard injuries and 
anterior and posterior cerebral excisions. Neuropsychologia 1992; 30: 807-814.  
18. Karnath HO, Wallesch CW. Inflexibility of mental planning: A characteristic disorder 
with prefrontal lobe lesions. Neuropsychologia 1992; 30: 1011-1016. 
19. Eslinger PJ, Grattan LM. Frontal lobe and frontal-striatal substrates for different forms of 
human cognitive flexibility. Neuropsychologia 1993; 31: 17-28.  
20. Duncan J, Burgess P, Emslie H. Fluid intelligence after frontal lobe lesions. 
Neuropsychologia 1995; 33: 261-268.  
21. Beversdorf DQ, Heilman KM. Facilitory paratonia and frontal lobe functioning. 
Neurology 1998; 51: 968-971.  
22. Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. 
Neurology 1993; 43: 2412-2414.  
23. Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull 1988; 24: 637-639.  
24. Folstein ME, Folstein, SE, McHugh PR. “Mini-mental state”. J Psychiatr Res 1975; 12: 
189-198.  
25. Brandt J. The Hopkins Verbal Learning Test: Development of a new verbal memory test 
with six equivalent forms. Clin Neuropsychol 1991; 5: 125-142. 
26. Kaplan EF, Goodglass H, Weintraub S. The Boston Naming Test (2nd Ed.). Philadelphia: 
Lea & Febiger, 1983.  
27. Rey A. L’examen Psychologique dans les cas d’encéphalopathie traumatique. Archives 
de Psychologie 1944; 28: 286-340. 
28. Osterieth PA. Le test de copie d’une figure complexe. Archives de Psychologie 1944; 30: 
206-356. 
29. Corwin J, Bylsma. Translations of excerpts from André Rey’s Psychological examination 
of traumatic encephalopathy and P.A. Osterrieth’s The Complex Figure Copy Test. Clin 
Neuropsychol 1993; 7: 3-15. 
30. Beversdorf DQ, Hughes JK, Steinberg BA, Lewis LD, Heilman KM. Noradrenergic 
modulation of cognitive flexibility in problem solving. NeuroReport 1999; 10: 2763-
2767. 
31. Guilford LP. The Nature of Human Intelligence. New York: McGraw-Hill, 1967.  
32. Lawton MP, Brody EM. Assessment of older people: self-maintaining and instrumental 
activities of daily living. Gerontologist 1969; 9: 179-186. 
33. Krikorian R, Nash TA, Shidler MD, Shukitt-Hale B, Joseph JA. Concord grape juice 
supplementation improves memory function in older adults with mild cognitive 
impairment. Br J Nutr 2010; 103: 730-734.  
34. Krikorian R, Shidler MD, Nash TA, Kalt W, Vinqvist-Tymchuk MR, Shukitt-Hale B, 

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Joseph JA. Blueberry supplementation improves memory in older adults. J Agric Food 
Chem 2010; 58: 3996-4000.  
35. Holmes C, Cunningham C, Zotova E, Culliford D, Perry VH. Proinflammatory cytokines, 
sickness behavior, and Alzheimer disease. Neurology 2011; 77: 212-218. 
36. Lau FC, Bielinski DF, Joseph JA. Inhibitory effects of blueberry extract on the 
production of inflammatory mediators in lipopolysaccharide-activated BV2 microglia. J 
Neurosci Res 2007; 85: 1010–1017. 
37. Lau FC, Shukitt-Hale B, Joseph JA. Nutritional intervention in brain aging: reducing the 
effects of inflammation and oxidative stress. Sub-cell Biochem 2007; 42: 299–318.  
38. Murkovic M, Abuja PM, Bergmann AR, Zirngast A, Adam U, Winklhofer-Roob BM, 
Topkal H. Effects of elderberry juice on fasting and postprandial serum lipids and low-
density lipoprotein oxidation in healthy volunteers: a randomized, double-blind, placebo-
controlled study. Eur J Clin Nutr 2004; 58: 244-249. 
39. Schneider LS, Olin JT, Doody RS, et al. Validity and reliability of the Alzheimer’s 
Disease Cooperative Study: Clinical Global Impression of Change. Alzheimer Dis Assoc 
Disord 1997; 11:S22-S31. 
3. Trial Objectives and Purpose 
 
Our aim is to begin to explore the potential translational impact of elderberry juice, a botanical 
agent. To achieve this, we will perform a pilot trial of elderberry juice in patients with mild 
cognitive impairment (MCI). It is critical to determine whether the course of development of 
Alzheimer’s can be altered in this high-risk population. Our primary outcome measure will be 
visuospatial problem solving, as this has been shown to be sensitive to drug effects in MCI. We 
will also track other cognitive outcomes as well as the incidence of progression to dementia. 
Furthermore, we will examine inflammatory markers to begin to explore the potential 
mechanism of its effect. The results of this study will yield pilot data for publication and for 
development of a larger clinical trial for which external funds will be sought. 
4. Trial Design 
 
4.1 A specific statement of the primary endpoints: 
 
Subjects will be assessed for changes in cognitive performance measures: CDR (for 
determination of progression to dementia), MMSE (general cognition), IADL (functional 
ability), HVLT (memory), BNT (language), Rey CFT (spatial function), anagrams (verbal 
cognitive flexibility), and VPS (spatial cognitive flexibility).  
 
4.2 A description of the type/design of trial: 
 
Double-blinded placebo-controlled pilot trial 
 
4.3 A description of the measures taken to minimize/avoid bias: 
 

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Twenty of the subjects will be randomly assigned to receive elderberry juice and twenty control 
subjects will be randomly assigned to receive an equal amount of a flavored liquid with no 
nutritional content as a placebo control group. The clinicians will be blinded as to group, as will 
be the assessor. Neetu Nair, a graduate student in Dr. Beversdorf’s lab who is otherwise 
uninvolved in the study, will keep the unblinding code in case a need arises to break the code for 
clinical purposes or preliminary data analyses. 
 
4.4 A description of the trial treatment(s) and the dosage and dosage regimen of the 
investigational product(s): 
 
Subjects will drink 5 ml juice by mouth, diluted in 8oz of water, three times daily. Subjects will 
be given sufficient juice at each visit to last until the next visit. Juice containers will be clearly 
labeled indicating the contents as a research supplement with directions advising subjects of dose 
schedule.  Subjects and caregivers will also be asked to check each dose on a dose log (indicating 
day of trial, date, time, and dose), and will bring the juice containers to the next visit to confirm 
that a proper amount has been administered.  
 
 
4.5 Subject Involvement: 
 
Prior to initiation of elderberry juice or placebo, baseline visit 1, subjects will be assessed with 
the CDR (for determination of progression to dementia), MMSE (general cognition), IADL 
(functional ability), HVLT (memory), BNT (language), Rey CFT (spatial function), anagrams 
(verbal cognitive flexibility), and VPS (spatial cognitive flexibility). They will also be 
administered a Food Frequency Questionnaire to determine any individual differences in diet that 
might be relevant to the current study’s findings. After initiation of elderberry juice or control, 
subjects will be retested at 12 weeks, visit 2, (the timeframe that revealed significant effects with 
other anthocyanin-rich fruit preparations (33,34), 6 months, visit 3, and (pending resubmission 
for second year of support) 12 months, visit 4. At each visit following baseline the Clinical 
Global Impression of Change (CGIC) will also be administered. Blood samples (30mL) will be 
obtained at baseline and each time point in the trial to determine immunological markers, 4 times 
total if subject progresses through all time points. 
 
4.6 Maintenance of trial treatment randomization codes: 
 
The clinicians will be blinded as to group, as will be the assessor. Neetu Nair, a graduate student 
in Dr. Beversdorf’s lab who is otherwise uninvolved in the study, will keep the unblinding code 
in case a need arises to break the code for clinical purposes or preliminary data analyses. This 
will be securely stored in her lab space at 181 Galena Hall. All subject data will be coded to a 
study specific code and all identifying information will be stored on a separate secure server.  
 
6.2 The number of subjects planned to be enrolled and reason for choice of sample size: 
 
 In other research examining the effects of other anthocyane-rich fruit extracts on MCI, a 
significant effect was revealed on word list memory with 12 subjects (33). In this study, the 
subjects in the treatment group improved their word list memory scores from 35.2 to 38.6, with a 

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standard deviation of less than 2. Based upon this data, the power of a study at the level of 
α=0.008 (adjusted for multiple measures for the various cognitive tasks) with a sample of 13 
would be 0.95 for detecting an effect of elderberry juice if it has similar effects as the grape juice 
on memory, and a sample of 18 would yield a power of 0.99. Therefore, we expect that the 
sample size of 20 per group (total 40) would be sufficient to reveal effects on word list memory 
(HVLT), as well as our other cognitive and behavioral outcome measures (VPS, MMSE, Rey 
CFT, BNT, and IADL), if their performance follows the same response as observed with word 
list memory. This pilot study will also yield results for the purpose of deriving power 
calculations for determination of appropriate sample sizes for larger, subsequent studies.  
Dr. Beversdorf and Dr. Shenker see at least 80 patients with MCI each year in their clinics. Most 
of these patients have expressed a willingness to participate in research. We may need to enroll 
up to 60 subjects to obtain a sufficient set of 40.  
6.3 The selection of subjects to be included in the analyses: 
 
Subjects taking less than 75% of the scheduled dose or failing to complete at least one follow-up 
session will be excluded from analysis.  
7. Potential Risks Related to Drug 
 
The elderberry can cause problems for people with a known allergy in the Caprifoliaceae family 
(honeysuckle). The related side effects are given below.  
▪ There are reports of gastrointestinal distress, diarrhea, vomiting, abdominal cramps, and 
weakness after drinking elderberry juice made from crushed leaves, stems, and uncooked 
elderberries. Notably, toxicity typically arises from uncooked berries and 
preparations for this study will be carried out to minimize such reactions.  
▪ In theory, high doses or long-term use of elder flowers may have diuretic (urine-
producing) effects. People taking diuretics or drugs that interact with diuretics should use 
caution when taking products containing elder. 
▪ Elder may also lower blood sugar levels. Dizziness, headache, convulsions, and rapid 
heart rate have also been reported. 
8. Data Handling and Recordkeeping 
 
Information produced by this study will be stored in the study PIs files located in M741 in the 
Center for Translational Neuroscience in the University of Missouri School of Medicine and on a 
secure server identified by a code number only. The code key will be kept on a separate secure 
server. Identifiable information contained in the records will not be given to anyone not 
associated with the study without written consent except as required by law.