- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04744922
Clinical and Biological Effects of Citrus-phytochemicals in Subjective Cognitive Decline.
Clinical and Biological Effects of Citrus-phytochemicals in Subjective Cognitive Decline: a Pilot Randomized Controlled Trial.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Background: Alzheimer's disease (AD) is a neurodegenerative disorder which represents a major health issue and financial burden for health care systems around the world. The impact will further increase over the next decades due to increasing life expectancies. AD leads to progressive and irreversible disturbances of cognition and functional abilities. AD is the fifth-leading cause of death among those age 65 and older and is also a leading cause of disability and poor health. Due to the absence of a cure against AD, the public health priority has focused more recently on improvement of cognitive performance in older age and, possibly, prevention of cognitive decline. Subjective cognitive decline (SCD) in older adults is increasingly recognized as a potential indicator of non-normative cognitive decline and eventual progression to dementia. Longitudinal studies in SCD showed an up to 4.5-fold increased risk for progression to mild cognitive impairment. SCD has also been characterized by pathological changes of the brain associated with AD. These findings suggest that SCD may be an early clinical marker for AD, making an ideal target to test preventive interventions. Several nutraceuticals have displayed over the years the ability or potential to improve cognitive impairment. Among these, auraptene (AUR) and naringenin (NAR) are natural bioactive compounds derived from peels of Citrus fruits, with a strong preclinical rationale for cognitive enhancement. In fact, preclinical studies showed that they have anti-inflammatory, antioxidant, and neuroprotective effects in mouse brain and, specifically, in AD mouse models. These effects are mediated by a number of neuropeptides, growth factors, hormones, and cytokines, which are components of the neuroendocrine and immune (NEI) system, a complex network of communication, which showed altered functioning in ageing and neurodegenerative diseases.
The capacity of some nutraceutical in restoring and remodelling the NEI response at both neuroendocrine and immune level, could represent a new strategy in order to reach healthy ageing and prevent cognitive decline in the elderly. This perspective is supported by the results of a randomized, placebo-controlled, double blind study of 84 older adults, in which administration of AUR for 24 weeks showed significantly higher percentage of improvement in the immediate memory in the AUR group compared to the placebo.
Specific aims: This is a pilot randomized controlled trial to determine the cognitive and biological effects of Citrus peels extracts standardized in auraptene and naringenin, in individuals with SCD.
Specific aim 1. The investigators will enrol 80 individuals with SCD randomized into two groups of treatments, i.e. control and Citrus peels extracts. Cognitive assessment will be carried out at baseline and after 9 months of treatment, in order to evaluate the effect on cognition.
The investigators hypothesize that treatment group has an improvement in cognition compared to placebo group.
Specific aim 2. To evaluate the biological effects of the Citrus peels extracts treatment on the NEI system, through blood samples taken at baseline, and after 9 months of treatment.
The investigators hypothesize that treatment group has an improvement in the NEI functions as indicated by biological markers (increase of the growth factors, reduction of stress hormones levels, reduction of inflammation) compared to placebo group.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Samantha Galluzzi
- Phone Number: 0039 0303501302
- Email: sgalluzzi@fatebenefratelli.eu
Study Contact Backup
- Name: Ilaria Passeggia
- Phone Number: 0039 0303501380
- Email: ipasseggia@fatebenefratelli.eu
Study Locations
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-
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Brescia, Italy, 25125
- IRCCS Centro San Giovanni di Dio Fatebenefratelli
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- subjective cognitive decline,
- lack of objective cognitive impairment.
Exclusion Criteria:
- clinically significant depression and anxiety,
- psychiatric disorders,
- unstable medical conditions.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Auraptene and Naringenin Arm
One capsule a day for 9 months
|
One capsule a day for 9 months
|
Placebo Comparator: Control Arm
One capsule a day for 9 months
|
One capsule a day for 9 months
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Cognitive outcome
Time Frame: 9 months
|
Repeatable Battery for the Assessment of the Neuropsychological Status (R-BANS). The minimum score is 40 and the maximum is 160. Higher scores mean a better performances. |
9 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Biological outcome
Time Frame: 9 months
|
Interleukin-8
|
9 months
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Samantha Galluzzi, IRCCS Centro San Giovanni di Dio Fatebenefratelli
Publications and helpful links
General Publications
- Jessen F, Amariglio RE, van Boxtel M, Breteler M, Ceccaldi M, Chetelat G, Dubois B, Dufouil C, Ellis KA, van der Flier WM, Glodzik L, van Harten AC, de Leon MJ, McHugh P, Mielke MM, Molinuevo JL, Mosconi L, Osorio RS, Perrotin A, Petersen RC, Rabin LA, Rami L, Reisberg B, Rentz DM, Sachdev PS, de la Sayette V, Saykin AJ, Scheltens P, Shulman MB, Slavin MJ, Sperling RA, Stewart R, Uspenskaya O, Vellas B, Visser PJ, Wagner M; Subjective Cognitive Decline Initiative (SCD-I) Working Group. A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease. Alzheimers Dement. 2014 Nov;10(6):844-52. doi: 10.1016/j.jalz.2014.01.001. Epub 2014 May 3.
- Rebello CJ, Beyl RA, Lertora JJL, Greenway FL, Ravussin E, Ribnicky DM, Poulev A, Kennedy BJ, Castro HF, Campagna SR, Coulter AA, Redman LM. Safety and pharmacokinetics of naringenin: A randomized, controlled, single-ascending-dose clinical trial. Diabetes Obes Metab. 2020 Jan;22(1):91-98. doi: 10.1111/dom.13868. Epub 2019 Sep 30.
- Rabin LA, Smart CM, Crane PK, Amariglio RE, Berman LM, Boada M, Buckley RF, Chetelat G, Dubois B, Ellis KA, Gifford KA, Jefferson AL, Jessen F, Katz MJ, Lipton RB, Luck T, Maruff P, Mielke MM, Molinuevo JL, Naeem F, Perrotin A, Petersen RC, Rami L, Reisberg B, Rentz DM, Riedel-Heller SG, Risacher SL, Rodriguez O, Sachdev PS, Saykin AJ, Slavin MJ, Snitz BE, Sperling RA, Tandetnik C, van der Flier WM, Wagner M, Wolfsgruber S, Sikkes SA. Subjective Cognitive Decline in Older Adults: An Overview of Self-Report Measures Used Across 19 International Research Studies. J Alzheimers Dis. 2015 Sep 24;48 Suppl 1(0 1):S63-86. doi: 10.3233/JAD-150154.
- Reisberg B, Shulman MB, Torossian C, Leng L, Zhu W. Outcome over seven years of healthy adults with and without subjective cognitive impairment. Alzheimers Dement. 2010 Jan;6(1):11-24. doi: 10.1016/j.jalz.2009.10.002.
- Amariglio RE, Mormino EC, Pietras AC, Marshall GA, Vannini P, Johnson KA, Sperling RA, Rentz DM. Subjective cognitive concerns, amyloid-beta, and neurodegeneration in clinically normal elderly. Neurology. 2015 Jul 7;85(1):56-62. doi: 10.1212/WNL.0000000000001712. Epub 2015 Jun 5.
- Mecocci P, Tinarelli C, Schulz RJ, Polidori MC. Nutraceuticals in cognitive impairment and Alzheimer's disease. Front Pharmacol. 2014 Jun 23;5:147. doi: 10.3389/fphar.2014.00147. eCollection 2014.
- Okuyama S, Morita M, Kaji M, Amakura Y, Yoshimura M, Shimamoto K, Ookido Y, Nakajima M, Furukawa Y. Auraptene Acts as an Anti-Inflammatory Agent in the Mouse Brain. Molecules. 2015 Nov 10;20(11):20230-9. doi: 10.3390/molecules201119691.
- Okuyama S, Kanzaki T, Kotani Y, Katoh M, Sawamoto A, Nakajima M, Furukawa Y. Continual Treatment with the Peels of Citrus kawachiensis (Kawachi Bankan) Protects against Dopaminergic Neuronal Cell Death in a Lipopolysaccharide-Induced Model of Parkinson's Disease. J Nutr Sci Vitaminol (Tokyo). 2019;65(2):205-208. doi: 10.3177/jnsv.65.205.
- Ghofrani S, Joghataei MT, Mohseni S, Baluchnejadmojarad T, Bagheri M, Khamse S, Roghani M. Naringenin improves learning and memory in an Alzheimer's disease rat model: Insights into the underlying mechanisms. Eur J Pharmacol. 2015 Oct 5;764:195-201. doi: 10.1016/j.ejphar.2015.07.001. Epub 2015 Jul 3.
- Okuyama S, Kotani Y, Yamamoto K, Sawamoto A, Sugawara K, Sudo M, Ohkubo Y, Tamanaha A, Nakajima M, Furukawa Y. The peel of Citrus kawachiensis (kawachi bankan) ameliorates microglial activation, tau hyper-phosphorylation, and suppression of neurogenesis in the hippocampus of senescence-accelerated mice. Biosci Biotechnol Biochem. 2018 May;82(5):869-878. doi: 10.1080/09168451.2018.1433993. Epub 2018 Feb 9.
- Sanchez-Rodriguez E, Biel-Glesson S, Fernandez-Navarro JR, Calleja MA, Espejo-Calvo JA, Gil-Extremera B, de la Torre R, Fito M, Covas MI, Vilchez P, Alche JD, Martinez de Victoria E, Gil A, Mesa MD. Effects of Virgin Olive Oils Differing in Their Bioactive Compound Contents on Biomarkers of Oxidative Stress and Inflammation in Healthy Adults: A Randomized Double-Blind Controlled Trial. Nutrients. 2019 Mar 6;11(3):561. doi: 10.3390/nu11030561.
- ThyagaRajan S, Priyanka HP. Bidirectional communication between the neuroendocrine system and the immune system: relevance to health and diseases. Ann Neurosci. 2012 Jan;19(1):40-6. doi: 10.5214/ans.0972.7531.180410.
- Galluzzi S, Zanardini R, Ferrari C, Gipponi S, Passeggia I, Rampini M, Sgro G, Genovese S, Fiorito S, Palumbo L, Pievani M, Frisoni GB, Epifano F. Cognitive and biological effects of citrus phytochemicals in subjective cognitive decline: a 36-week, randomized, placebo-controlled trial. Nutr J. 2022 Oct 17;21(1):64. doi: 10.1186/s12937-022-00817-6.
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 270/2020
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Access Criteria
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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