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Tian P, Zhu X, Liu Z, Bian B, Jia F, Dou L, Jie Y, Lv X, Zhao T, Li D. Effects of vitamin D on brain function in preschool children with autism spectrum disorder: a resting-state functional MRI study. BMC Psychiatry 2025; 25:198. [PMID: 40033268 DOI: 10.1186/s12888-025-06534-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 01/24/2025] [Indexed: 03/05/2025] Open
Abstract
BACKGROUND Previous studies indicate vitamin D impacts autism spectrum disorder (ASD), but its relationship with brain function is unclear. This study investigated the association between serum 25-hydroxyvitamin D [25(OH)D] levels and brain function in preschool children with ASD using resting-state functional magnetic resonance imaging (rs-fMRI), and explored correlations with clinical symptoms. METHODS A total of 226 ASD patients underwent rs-fMRI scanning and serum 25(OH)D testing. Clinical symptoms were assessed using Childhood Autism Rating Scale (CARS) and Autism Behavior Checklist (ABC). Patients were categorized into mild and severe groups based on the CARS, and further divided into normal (NVD), insufficient (VDI), and deficient (VDD) serum 25(OH)D levels. Changes in brain function among these groups were analyzed using regional homogeneity (ReHo), with ABC scores used for correlation analysis. RESULTS In mild ASD, ReHo increased in the right postcentral gyrus and left precuneus in the VDI and VDD groups compared to NVD, and decreased in the bilateral middle cingulate gyrus and left superior frontal gyrus in the VDD group compared to VDI. In severe ASD, ReHo decreased in the right middle occipital gyrus and increased in the right insula in the VDI group compared to NVD, and increased in the right superior frontal gyrus in the VDD group compared to VDI. Correlation analysis revealed that in mild ASD, ReHo in the right postcentral gyrus was positively correlated with body and object use scores in the NVD and VDI groups, while ReHo in the right middle cingulate gyrus was negatively correlated with relating scores in the VDD and VDI groups. In severe ASD, ReHo in the right insula was positively correlated with language scores in the NVD and VDI groups. CONCLUSIONS ASD patients with lower serum 25(OH)D levels show multiple brain functional abnormalities, with specific brain region alterations linked to symptom severity. These findings enhance our understanding of vitamin D's impact on ASD and suggest that future research may explore its therapeutic potential.
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Affiliation(s)
- Pu Tian
- Department of Radiology, The First Hospital of Jilin University, Changchun, 130012, Jilin, China
| | - Xiaona Zhu
- Department of Radiology, The First Hospital of Jilin University, Changchun, 130012, Jilin, China
| | - Zhuohang Liu
- Department of Radiology, The First Hospital of Jilin University, Changchun, 130012, Jilin, China
| | - Bingyang Bian
- Department of Radiology, The First Hospital of Jilin University, Changchun, 130012, Jilin, China
| | - Feiyong Jia
- Department of Developmental and Behavioral Pediatrics, The First Hospital of Jilin University, No. 71, Xinmin Street, Changchun, 130021, Jilin, China
| | - Le Dou
- Department of Radiology, The First Hospital of Jilin University, Changchun, 130012, Jilin, China
| | - Yige Jie
- Department of Radiology, The First Hospital of Jilin University, Changchun, 130012, Jilin, China
| | - Xuerui Lv
- Department of Radiology, The First Hospital of Jilin University, Changchun, 130012, Jilin, China
| | - Tianyi Zhao
- Department of Radiology, The First Hospital of Jilin University, Changchun, 130012, Jilin, China
| | - Dan Li
- Department of Radiology, The First Hospital of Jilin University, Changchun, 130012, Jilin, China.
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Skv M, Abraham SM, Eshwari O, Golla K, Jhelum P, Maity S, Komal P. Tremendous Fidelity of Vitamin D3 in Age-related Neurological Disorders. Mol Neurobiol 2024; 61:7211-7238. [PMID: 38372958 DOI: 10.1007/s12035-024-03989-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 01/23/2024] [Indexed: 02/20/2024]
Abstract
Vitamin D3 (VD) is a secosteroid hormone and shows a pleiotropic effect in brain-related disorders where it regulates redox imbalance, inflammation, apoptosis, energy production, and growth factor synthesis. Vitamin D3's active metabolic form, 1,25-dihydroxy Vitamin D3 (1,25(OH)2D3 or calcitriol), is a known regulator of several genes involved in neuroplasticity, neuroprotection, neurotropism, and neuroinflammation. Multiple studies suggest that VD deficiency can be proposed as a risk factor for the development of several age-related neurological disorders. The evidence for low serum levels of 25-hydroxy Vitamin D3 (25(OH)D3 or calcidiol), the major circulating form of VD, is associated with an increased risk of Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), dementia, and cognitive impairment. Despite decades of evidence on low VD association with neurological disorders, the precise molecular mechanism behind its beneficial effect remains controversial. Here, we will be delving into the neurobiological importance of VD and discuss its benefits in different neuropsychiatric disorders. The focus will be on AD, PD, and HD as they share some common clinical, pathological, and epidemiological features. The central focus will be on the different attributes of VD in the aspect of its anti-oxidative, anti-inflammatory, anti-apoptotic, anti-cholinesterase activity, and psychotropic effect in different neurodegenerative diseases.
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Affiliation(s)
- Manjari Skv
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India
| | - Sharon Mariam Abraham
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India
| | - Omalur Eshwari
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India
| | - Kishore Golla
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India
| | - Priya Jhelum
- Centre for Research in Neuroscience and Brain Program, The Research Instituteof the, McGill University Health Centre , Montreal, QC, Canada
| | - Shuvadeep Maity
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India
| | - Pragya Komal
- Department of Biological Sciences, Birla Institute of Technology and Science-Pilani (BITS-Pilani) Hyderabad campus, Shameerpet-Mandal, Hyderabad, Telangana, India.
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Anwar MJ, Alenezi SK, Alhowail AH. Molecular insights into the pathogenic impact of vitamin D deficiency in neurological disorders. Biomed Pharmacother 2023; 162:114718. [PMID: 37084561 DOI: 10.1016/j.biopha.2023.114718] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/12/2023] [Accepted: 04/14/2023] [Indexed: 04/23/2023] Open
Abstract
Neurological disorders are the major cause of disability, leading to a decrease in quality of life by impairing cognitive, sensorimotor, and motor functioning. Several factors have been proposed in the pathogenesis of neurobehavioral changes, including nutritional, environmental, and genetic predisposition. Vitamin D (VD) is an environmental and nutritional factor that is widely distributed in the central nervous system's subcortical grey matter, neurons of the substantia nigra, hippocampus, thalamus, and hypothalamus. It is implicated in the regulation of several brain functions by preserving neuronal structures. It is a hormone rather than a nutritional vitamin that exerts a regulatory role in the pathophysiology of several neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, and multiple sclerosis. A growing body of epidemiological evidence suggests that VD is critical in neuronal development and shows neuroprotective effects by influencing the production and release of neurotrophins, antioxidants, immunomodulatory, regulation of intracellular calcium balance, and direct effect on the growth and differentiation of nerve cells. This review provides up-to-date and comprehensive information on vitamin D deficiency, risk factors, and clinical and preclinical evidence on its relationship with neurological disorders. Furthermore, this review provides mechanistic insight into the implications of vitamin D and its deficiency on the pathogenesis of neurological disorders. Thus, an understanding of the crucial role of vitamin D in the neurobiology of neurodegenerative disorders can assist in the better management of vitamin D-deficient individuals.
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Affiliation(s)
- Md Jamir Anwar
- Department of Pharmacology and Toxicology, Unaizah College of Pharmacy, Qassim University, Qassim, Unaizah 51911, Saudi Arabia
| | - Sattam Khulaif Alenezi
- Department of Pharmacology and Toxicology, Unaizah College of Pharmacy, Qassim University, Qassim, Unaizah 51911, Saudi Arabia.
| | - Ahmad Hamad Alhowail
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Qassim, Buraydah 51452, Saudi Arabia
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Quialheiro A, d´Orsi E, Moreira JD, Xavier AJ, Peres MA. The association between vitamin D and BDNF on cognition in older adults in Southern Brazil. Rev Saude Publica 2022; 56:109. [PMID: 36629701 PMCID: PMC9749663 DOI: 10.11606/s1518-8787.2022056004134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 01/26/2022] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE To estimate the association between vitamin D and the cognitive decline of older adults and evaluate whether this association is mediated by brain-derived neurotrophic factor (BDNF) serum concentration. METHODS Cross-sectional study nested in a population-based cohort. Of the 604 participants in the complementary examination of the EpiFloripa Study, 576 older adults (60 years or older) were eligible for the study. The outcome is cognitive decline evaluated by the Mini-Mental State Examination, the exposure is vitamin D, and BDNF is the mediator. The control variables are age, sex, per capita family income, and educational level. The direct effect of vitamin D and BDNF on cognitive decline and the indirect effect mediated by BDNF was evaluated using path analysis, with the estimation of standardized coefficients. RESULTS Among the participants, we observed a direct and positive effect of vitamin D on cognitive function (Coef: 0.06; 95%CI: 0.02 to 0.11; p < 0.001) and serum BDNF concentration (Coef: 21.55; 95%CI: 9.92 to 33.17; p = 0.002), i.e., the higher the vitamin D, the higher the cognitive function and serum level of BDNF. CONCLUSION There was an association between vitamin D on serum BDNF and on cognitive decline in older adults. Moreover, BDNF did not have an effect on cognitive decline, so BDNF was not a mediator of the vitamin D effect on cognitive decline.
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Affiliation(s)
- Anna Quialheiro
- Universidade Federal de Santa CatarinaPrograma de Pós-Graduação em Saúde ColetivaFlorianópolisSCBrasil Universidade Federal de Santa Catarina. Programa de Pós-Graduação em Saúde Coletiva. Florianópolis, SC, Brasil,Universidade do Minho. Escola de MedicinaInstituto de Investigação em Ciências da Vida e da SaúdeBragaPortugal Universidade do Minho. Escola de Medicina. Instituto de Investigação em Ciências da Vida e da Saúde. Braga, Portugal
| | - Eleonora d´Orsi
- Universidade Federal de Santa CatarinaPrograma de Pós-Graduação em Saúde ColetivaFlorianópolisSCBrasil Universidade Federal de Santa Catarina. Programa de Pós-Graduação em Saúde Coletiva. Florianópolis, SC, Brasil
| | - Júlia Dubois Moreira
- Universidade Federal de Santa CatarinaPrograma de Pós-Graduação em NutriçãoFlorianópolisSCBrasil Universidade Federal de Santa Catarina. Programa de Pós-Graduação em Nutrição. Florianópolis, SC, Brasil
| | - André Junqueira Xavier
- Universidade Federal de Santa CatarinaPrograma de Pós-Graduação em Saúde ColetivaFlorianópolisSCBrasil Universidade Federal de Santa Catarina. Programa de Pós-Graduação em Saúde Coletiva. Florianópolis, SC, Brasil,Universidade do Sul de Santa CatarinaPalhoçaSCBrasil Universidade do Sul de Santa Catarina. Curso de Medicina. Palhoça, SC, Brasil
| | - Marco Aurélio Peres
- National Dental Research Institute SingaporeNational Dental Centre SingaporeSingapore National Dental Research Institute Singapore. National Dental Centre Singapore. Singapore,Duke-NUS Medical SchoolOral Health ACPHealthServices and Systems Research ProgrammeSingapore Duke-NUS Medical School. Oral Health ACP. HealthServices and Systems Research Programme. Singapore
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Beauchet O, Cooper-Brown LA, Allali G. Vitamin D Supplementation and Cognition in Adults: A Systematic Review of Randomized Controlled Trials. CNS Drugs 2021; 35:1249-1264. [PMID: 34806158 DOI: 10.1007/s40263-021-00876-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/27/2021] [Indexed: 11/24/2022]
Abstract
BACKGROUND The role of vitamin D supplementation in improving cognition and slowing the incidence of minor and major neurocognitive disorders is a matter of debate. To our knowledge, no systematic review of randomized controlled trials (RCTs) has examined this question in adults. OBJECTIVES The purpose of this systematic review is to synthesize the evidence regarding the effects of vitamin D supplementation on cognitive performance and neurocognitive disorders in adults. METHODS A systematic search of scientific articles in English or French was conducted. The MEDLINE (PubMed), EMBASE (Ovid, EMBASE), PsychINFO, and Cochrane Central databases were searched for records without any limit on publication date in May 2021. Inclusion criteria were (1) human participants, (2) RCT, (3) participant age ≥ 18, (4) vitamin D supplementation as the intervention, and (5) cognition (i.e., cognitive performance or cognitive status such as cognitively healthy or minor and major neurocognitive disorder) as the primary outcome. Two independent reviewers both assessed all eligible studies' full texts and the risk of bias arising from methodological issues using a standardized procedure. RESULTS Of the 2137 abstracts identified, 61 (2.9%) met screening inclusion criteria. After full text examination, 41 records (67.2%) were excluded. As a result, 20 RCTs (32.8%) were included in the systematic review. The review yielded mixed findings and, thus, failed to find evidence supporting cognitive benefits from vitamin D supplementation or suggesting a causal association between vitamin D and cognitive function. Half of the RCTs reported mixed results, one quarter negative results, and the last quarter positive effects for vitamin D supplementation on cognitive performance. The variability in serum 25-dihydroxyvitamin D concentration thresholds, the cognitive tests employed, the supplementation doses, and the samples' characteristics (i.e., ethnicity or number of participants) may explain these mixed findings. CONCLUSION This systematic review of RCTs does not support a role for vitamin D supplementation in enhancing cognition in adults.
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Affiliation(s)
- Olivier Beauchet
- Department of Medicine, University of Montreal, Montreal, QC, Canada. .,Research Center of the Geriatric University Institute of Montreal, Montreal, QC, Canada. .,Division of Geriatric Medicine, Department of Medicine, Sir Mortimer B. Davis Jewish General Hospital and Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada. .,Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
| | - Liam A Cooper-Brown
- Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada
| | - Gilles Allali
- Leenaards Memory Center, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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Vitamin D Supplement for Prevention of Alzheimer's Disease: A Systematic Review and Meta-Analysis. Am J Ther 2021; 28:e638-e648. [DOI: 10.1097/mjt.0000000000001302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Panza F, La Montagna M, Lampignano L, Zupo R, Bortone I, Castellana F, Sardone R, Borraccino L, Dibello V, Resta E, Altamura M, Daniele A, Lozupone M. Vitamin D in the development and progression of alzheimer's disease: implications for clinical management. Expert Rev Neurother 2021; 21:287-301. [PMID: 33406925 DOI: 10.1080/14737175.2021.1873768] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Although the pathophysiological bases of Alzheimer's disease (AD) remain incompletely understood and disease-modifying therapies are not available, intervention on modifiable risk factors is warranted. Research on nutrition and dietary components is challenging and controversies still persist about the role of micro- and macronutrients and health outcomes in dementia. Importantly, results of preclinical investigations have shown that vitamin D triggers different neural pathways that may be protective against these neurodegenerative mechanisms, including the deposition of amyloid plaques, inflammatory processes, neurofibrillary degeneration, glutamatergic excitotoxicity, excessive intraneuronal calcium influx, and oxidative stress, although its relationship with AD still needs to be fully understood. AREAS COVERED The authors analyzed the recent evidence about the effects of vitamin D insufficiency on AD and the role of supplementation. EXPERT OPINION Both insufficient (25-49.9 ng/ml) and deficient levels (<25 ng/ml) of vitamin D may contribute to an increased susceptibility to AD. However, further well-designed prospective studies are needed for a better understanding of the involvement of low vitamin D concentrations in the AD natural history. Randomized clinical trials will also be necessary to address the issue of causality and determine whether vitamin D supplementation may be effective for the prevention or treatment of AD.
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Affiliation(s)
- Francesco Panza
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Maddalena La Montagna
- Psychiatric Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Luisa Lampignano
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Roberta Zupo
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Ilaria Bortone
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Fabio Castellana
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Rodolfo Sardone
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy
| | - Luisa Borraccino
- Psychiatric Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Vittorio Dibello
- Frailty Phenotypes Research Unit, "Salus in Apulia Study", National Institute of Gastroenterology "Saverio De Bellis", Research Hospital, Bari, Italy.,Department of Orofacial Pain & Dysfunction, Academic Centre of Dentistry Amsterdam (ACTA), University of Amsterdam & Vrije Universiteit Amsterdam, The Netherlands
| | - Emanuela Resta
- Department of Cardiac, Thoracic, and Vascular Science, Institute of Respiratory Disease, University of Bari Aldo Moro, Bari, Italy.,Translational Medicine & Management of Health Systems, University of Foggia, Foggia, Italy
| | - Mario Altamura
- Psychiatric Unit, Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy
| | - Antonio Daniele
- Institute of Neurology, Catholic University of Sacred Heart, Rome, Italy.,Institute of Neurology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Madia Lozupone
- Neurodegenerative Disease Unit, Department of Basic Medicine, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
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Calsolaro V, Bottari M, Coppini G, Lemmi B, Monzani F. Endocrine dysfunction and cognitive impairment. Minerva Endocrinol (Torino) 2021; 46:335-349. [PMID: 33435644 DOI: 10.23736/s2724-6507.20.03295-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Dementia is a highly prevalent chronic disease among the older population, affecting more than 50 million people worldwide and representing a huge healthcare, social and economic burden. Dementia, and in particular Alzheimer's disease, prevalence is expected to raise within the next few years. Unfortunately, no disease-modifying therapies are available so far, despite a plethora of clinical trials targeting the hallmarks of Alzheimer's disease. Given these premises, it appears crucial to address not only the neuropathological correlates of the disease, but also the modifiable risk factors. Among them, evidence suggest a role of the endocrine system not only in the brain development, but also in the maintenance of its health, having neurotrophic, antioxidant and metabolic functions crucial for the cognitive abilities. This review focuses on the evidence evaluating the impact of the endocrine systems, in particular thyroid function, insulin resistance, parathyroid hormone, vitamin D and sexual hormones on cognitive status. Results from epidemiological, preclinical and some clinical studies demonstrated the link between thyroid, parathyroid hormone and vitamin D and cognitive status, between diabetes, and insulin resistance in particular, and dementia, between sexual and adrenal hormones, particularly estrogen variation at menopause, and cognitive decline. The growing interest on the modifiable risks factors of cognitive decline increased the knowledge about the complex interplay of endocrine systems and cognition, highlighting the need and the usefulness of a multidisciplinary approach to the prevention of a complex and devastating disease.
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Affiliation(s)
- Valeria Calsolaro
- Geriatrics Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Marina Bottari
- Geriatrics Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Giulia Coppini
- Geriatrics Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Bianca Lemmi
- Geriatrics Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy
| | - Fabio Monzani
- Geriatrics Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy -
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Ertilav E, Barcin NE, Ozdem S. Comparison of Serum Free and Bioavailable 25-Hydroxyvitamin D Levels in Alzheimer's Disease and Healthy Control Patients. Lab Med 2020; 52:219-225. [PMID: 32893866 DOI: 10.1093/labmed/lmaa066] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE Many studies have investigated lower 25-hydroxyvitamin D (25[OH]D) levels in patients with Alzheimer's disease (AD) compared with those in control patients. In the present study, we aimed to evaluate serum free and bioavailable 25(OH)D levels in patients with AD and in healthy control patients. METHODS The AD group consisted of 85 patients aged >60 years who were diagnosed with possible AD according to National Institute on Aging-Alzheimer's Association criteria and 85 healthy control patients. Serum levels of total 1,25-dihydroxyvitamin D, total 25(OH)D, vitamin D binding protein (VDBP), parathormone, calcium, phosphorus and albumin, free 25(OH)D, bioavailable 25(OH)D, and the bioavailable 25(OH)D/total 25(OH)D ratio were compared in both groups. RESULTS Total 25(OH)D, free 25(OH)D, bioavailable 25(OH)D, and the bioavailable 25(OH)D/total 25(OH)D ratio were significantly lower (P <.001, P <.001, P <.001, P <.05, respectively) in the AD group, whereas the VDBP level was significantly higher (P <.05) in the AD than in the control group. CONCLUSION Free and bioavailable 25(OH)D detected at lower levels in patients with AD limit the target central effects of 25(OH)D; this result suggests that reduced levels of the active free form of vitamin D may be a risk factor for AD and dementia.
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Affiliation(s)
- Esra Ertilav
- Department of Neurology, Adnan Menderes University Faculty of Medicine, Aydın, Turkey
| | - Nur Ebru Barcin
- Department of Neurology, and Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Sebahat Ozdem
- Department of Biochemistry, Akdeniz University Faculty of Medicine, Antalya, Turkey
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Çubukçu M, Acı R, Müderrisoğlu S. Evaluation of Vitamin D Levels According to Age, Sex and Seasonal Characteristics in Samsun. ANKARA MEDICAL JOURNAL 2019. [DOI: 10.17098/amj.652002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Rusińska A, Płudowski P, Walczak M, Borszewska-Kornacka MK, Bossowski A, Chlebna-Sokół D, Czech-Kowalska J, Dobrzańska A, Franek E, Helwich E, Jackowska T, Kalina MA, Konstantynowicz J, Książyk J, Lewiński A, Łukaszkiewicz J, Marcinowska-Suchowierska E, Mazur A, Michałus I, Peregud-Pogorzelski J, Romanowska H, Ruchała M, Socha P, Szalecki M, Wielgoś M, Zwolińska D, Zygmunt A. Vitamin D Supplementation Guidelines for General Population and Groups at Risk of Vitamin D Deficiency in Poland-Recommendations of the Polish Society of Pediatric Endocrinology and Diabetes and the Expert Panel With Participation of National Specialist Consultants and Representatives of Scientific Societies-2018 Update. Front Endocrinol (Lausanne) 2018; 9:246. [PMID: 29904370 PMCID: PMC5990871 DOI: 10.3389/fendo.2018.00246] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 05/02/2018] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Vitamin D deficiency is an important public health problem worldwide. Vitamin D deficiency confers a significant risk for both skeletal and non-skeletal disorders and a number of lifelong negative health outcomes. The objectives of this evidence-based guidelines document are to provide health care professionals in Poland, an updated recommendation for the prevention, diagnosis and treatment of vitamin D deficiency. METHODS A systematic literature search examining the prevention and treatment strategies for vitamin D deficiency was conducted. Updated recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation system describing the strength of the recommendation and the quality of supporting evidence. Twenty-seven contributors representing different areas of expertise and medical specialties, including pediatricians, geriatricians, endocrinologists, epidemiologists, nephrologists, gynecologists and obstetricians evaluated the available published evidence related to vitamin D, formulated the goals of this document and developed a common consolidated position. The consensus group, representing six national specialist consultants and eight Polish and international scientific organizations/societies, participated in the process of grading evidence and drawing up the general and specific recommendations. RESULTS The updated recommendations define the diagnostic criteria for the evaluation of vitamin D status and describe the prevention and treatment strategies of vitamin D deficiency in the general population and in groups at increased risk of the deficiency. Age- and weight-specific recommendations for prevention, supplementation and treatment of vitamin D deficiency are presented, and detailed practice guidance is discussed regarding the management in primary and specialized health care. CONCLUSION Vitamin D deficiency remains still highly prevalent in Poland, in all age groups. Currently, there is a great necessity to implement a regular supplementation with recommended doses and to develop an effective strategy to alleviate vitamin D deficiency in the population. These updated recommendations are addressed to health professionals and the authorities pursuing comprehensive health policies and should also be included in public health programs aimed at preventing a broad spectrum of chronic diseases.
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Affiliation(s)
- Agnieszka Rusińska
- Department of Paediatric Propedeutics and Bone Metabolic Diseases, Medical University of Lodz, Lodz, Poland
| | - Paweł Płudowski
- Department of Biochemistry, Radioimmunology and Experimental Medicine, The Children’s Memorial Health Institute, Warsaw, Poland
- *Correspondence: Paweł Płudowski, ,
| | - Mieczysław Walczak
- Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University, Szczecin, Poland
| | | | - Artur Bossowski
- Department of Pediatrics, Endocrinology and Diabetology with Cardiology Divisions, Medical University of Bialystok, Bialystok, Poland
| | - Danuta Chlebna-Sokół
- Department of Paediatric Propedeutics and Bone Metabolic Diseases, Medical University of Lodz, Lodz, Poland
| | - Justyna Czech-Kowalska
- Department of Neonatology and Neonatal Intensive Care Unit, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Anna Dobrzańska
- Department of Neonatology and Neonatal Intensive Care Unit, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Edward Franek
- Mossakowski Medical Research Center, Polish Academy of Sciences, Department of Internal Diseases, Endocrinology and Diabetology, Central Hospital MSWiA, Warsaw, Poland
| | - Ewa Helwich
- Department of Neonatology, Institute of Mother and Child, Warsaw, Poland
| | - Teresa Jackowska
- Department of Pediatrics, The Medical Centre of Postgraduate Education, Warsaw, Poland
| | - Maria A. Kalina
- Division of Clinical Genetics, Department of Molecular Biology and Genetics, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Jerzy Konstantynowicz
- Department of Pediatric Rheumatology, Immunology, and Metabolic Bone Diseases, Medical University of Bialystok, Bialystok, Poland
| | - Janusz Książyk
- Department of Pediatrics, Nutrition and Metabolic Diseases, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Andrzej Lewiński
- Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Polish Mother’s Memorial Hospital – Research Institute, Lodz, Poland
| | - Jacek Łukaszkiewicz
- Faculty of Pharmacy with Laboratory Medicine, Medical University of Warsaw, Warsaw, Poland
| | | | - Artur Mazur
- 2nd Department of Pediatrics, Endocrinology, Diabetology, University of Rzeszow, Rzeszow, Poland
| | - Izabela Michałus
- Department of Paediatric Propedeutics and Bone Metabolic Diseases, Medical University of Lodz, Lodz, Poland
| | | | - Hanna Romanowska
- Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University, Szczecin, Poland
| | - Marek Ruchała
- Department of Endocrinology, Metabolism and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Piotr Socha
- Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw, Poland
| | - Mieczysław Szalecki
- Clinic of Endocrinology and Diabetology, The Children’s Memorial Health Institute, Warsaw, Poland
- Faculty of Medicine and Health Sciences, Jan Kochanowski Univeristy, Kielce, Poland
| | - Mirosław Wielgoś
- 1st Department of Obstetrics and Gynecology, Medical University of Warsaw, Warsaw, Poland
| | - Danuta Zwolińska
- Department of Pediatric Nephrology, Wroclaw Medical University, Wroclaw, Poland
| | - Arkadiusz Zygmunt
- Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Polish Mother’s Memorial Hospital – Research Institute, Lodz, Poland
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Grimm MOW, Thiel A, Lauer AA, Winkler J, Lehmann J, Regner L, Nelke C, Janitschke D, Benoist C, Streidenberger O, Stötzel H, Endres K, Herr C, Beisswenger C, Grimm HS, Bals R, Lammert F, Hartmann T. Vitamin D and Its Analogues Decrease Amyloid-β (Aβ) Formation and Increase Aβ-Degradation. Int J Mol Sci 2017; 18:E2764. [PMID: 29257109 PMCID: PMC5751363 DOI: 10.3390/ijms18122764] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 12/01/2017] [Accepted: 12/13/2017] [Indexed: 12/11/2022] Open
Abstract
Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-β (Aβ), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aβ-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D₂ and D₃ analogues decreased Aβ-production and increased Aβ-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aβ-producing enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased β-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention.
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Affiliation(s)
- Marcus O W Grimm
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
- Neurodegeneration and Neurobiology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
- Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Andrea Thiel
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Anna A Lauer
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Jakob Winkler
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Johannes Lehmann
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
- Department of Internal Medicine II-Gastroenterology, Saarland University Hospital, Saarland University, Kirrberger Str. 100, 66421 Homburg/Saar, Germany.
| | - Liesa Regner
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Christopher Nelke
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Daniel Janitschke
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Céline Benoist
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Olga Streidenberger
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Hannah Stötzel
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Kristina Endres
- Department of Psychiatry and Psychotherapy, Clinical Research Group, University Medical Centre Johannes Gutenberg, University of Mainz, Untere Zahlbacher Str. 8, 55131 Mainz, Germany.
| | - Christian Herr
- Department of Internal Medicine V-Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Christoph Beisswenger
- Department of Internal Medicine V-Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Heike S Grimm
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Robert Bals
- Department of Internal Medicine V-Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
| | - Frank Lammert
- Department of Internal Medicine II-Gastroenterology, Saarland University Hospital, Saarland University, Kirrberger Str. 100, 66421 Homburg/Saar, Germany.
| | - Tobias Hartmann
- Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
- Neurodegeneration and Neurobiology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
- Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany.
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Vitamin D and Neurological Diseases: An Endocrine View. Int J Mol Sci 2017; 18:ijms18112482. [PMID: 29160835 PMCID: PMC5713448 DOI: 10.3390/ijms18112482] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 11/18/2017] [Accepted: 11/20/2017] [Indexed: 02/07/2023] Open
Abstract
Vitamin D system comprises hormone precursors, active metabolites, carriers, enzymes, and receptors involved in genomic and non-genomic effects. In addition to classical bone-related effects, this system has also been shown to activate multiple molecular mediators and elicit many physiological functions. In vitro and in vivo studies have, in fact, increasingly focused on the "non-calcemic" actions of vitamin D, which are associated with the maintenance of glucose homeostasis, cardiovascular morbidity, autoimmunity, inflammation, and cancer. In parallel, growing evidence has recognized that a multimodal association links vitamin D system to brain development, functions and diseases. With vitamin D deficiency reaching epidemic proportions worldwide, there is now concern that optimal levels of vitamin D in the bloodstream are also necessary to preserve the neurological development and protect the adult brain. The aim of this review is to highlight the relationship between vitamin D and neurological diseases.
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14
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Patel P, Shah J. Role of Vitamin D in Amyloid clearance via LRP-1 upregulation in Alzheimer's disease: A potential therapeutic target? J Chem Neuroanat 2017; 85:36-42. [PMID: 28669880 DOI: 10.1016/j.jchemneu.2017.06.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 05/22/2017] [Accepted: 06/27/2017] [Indexed: 12/18/2022]
Abstract
Amyloid beta (Aβ) deposition is considered to be one of the primary reason to trigger Alzheimer's disease (AD). Literature clearly suggests decline in Aβ clearance to be accountable for progression of late onset AD as compared to augmented Aβ production. There may be several pathways for Aβ clearance out of which one of the major pathway is the vascular-mediated removal of Aβ from the brain across the blood-brain barrier (BBB) via efflux pumps or receptors. Among Aβ scavenger receptors, low density lipoprotein receptor related protein (LRP-1) has been most extensively studied. LRP-1, is highly expressed in neurons and located on abluminal side of the brain capillaries whose expression decreases in AD patients which give rise to increased cerebral Aβ deposition. Recent evidences reveal that post 1,25-(OH)2D3 treatment, LRP1 expression increases significantly for both in-vivo and in-vitro studies, since Vitamin D receptors (VDR) are broadly expressed in brain. Biological actions of Vitamin D are mediated via its nuclear hormone receptor vitamin D receptor (VDR) and is found to regulate many genes. Several lines of evidence suggest that VDR deficiency/inhibition can be a potential risk factor for AD and sufficient Vitamin D supplementation is beneficial to prevent AD onset/pathology or slow down the progression of disease. The present review establishes a strong correlation between Vitamin D and LRP-1 and their possible involvement in Aβ clearance and thereby emerging as new therapeutic target.
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Affiliation(s)
- Parmi Patel
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, India.
| | - Jigna Shah
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, India.
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15
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Downey CL, Young A, Burton EF, Graham SM, Macfarlane RJ, Tsapakis EM, Tsiridis E. Dementia and osteoporosis in a geriatric population: Is there a common link? World J Orthop 2017; 8:412-423. [PMID: 28567345 PMCID: PMC5434348 DOI: 10.5312/wjo.v8.i5.412] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/28/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the existence of a common pathological link between dementia and osteoporosis through reviewing the current evidence base.
METHODS This paper reviews the current literature on osteoporosis and dementia in order to ascertain evidence of a common predisposing aetiology. A literature search of Ovid MED-LINE (1950 to June 2016) was conducted. The keywords “osteoporosis”, “osteoporotic fracture”, “dementia” and “Alzheimer’s disease” (AD) were used to determine the theoretical links with the most significant evidence base behind them. The key links were found to be vitamins D and K, calcium, thyroid disease, statins, alcohol and sex steroids. These subjects were then searched in combination with the previous terms and the resulting papers manually examined. Theoretical, in vitro and in vivo research were all used to inform this review which focuses on the most well developed theoretical common causes for dementia (predominantly Alzheimer’s type) and osteoporosis.
RESULTS Dementia and osteoporosis are multifaceted disease processes with similar epidemiology and a marked increase in prevalence in elderly populations. The existence of a common link between the two has been suggested despite a lack of clear pathological overlap in our current understanding. Research to date has tended to be fragmented and relatively weak in nature with multiple confounding factors reflecting the difficulties of in vivo experimentation in the population of interest. Despite exploration of various possible mechanisms in search for a link between the two pathologies, this paper found that it is possible that these associations are coincidental due to the nature of the evidence available. One finding in this review is that prior investigation into common aetiologies has found raised amyloid beta peptide levels in osteoporotic bone tissue, with a hypothesis that amyloid beta disorders are systemic disorders resulting in differing tissue manifestations. However, our findings were that the most compelling evidence of a common yet independent aetiology lies in the APOE4 allele, which is a well-established risk for AD but also carries an independent association with fracture risk. The mechanism behind this is thought to be the reduced plasma vitamin K levels in individuals exhibiting the APOE4 allele which may be amplified by the nutritional deficiencies associated with dementia, which are known to include vitamins K and D. The vitamin theory postulates that malnutrition and reduced exposure to sunlight in patients with AD leads to vitamin deficiencies.
CONCLUSION Robust evidence remains to be produced regarding potential links and regarding the exact aetiology of these diseases and remains relevant given the burden of dementia and osteoporosis in our ageing population. Future research into amyloid beta, APOE4 and vitamins K and D as the most promising aetiological links should be welcomed.
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16
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Does high dose vitamin D supplementation enhance cognition?: A randomized trial in healthy adults. Exp Gerontol 2017; 90:90-97. [DOI: 10.1016/j.exger.2017.01.019] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 11/24/2016] [Accepted: 01/22/2017] [Indexed: 12/18/2022]
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The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease. Int J Mol Sci 2016; 17:ijms17111785. [PMID: 27792188 PMCID: PMC5133786 DOI: 10.3390/ijms17111785] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 10/14/2016] [Accepted: 10/20/2016] [Indexed: 12/25/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population, currently affecting 46 million people worldwide. Histopathologically, the disease is characterized by the occurrence of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles containing the microtubule-associated protein tau. Aβ peptides are derived from the sequential processing of the amyloid precursor protein (APP) by enzymes called secretases, which are strongly influenced by the lipid environment. Several vitamins have been reported to be reduced in the plasma/serum of AD-affected individuals indicating they have an impact on AD pathogenesis. In this review we focus on vitamin E and the other lipophilic vitamins A, D, and K, and summarize the current knowledge about their status in AD patients, their impact on cognitive functions and AD risk, as well as their influence on the molecular mechanisms of AD. The vitamins might affect the generation and clearance of Aβ both by direct effects and indirectly by altering the cellular lipid homeostasis. Additionally, vitamins A, D, E, and K are reported to influence further mechanisms discussed to be involved in AD pathogenesis, e.g., Aβ-aggregation, Aβ-induced neurotoxicity, oxidative stress, and inflammatory processes, as summarized in this article.
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18
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Keeney JT, Butterfield DA. Vitamin D deficiency and Alzheimer disease: Common links. Neurobiol Dis 2015; 84:84-98. [DOI: 10.1016/j.nbd.2015.06.020] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 06/26/2015] [Accepted: 06/30/2015] [Indexed: 12/31/2022] Open
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Vitamin D and Alzheimer's Disease: Neurocognition to Therapeutics. Int J Alzheimers Dis 2015; 2015:192747. [PMID: 26351614 PMCID: PMC4553343 DOI: 10.1155/2015/192747] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2015] [Accepted: 07/16/2015] [Indexed: 12/21/2022] Open
Abstract
Alzheimer's disease (AD), the major cause of dementia worldwide, is characterized by progressive loss of memory and cognition. The sporadic form of AD accounts for nearly 90% of the patients developing this disease. The last century has witnessed significant research to identify various mechanisms and risk factors contributing to the complex etiopathogenesis of AD by analyzing postmortem AD brains and experimenting with animal and cell culture based models. However, the treatment strategies, as of now, are only symptomatic. Accumulating evidences suggested a significant association between vitamin D deficiency, dementia, and AD. This review encompasses the beneficial role of vitamin D in neurocognition and optimal brain health along with epidemiological evidence of the high prevalence of hypovitaminosis D among aged and AD population. Moreover, disrupted signaling, altered utilization of vitamin D, and polymorphisms of several related genes including vitamin D receptor (VDR) also predispose to AD or AD-like neurodegeneration. This review explores the relationship between this gene-environmental influence and long term vitamin D deficiency as a risk factor for development of sporadic AD along with the role and rationale of therapeutic trials with vitamin D. It is, therefore, urgently warranted to further establish the role of this potentially neuroprotective vitamin in preventing and halting progressive neurodegeneration in AD patients.
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20
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Lam V, Albrecht MA, Takechi R, Prasopsang P, Lee YP, Foster JK, Mamo JCL. Serum 25-hydroxyvitamin D is associated with reduced verbal episodic memory in healthy, middle-aged and older adults. Eur J Nutr 2015; 55:1503-13. [DOI: 10.1007/s00394-015-0968-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Accepted: 06/16/2015] [Indexed: 11/30/2022]
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21
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Brouwer-Brolsma EM, Dhonukshe-Rutten RA, van Wijngaarden JP, van de Zwaluw NL, in 't Veld PH, Wins S, Swart KM, Enneman AW, Ham AC, van Dijk SC, van Schoor NM, van der Velde N, Uitterlinden AG, Lips P, Kessels RP, Steegenga WT, Feskens EJ, de Groot LC. Cognitive Performance: A Cross-Sectional Study on Serum Vitamin D and Its Interplay With Glucose Homeostasis in Dutch Older Adults. J Am Med Dir Assoc 2015; 16:621-7. [DOI: 10.1016/j.jamda.2015.02.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 02/16/2015] [Accepted: 02/16/2015] [Indexed: 01/22/2023]
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Blasco H, Madji Hounoum B, Dufour-Rainfray D, Patin F, Maillot F, Beltran S, Gordon PH, Andres CR, Corcia P. Vitamin D is Not a Protective Factor in ALS. CNS Neurosci Ther 2015; 21:651-6. [PMID: 26096806 DOI: 10.1111/cns.12423] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 05/18/2015] [Accepted: 05/22/2015] [Indexed: 12/13/2022] Open
Abstract
AIMS Vitamin D deficiency has been associated with poorer prognosis in ALS. Better understanding of the role of vitamin D in ALS is needed to determine whether trials of systematic supplementation are justified. Our aim was to report vitamin D levels during the course of ALS and to evaluate its relationship with clinical parameters at diagnosis and with disease progression. METHODS We prospectively collected vitamin D serum concentrations from 125 consecutive ALS patients. Cox proportional hazard models analyzed the relationship between vitamin D concentrations, clinical parameters, and survival. RESULTS The mean vitamin D concentration was below our laboratory's lower limit of normal (P < 0.0001) and did not change during the course of the disease. The concentrations were higher in patients with bulbar onset (P = 0.003) and were negatively associated with body mass index (BMI) (P = 0.0095). Models with ALSFRS-R (ALS Functional Rating Scale-Revised) and BMI as a covariates showed that vitamin D concentrations predicted worse prognosis. CONCLUSION The distribution of vitamin D concentrations in our cohort was consistent with previous reports. Surprisingly, we noted a negative effect of higher vitamin D levels on prognosis in ALS. More detailed research is warranted to determine whether manipulation of vitamin D could be beneficial to patients.
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Affiliation(s)
- Hélène Blasco
- Unité mixte de recherche U930, Institut National de la Santé et de la Recherche Médicale, Université François-Rabelais, Tours, France.,Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours, Tours, France
| | - Blandine Madji Hounoum
- Unité mixte de recherche U930, Institut National de la Santé et de la Recherche Médicale, Université François-Rabelais, Tours, France
| | - Diane Dufour-Rainfray
- Unité mixte de recherche U930, Institut National de la Santé et de la Recherche Médicale, Université François-Rabelais, Tours, France.,Laboratoire de Médecine Nucléaire in vitro, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours, Tours, France
| | - Franck Patin
- Unité mixte de recherche U930, Institut National de la Santé et de la Recherche Médicale, Université François-Rabelais, Tours, France
| | - François Maillot
- Service de Médecine Interne, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours, Tours, France.,INSERM U1069, Tours, France
| | - Stéphane Beltran
- Centre SLA, Service de Neurologie, Centre Hospitalier Régional Universitaire de Tours, Tours, France
| | | | - Christian R Andres
- Unité mixte de recherche U930, Institut National de la Santé et de la Recherche Médicale, Université François-Rabelais, Tours, France.,Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours, Tours, France
| | - Philippe Corcia
- Unité mixte de recherche U930, Institut National de la Santé et de la Recherche Médicale, Université François-Rabelais, Tours, France.,Centre SLA, Service de Neurologie, Centre Hospitalier Régional Universitaire de Tours, Tours, France
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Annweiler C, Dursun E, Féron F, Gezen-Ak D, Kalueff AV, Littlejohns T, Llewellyn DJ, Millet P, Scott T, Tucker KL, Yilmazer S, Beauchet O. 'Vitamin D and cognition in older adults': updated international recommendations. J Intern Med 2015; 277:45-57. [PMID: 24995480 DOI: 10.1111/joim.12279] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Hypovitaminosis D, a condition that is highly prevalent in older adults aged 65 years and above, is associated with brain changes and dementia. Given the rapidly accumulating and complex contribution of the literature in the field of vitamin D and cognition, clear guidance is needed for researchers and clinicians. METHODS International experts met at an invitational summit on 'Vitamin D and Cognition in Older Adults'. Based on previous reports and expert opinion, the task force focused on key questions relating to the role of vitamin D in Alzheimer's disease and related disorders. Each question was discussed and voted using a Delphi-like approach. RESULTS The experts reached an agreement that hypovitaminosis D increases the risk of cognitive decline and dementia in older adults and may alter the clinical presentation as a consequence of related comorbidities; however, at present, vitamin D level should not be used as a diagnostic or prognostic biomarker of Alzheimer's disease due to lack of specificity and insufficient evidence. This population should be screened for hypovitaminosis D because of its high prevalence and should receive supplementation, if necessary; but this advice was not specific to cognition. During the debate, the possibility of 'critical periods' during which vitamin D may have its greatest impact on the brain was addressed; whether hypovitaminosis D influences cognition actively through deleterious effects and/or passively by loss of neuroprotection was also considered. CONCLUSIONS The international task force agreed on five overarching principles related to vitamin D and cognition in older adults. Several areas of uncertainty remain, and it will be necessary to revise the proposed recommendations as new findings become available.
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Affiliation(s)
- C Annweiler
- Department of Neuroscience, Division of Geriatric Medicine and Memory Clinic, UPRES EA 4638, UNAM, Angers University Hospital, Angers, France; Department of Medical Biophysics, Robarts Research Institute, Schulich School of Medicine and Dentistry, the University of Western Ontario, London, ON, Canada
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Neves-Carvalho A, Logarinho E, Freitas A, Duarte-Silva S, Costa MDC, Silva-Fernandes A, Martins M, Serra SC, Lopes AT, Paulson HL, Heutink P, Relvas JB, Maciel P. Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells. Hum Mol Genet 2014; 24:100-17. [PMID: 25143392 DOI: 10.1093/hmg/ddu422] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The physiological function of Ataxin-3 (ATXN3), a deubiquitylase (DUB) involved in Machado-Joseph Disease (MJD), remains elusive. In this study, we demonstrate that ATXN3 is required for neuronal differentiation and for normal cell morphology, cytoskeletal organization, proliferation and survival of SH-SY5Y and PC12 cells. This cellular phenotype is associated with increased proteasomal degradation of α5 integrin subunit (ITGA5) and reduced activation of integrin signalling and is rescued by ITGA5 overexpression. Interestingly, silencing of ATXN3, overexpression of mutant versions of ATXN3 lacking catalytic activity or bearing an expanded polyglutamine (polyQ) tract led to partially overlapping phenotypes. In vivo analysis showed that both Atxn3 knockout and MJD transgenic mice had decreased levels of ITGA5 in the brain. Furthermore, abnormal morphology and reduced branching were observed both in cultured neurons expressing shRNA for ATXN3 and in those obtained from MJD mice. Our results show that ATXN3 rescues ITGA5 from proteasomal degradation in neurons and that polyQ expansion causes a partial loss of this cellular function, resulting in reduced integrin signalling and neuronal cytoskeleton modifications, which may be contributing to neurodegeneration.
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Affiliation(s)
- Andreia Neves-Carvalho
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães and
| | - Elsa Logarinho
- Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal
| | - Ana Freitas
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães and
| | - Sara Duarte-Silva
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães and
| | | | - Anabela Silva-Fernandes
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães and
| | - Margarida Martins
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães and
| | - Sofia Cravino Serra
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães and
| | - André T Lopes
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães and
| | - Henry L Paulson
- Department of Neurology, University of Michigan, Ann Arbor, MI, USA and
| | - Peter Heutink
- German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
| | - João B Relvas
- Institute for Molecular and Cell Biology, University of Porto, Porto, Portugal
| | - Patrícia Maciel
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães and
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No role for vitamin D or a moderate fat diet in aging induced cognitive decline and emotional reactivity in C57BL/6 mice. Behav Brain Res 2014; 267:133-43. [DOI: 10.1016/j.bbr.2014.03.038] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 03/18/2014] [Accepted: 03/20/2014] [Indexed: 01/29/2023]
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Annweiler C. [Vitamin D and Alzheimer's disease: from an intriguing idea to a therapeutic option]. Biol Aujourdhui 2014; 208:89-95. [PMID: 24948022 DOI: 10.1051/jbio/2014005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Indexed: 06/03/2023]
Abstract
Beyond the classically described regulation of calcium and bone metabolism, vitamin D is a neurosteroid hormone essential to neurophysiological function (regulation of neurotransmitters and neurotrophins) with anti-inflammatory and antioxidant neuroprotective action. In contrast, hypovitaminosis D, which is extremely frequent in the elderly, may result in neurological dysfunction and may explain part of the cognitive disorders in this population. Epidemiology is consistent with this notion and has repeatedly shown an association between hypovitaminosis D and cognitive decline, either in the general population or in Alzheimer's patients. Preliminary intervention trials confirm the causal relationship and quantify the cognitive effect of vitamin D supplementation in the elderly. This raises prospects for primary/secondary prevention of cognitive decline by exogenous supplies of vitamin D. In particular, although current anti-dementia drugs are only symptomatic, future treatment options could rely on drug combinations preventing several neurodegenerative mechanisms at once. As such, vitamin D enhances the efficacy of memantine in terms of neuronal protection and prevention of cognitive decline in Alzheimer's disease.
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Affiliation(s)
- Cédric Annweiler
- Pôle de Neurosciences, Service de Gériatrie, Centre Hospitalier Universitaire d'Angers, Centre Mémoire Ressources Recherche, Centre de Recherche sur l'Autonomie et la Longévité (CeRAL), UPRES EA 4638, Université d'Angers, UNAM, 49933 Angers, France - Robarts Research Institute, the University of Western Ontario, London, Ontario, Canada
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Deb S, Chin MY, Adomat H, Guns EST. Ginsenoside-mediated blockade of 1α,25-dihydroxyvitamin D3 inactivation in human liver and intestine in vitro. J Steroid Biochem Mol Biol 2014; 141:94-103. [PMID: 24486455 DOI: 10.1016/j.jsbmb.2014.01.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2013] [Revised: 12/21/2013] [Accepted: 01/22/2014] [Indexed: 12/19/2022]
Abstract
The beneficial effects of vitamin D3 are exerted through 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], the dihydroxy metabolite of vitamin D3. Hepatic and intestinal biotransformation of 1α,25(OH)2D3 and modifiers of metabolic capacity could be important determinants of bioavailability in serum and tissues. Ginsenosides and their aglycones, mainly 20(S)-protopanaxadiol (aPPD) and 20(S)-protopanaxatriol (aPPT), are routinely ingested as health supplements. The purpose of the present study was to investigate the potential of ginsenosides and their aglycones to block hepatic and intestinal inactivation of 1α,25(OH)2D3, which is the most potent ligand of vitamin D receptor. In vitro biotransformation reactions were initiated with NADPH regenerating solutions following initial preincubation of pooled human hepatic or intestinal microsomal protein or human recombinant CYP3A4 supersomes with 1α,25(OH)2D3 or midazolam. Formation of hydroxylated metabolites of 1α,25(OH)2D3 or midazolam was analyzed using liquid chromatography-mass spectrometry. Co-incubation of 1α,25(OH)2D3 with various ginsenosides (Rg1, Rh2, aPPD, aPPT and total ginsenosides) led to differential inhibition (30-100%) of its hydroxylation. Results suggest that aPPD, aPPT and Rh2 strongly attenuated the hydroxylation of 1α,25(OH)2D3. Follow up inhibition studies with aPPD and aPPT at varying concentrations (0.5-100μM) led to up to 91-100% inhibition of formation of hydroxylated metabolites of 1α,25(OH)2D3 thus preventing inactivation of active vitamin D3. The IC50 values of aPPD or aPPT for the most abundant hydroxylated metabolites of 1α,25(OH)2D3 ranged from 3.3 to 9.0μM in human microsomes. The inhibitory mechanism of aPPD or aPPT for CYP3A4-mediated biotransformation of 1α,25(OH)2D3 was competitive in nature (apparent Ki: 1.7-2.9μM). Similar inhibitory effects were also observed upon addition of aPPD or aPPT into midazolam hydroxylation assay. In summary, our results suggest that ginsenosides, specifically aPPD and aPPT, inhibit the CYP3A4-mediated catabolism of active vitamin D3 in human liver and intestine, potentially providing additional vitamin D-related benefits to patients with cancer, neurodegenerative and metabolic diseases.
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Affiliation(s)
- Subrata Deb
- The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6
| | - Mei Yieng Chin
- The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6
| | - Hans Adomat
- The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6
| | - Emma S Tomlinson Guns
- The Vancouver Prostate Centre at Vancouver General Hospital, 2660 Oak Street, Vancouver, BC, Canada V6H 3Z6.
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Annweiler C, Beauchet O. Vitamin d in older adults: the need to specify standard values with respect to cognition. Front Aging Neurosci 2014; 6:72. [PMID: 24782767 PMCID: PMC3995037 DOI: 10.3389/fnagi.2014.00072] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2014] [Accepted: 03/31/2014] [Indexed: 12/22/2022] Open
Affiliation(s)
- Cédric Annweiler
- Department of Neuroscience, Division of Geriatric Medicine and Memory Clinic, Angers University Hospital, UPRES EA 4638, University of Angers, UNAM , Angers , France ; Department of Medical Biophysics, Schulich School of Medicine and Dentistry, Robarts Research Institute, The University of Western Ontario , London, ON , Canada
| | - Olivier Beauchet
- Department of Neuroscience, Division of Geriatric Medicine and Memory Clinic, Angers University Hospital, UPRES EA 4638, University of Angers, UNAM , Angers , France
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Annweiler C, Annweiler T, Montero-Odasso M, Bartha R, Beauchet O. Vitamin D and brain volumetric changes: Systematic review and meta-analysis. Maturitas 2014; 78:30-9. [PMID: 24674855 DOI: 10.1016/j.maturitas.2014.02.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 02/24/2014] [Indexed: 01/20/2023]
Abstract
Vitamin D has multiple functions in the nervous system. Our objective was to systematically review and quantitatively synthesize evidence on the location and nature of brain morphometric changes linked to vitamin D depletion or repletion. A Medline search was conducted in February 2014, without limit of date and language restriction, using the MeSH terms "Vitamin D" OR "Ergocalciferols" combined with "Brain Mapping" OR "Magnetic Resonance Imaging" OR "Tomography, X-ray Computed" OR "Tomography, Emission-Computed, Single-Photon" OR "Positron-Emission Tomography" OR "Nuclear Medicine" OR "Radionucleide Imaging". Of the 376 selected studies, nine observational studies - two animal and seven human studies - met the selection criteria. The number of participants ranged from 20 to 333 (40-79% female). Three studies were eligible for fixed-effects meta-analysis of bias-corrected effect size of the difference in lateral ventricle volume between cases with vitamin D depletion and controls. Results showed that vitamin D depletion was associated with lower brain volume, specifically larger lateral ventricles. The pooled effect size was 1.01 [95% CI: 0.62; 1.41], a 'large' effect size indicating that the ventricle volume was 1.01 SD higher with vitamin D depletion. Results on brain subvolumes were mixed, and indicated that brain atrophy with vitamin D depletion could be explained not by temporal lobe atrophy but rather by loss of matter at the cranial vertex, possibly in the precuneus cortex. In conclusion, despite increasing evidence arguing for an action of vitamin D in the brain, data is sparse regarding brain morphological changes related to vitamin D depletion. The retrieved association between vitamin D depletion and brain atrophy provides a scientific base for vitamin D replacement trials.
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Affiliation(s)
- Cedric Annweiler
- Department of Neuroscience, Division of Geriatric Medicine and Memory Clinic, Angers University Hospital, UPRES EA 4638, University of Angers, UNAM, Angers, France; Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada.
| | - Thierry Annweiler
- Department of Radiology, University Hospital of Saint-Etienne, France
| | - Manuel Montero-Odasso
- Gait and Brain Lab, Lawson Health Research Institute, Parkwood Hospital, The University of Western Ontario, London, Ontario, Canada
| | - Robert Bartha
- Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Olivier Beauchet
- Department of Neuroscience, Division of Geriatric Medicine and Memory Clinic, Angers University Hospital, UPRES EA 4638, University of Angers, UNAM, Angers, France; Biomathics, France
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Annweiler C, Karras SN, Anagnostis P, Beauchet O. Vitamin D supplements: a novel therapeutic approach for Alzheimer patients. Front Pharmacol 2014; 5:6. [PMID: 24478705 PMCID: PMC3904112 DOI: 10.3389/fphar.2014.00006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 01/08/2014] [Indexed: 02/01/2023] Open
Affiliation(s)
- Cedric Annweiler
- Department of Geriatric Medicine, UPRES EA 4638, University Hospital Angers, France ; Robarts Research Institute, University of Western Ontario London, ON, Canada
| | - Spyridon N Karras
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki Thessaloniki, Greece
| | - Panagiotis Anagnostis
- Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki Thessaloniki, Greece
| | - Olivier Beauchet
- Department of Geriatric Medicine, UPRES EA 4638, University Hospital Angers, France
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Grimm MOW, Lehmann J, Mett J, Zimmer VC, Grösgen S, Stahlmann CP, Hundsdörfer B, Haupenthal VJ, Rothhaar TL, Herr C, Bals R, Grimm HS, Hartmann T. Impact of Vitamin D on amyloid precursor protein processing and amyloid-β peptide degradation in Alzheimer's disease. NEURODEGENER DIS 2013; 13:75-81. [PMID: 24192346 DOI: 10.1159/000355462] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Accepted: 09/03/2013] [Indexed: 11/19/2022] Open
Abstract
Ninety percent of the elderly population has a vitamin D hypovitaminosis, and several lines of evidence suggest that there might be a potential causal link between Alzheimer's disease (AD) and a non-sufficient supply with vitamin D. However, the mechanisms linking AD to vitamin D have not been completely understood. The aim of our study is to elucidate the impact of 25(OH) vitamin D3 on amyloid precursor protein processing in mice and N2A cells utilizing very moderate and physiological vitamin D hypovitaminosis in the range of 20-30% compared to wild-type mice. We found that already under such mild conditions, amyloid-β peptide (Aβ) is significantly increased, which is caused by an increased β-secretase activity and BACE1 protein level. Additionally, neprilysin (NEP) expression is downregulated resulting in a decreased NEP activity further enhancing the effect of decreased vitamin D on the Aβ level. In line with the in vivo findings, corresponding effects were found with N2A cells supplemented with 25(OH) vitamin D3. Our results further strengthen the link between AD and vitamin D3 and suggest that supplementation of vitamin D3 might have a beneficial effect in AD prevention.
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Affiliation(s)
- Marcus O W Grimm
- Experimental Neurology, Saarland University, Homburg/Saar, Germany
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Annweiler C, Beauchet O. Vitamin D and cognition: recommendations for future trials. J Am Geriatr Soc 2013; 61:1049-1050. [PMID: 23772744 DOI: 10.1111/jgs.12287] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- Cedric Annweiler
- Department of Neuroscience, Division of Geriatric Medicine, UPRES EA 4638, UNAM, Angers University Hospital, Angers, France
- Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Olivier Beauchet
- Department of Neuroscience, Division of Geriatric Medicine, UPRES EA 4638, UNAM, Angers University Hospital, Angers, France
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33
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Brouwer-Brolsma EM, van de Rest O, Tieland M, van der Zwaluw NL, Steegenga WT, Adam JJ, van Loon LJC, Feskens EJM, de Groot LCPGM. Serum 25-hydroxyvitamin D is associated with cognitive executive function in Dutch prefrail and frail elderly: a cross-sectional study exploring the associations of 25-hydroxyvitamin D with glucose metabolism, cognitive performance and depression. J Am Med Dir Assoc 2013; 14:852.e9-17. [PMID: 23921196 DOI: 10.1016/j.jamda.2013.06.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Revised: 06/25/2013] [Accepted: 06/26/2013] [Indexed: 01/10/2023]
Abstract
OBJECTIVES The primary objective was to explore the possible association of serum 25-hydroxyvitamin D (25[OH]D) and vitamin D intake with markers of glucose metabolism, depression, and cognitive performance. In addition, we examined to what extent the associations between vitamin D and cognitive performance were modified or mediated by fasting plasma glucose (FPG) levels. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study using data of 127 frail or prefrail Dutch elderly, aged 65 years or older. Frailty was defined according to the criteria of Fried and colleagues. A participant was classified prefrail when 1 to 2 criteria were met; frailty was classified as the presence of 3 or more criteria. MEASUREMENTS Associations of 25(OH)D and vitamin D intake with markers of glucose metabolism and domain-specific cognitive performance were examined by multivariable regression analyses. The possible association of vitamin D with depression and global cognitive performance was explored by Poisson regression. RESULTS No associations were observed for 25(OH)D with FPG, fasting plasma insulin (FPI), Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR), or depression. In contrast, serum 25(OH)D was positively associated with executive functioning (β 0.007, P = .01) and tended to be associated with information-processing speed (β 0.006, P = .06). FPG did not modify or mediate these associations. Vitamin D intake was not associated with cognitive performance, glucose metabolism, or depression. CONCLUSION This cross-sectional study suggests an association of serum 25(OH)D with domain-specific cognitive performance, in particular executive functioning and possibly information-processing speed, but not with FPG, FPI, HOMA-IR, or depression. Whether these associations are causal is yet to be demonstrated.
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34
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Hu N, Yu JT, Tan L, Wang YL, Sun L, Tan L. Nutrition and the risk of Alzheimer's disease. BIOMED RESEARCH INTERNATIONAL 2013; 2013:524820. [PMID: 23865055 PMCID: PMC3705810 DOI: 10.1155/2013/524820] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Revised: 06/05/2013] [Accepted: 06/10/2013] [Indexed: 02/07/2023]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for the major cause of dementia, and the increasing worldwide prevalence of AD is a major public health concern. Increasing epidemiological studies suggest that diet and nutrition might be important modifiable risk factors for AD. Dietary supplementation of antioxidants, B vitamins, polyphenols, and polyunsaturated fatty acids are beneficial to AD, and consumptions of fish, fruits, vegetables, coffee, and light-to-moderate alcohol reduce the risk of AD. However, many of the results from randomized controlled trials are contradictory to that of epidemiological studies. Dietary patterns summarizing an overall diet are gaining momentum in recent years. Adherence to a healthy diet, the Japanese diet, and the Mediterranean diet is associated with a lower risk of AD. This paper will focus on the evidence linking many nutrients, foods, and dietary patterns to AD.
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Affiliation(s)
- Nan Hu
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Number 5 Donghai Middle Road, Qingdao 266071, China
| | - Jin-Tai Yu
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Number 5 Donghai Middle Road, Qingdao 266071, China
- College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266003, China
| | - Lin Tan
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Number 5 Donghai Middle Road, Qingdao 266071, China
| | - Ying-Li Wang
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Number 5 Donghai Middle Road, Qingdao 266071, China
| | - Lei Sun
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Number 5 Donghai Middle Road, Qingdao 266071, China
| | - Lan Tan
- Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Number 5 Donghai Middle Road, Qingdao 266071, China
- College of Medicine and Pharmaceutics, Ocean University of China, Qingdao 266003, China
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35
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Cardoso BR, Cominetti C, Cozzolino SMF. Importance and management of micronutrient deficiencies in patients with Alzheimer's disease. Clin Interv Aging 2013; 8:531-42. [PMID: 23696698 PMCID: PMC3656646 DOI: 10.2147/cia.s27983] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia, and it generally affects the elderly. It has been suggested that diet is an intensively modifiable lifestyle factor that might reduce the risk of AD. Because epidemiological studies generally report the potential neuronal protective effects of various micronutrients, the aim of this study was to perform a literature review on the major nutrients that are related to AD, including selenium, vitamins C and E, transition metals, vitamin D, B-complex vitamins, and omega-3 fatty acids.
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Affiliation(s)
- Bárbara Rita Cardoso
- Faculty of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo, Brazil.
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36
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Effectiveness of the combination of memantine plus vitamin D on cognition in patients with Alzheimer disease: a pre-post pilot study. Cogn Behav Neurol 2013; 25:121-7. [PMID: 22960436 DOI: 10.1097/wnn.0b013e31826df647] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
OBJECTIVE To determine whether treatment with memantine plus vitamin D is more effective than memantine or vitamin D alone in improving cognition among patients with Alzheimer disease (AD). METHODS We studied 43 white outpatients (mean 84.7 ± 6.3 years; 65.1% women) with a new diagnosis of AD, who had not taken anti-dementia drugs or vitamin D supplements. We prescribed memantine alone (n = 18), vitamin D alone (n = 17), or memantine plus vitamin D (n = 8) for an average of 6 months. We assessed cognitive change with the Mini-Mental State Examination (MMSE). We used age, sex, pre-treatment MMSE score, and duration of treatment as covariables. RESULTS Before treatment, the 3 groups had comparable MMSE scores. At 6 months, participants taking memantine plus vitamin D increased their MMSE score by 4.0 ± 3.7 points (P = 0.034), while participants taking memantine alone remained stable (change of 0.0 ± 1.8 points; P = 0.891), as did those taking vitamin D alone (-0.6 ± 3.1 points; P = 0.504). Treatment with memantine plus vitamin D was associated with improvement in the MMSE score compared to memantine or vitamin D alone after adjustment for covariables (P < 0.01). Mixed regression analysis showed that the visit by combined treatments (memantine plus vitamin D) interaction was significant (P = 0.001), while memantine or vitamin D alone showed no effect. CONCLUSIONS Patients with AD who took memantine plus vitamin D for 6 months had a statistically and clinically relevant gain in cognition, underlining possible synergistic and potentiating benefits of the combination.
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37
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Eyles DW, Burne THJ, McGrath JJ. Vitamin D, effects on brain development, adult brain function and the links between low levels of vitamin D and neuropsychiatric disease. Front Neuroendocrinol 2013; 34:47-64. [PMID: 22796576 DOI: 10.1016/j.yfrne.2012.07.001] [Citation(s) in RCA: 452] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Revised: 06/19/2012] [Accepted: 07/02/2012] [Indexed: 01/27/2023]
Abstract
Increasingly vitamin D deficiency is being associated with a number of psychiatric conditions. In particular for disorders with a developmental basis, such as autistic spectrum disorder and schizophrenia the neurobiological plausibility of this association is strengthened by the preclinical data indicating vitamin D deficiency in early life affects neuronal differentiation, axonal connectivity, dopamine ontogeny and brain structure and function. More recently epidemiological associations have been made between low vitamin D and psychiatric disorders not typically associated with abnormalities in brain development such as depression and Alzheimer's disease. Once again the preclinical findings revealing that vitamin D can regulate catecholamine levels and protect against specific Alzheimer-like pathology increase the plausibility of this link. In this review we have attempted to integrate this clinical epidemiology with potential vitamin D-mediated basic mechanisms. Throughout the review we have highlighted areas where we think future research should focus.
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Affiliation(s)
- Darryl W Eyles
- Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, QLD 4076, Australia.
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38
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Vitamin D status and cause-specific mortality: a general population study. PLoS One 2012; 7:e52423. [PMID: 23285034 PMCID: PMC3527503 DOI: 10.1371/journal.pone.0052423] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2012] [Accepted: 11/14/2012] [Indexed: 02/06/2023] Open
Abstract
Background Vitamin D deficiency is associated with an increased risk of all-cause mortality in observational studies. The specific causes of death underlying this association lack clarity. We investigated the association between vitamin D status and cause-specific mortality. Methods We included a total of 9,146 individuals from the two population-based studies, Monica10 and Inter99, conducted in 1993–94 and 1999–2001, respectively. Vitamin D status was assessed as serum 25-hydroxyvitamin D. Information on causes of death was obtained from The Danish Register of Causes of Death until 31 December 2009. There were a total of 832 deaths (median follow-up 10.3 years). Results Multivariable Cox regression analyses with age as underlying time axis and vitamin D quartiles showed significant associations between vitamin D status and death caused by diseases of the respiratory system, the digestive system, and endocrine, nutritional and metabolic diseases with hazard ratios (HRs) 0.26 (ptrend = 0.0042), 0.28 (ptrend = 0.0040), and 0.21 (ptrend = 0.035), respectively, for the fourth vitamin D quartile compared to the first. We found non-significantly lower HRs for death caused by mental and behavioural diseases and diseases of the nervous system, but no association between vitamin D status and death caused by neoplasms or diseases of the circulatory system. Conclusion The associations of vitamin D status and cause-specific mortality suggest that we also look elsewhere (than to cardiovascular disease and cancer) to explain the inverse association between vitamin D status and mortality.
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Annweiler C, Beauchet O. Possibility of a new anti-alzheimer's disease pharmaceutical composition combining memantine and vitamin D. Drugs Aging 2012; 29:81-91. [PMID: 22233455 DOI: 10.2165/11597550-000000000-00000] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Alzheimer's disease (AD) is the leading cause of dementia. In addition to a decrease in brain cholinergic activity, AD is also marked by glutamatergic excitotoxicity that results in neuronal death, characterized clinically by a loss of learning and memory abilities. The currently available drugs for symptomatic treatment of AD (i.e. memantine and acetylcholinesterase inhibitors) only temporarily slow down the natural history of the disease process. Among them, memantine is the only one that acts as a non-competitive low-affinity modulator of N-methyl-D-aspartate (NMDA) receptors. Memantine's modulation of NMDA receptors has been reported to prevent the neuronal necrosis induced by glutamatergic calcium neurotoxicity, but not the neuronal apoptosis resulting from oxidative stress. This observation calls for new drug regimen strategies based on memantine combined with molecules having antioxidant effects, in order to create a multi-target therapy to increase neuronal protection and prevent AD progression. We wish to highlight that vitamin D is a secosteroid hormone that is suggested to have neuroprotective effects that include regulation of neuronal calcium homeostasis, as well as antioxidant, neurotrophic and anti-inflammatory properties. The combination of memantine plus vitamin D may provide, in one treatment, enhanced protection against several degenerative processes linked to AD. Based on the present rationale, a clinical trial testing this hypothesis is currently in recruitment (AD-IDEA trial; ClinicalTrials.gov identifier: NCT01409694). This new pharmaceutical composition may provide an effective solution to the problem of neuronal death and cognitive decline in AD.
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Affiliation(s)
- Cédric Annweiler
- Department of Neuroscience, Division of Geriatric Medicine, Angers University Hospital, Angers, France
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40
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Annweiler C, Rolland Y, Schott AM, Blain H, Vellas B, Beauchet O. Serum vitamin D deficiency as a predictor of incident non-Alzheimer dementias: a 7-year longitudinal study. Dement Geriatr Cogn Disord 2012; 32:273-8. [PMID: 22261995 DOI: 10.1159/000334944] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/26/2011] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hypovitaminosis D has been cross-sectionally associated with dementia and stroke. The objective of this longitudinal study was to determine whether serum vitamin D deficiency at baseline could predict the onset of non-Alzheimer dementias (NAD) within 7 years among older women. METHODS Forty high-functioning older women (78.4 years, 76.4/82.0; median, 25th/75th percentile) from the EPIDOS Toulouse study were divided into two groups based on vitamin D deficiency (i.e., serum 25-hydroxyvitamin D <10 ng/ml) at baseline. At the end of the 7-year follow-up period, women matching the DSM-IV but not the NINCDS-ADRDA criteria were diagnosed with NAD while those matching the NINCDS-ADRDA criteria were considered to have Alzheimer's disease (AD). Subtle cognitive impairments at baseline, cardiovascular risk factors and Parkinson's disease were used as potential confounders. RESULTS NAD was reported in 6 women (82.8 years, 80.6/86.0) after 7 years of follow-up. More NAD were observed in women with vitamin D deficiency (p = 0.023). There was no between-group difference regarding the onset of AD (p = 0.332). We found an association between vitamin D deficiency at baseline and the onset of NAD (adjusted odds ratio = 19.57, p = 0.042). Conversely, vitamin D deficiency was not associated with AD (p = 0.222). CONCLUSION Baseline vitamin D deficiency predicted the onset of NAD within 7 years among older women.
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Affiliation(s)
- C Annweiler
- Department of Neuroscience, Division of Geriatric Medicine, Angers University Hospital, Angers University Memory Center, University of Angers, UNAM, Angers, France. CeAnnweiler @ chu-angers.fr
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Annweiler C, Rolland Y, Schott AM, Blain H, Vellas B, Herrmann FR, Beauchet O. Higher Vitamin D Dietary Intake Is Associated With Lower Risk of Alzheimer's Disease: A 7-Year Follow-up. J Gerontol A Biol Sci Med Sci 2012; 67:1205-11. [DOI: 10.1093/gerona/gls107] [Citation(s) in RCA: 137] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Annweiler C, Fantino B, Gautier J, Beaudenon M, Thiery S, Beauchet O. Cognitive Effects of Vitamin D Supplementation in Older Outpatients Visiting a Memory Clinic: A Pre-Post Study. J Am Geriatr Soc 2012; 60:793-5. [DOI: 10.1111/j.1532-5415.2011.03877.x] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Cédric Annweiler
- Division of Geriatric Medicine; Department of Neuroscience; Angers University Hospital; Angers University Memory Center; UPRES EA 2646; University of Angers; UNAM; Angers; France
| | - Bruno Fantino
- Division of Geriatric Medicine; Department of Neuroscience; Angers University Hospital; Angers University Memory Center; UPRES EA 2646; University of Angers; UNAM; Angers; France
| | - Jennifer Gautier
- Division of Geriatric Medicine; Department of Neuroscience; Angers University Hospital; Angers University Memory Center; UPRES EA 2646; University of Angers; UNAM; Angers; France
| | - Melinda Beaudenon
- Division of Geriatric Medicine; Department of Neuroscience; Angers University Hospital; Angers University Memory Center; UPRES EA 2646; University of Angers; UNAM; Angers; France
| | - Samuel Thiery
- Division of Geriatric Medicine; Department of Neuroscience; Angers University Hospital; Angers University Memory Center; UPRES EA 2646; University of Angers; UNAM; Angers; France
| | - Olivier Beauchet
- Division of Geriatric Medicine; Department of Neuroscience; Angers University Hospital; Angers University Memory Center; UPRES EA 2646; University of Angers; UNAM; Angers; France
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Annweiler C, Fantino B, Parot-Schinkel E, Thiery S, Gautier J, Beauchet O. Alzheimer's disease--input of vitamin D with mEmantine assay (AD-IDEA trial): study protocol for a randomized controlled trial. Trials 2011; 12:230. [PMID: 22014101 PMCID: PMC3212921 DOI: 10.1186/1745-6215-12-230] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2011] [Accepted: 10/20/2011] [Indexed: 12/15/2022] Open
Abstract
Background Current treatments for Alzheimer's disease and related disorders (ADRD) are symptomatic and can only temporarily slow down ADRD. Future possibilities of care rely on multi-target drugs therapies that address simultaneously several pathophysiological processes leading to neurodegeneration. We hypothesized that the combination of memantine with vitamin D could be neuroprotective in ADRD, thereby limiting neuronal loss and cognitive decline. The aim of this trial is to compare the effect after 24 weeks of the oral intake of vitamin D3 (cholecalciferol) with the effect of a placebo on the change of cognitive performance in patients suffering from moderate ADRD and receiving memantine. Methods The AD-IDEA Trial is a unicentre, double-blind, randomized, placebo-controlled, intent-to-treat, superiority trial. Patients aged 60 years and older presenting with moderate ADRD (i.e., Mini-Mental State Examination [MMSE] score between 10-20), hypovitaminosis D (i.e., serum 25-hydroxyvitamin D [25OHD] < 30 ng/mL), normocalcemia (i.e., serum calcium < 2.65 mmol/L) and receiving no antidementia treatment at time of inclusion are being recruited. All participants receive memantine 20 mg once daily -titrated in 5 mg increments over 4 weeks- and each one is randomized to one of the two treatment options: either cholecalciferol (one 100,000 IU drinking vial every 4 weeks) or placebo (administered at the same pace). One hundred and twenty participants are being recruited and treatment continues for 24 weeks. Primary outcome measure is change in cognitive performance using Alzheimer's Disease Assessment Scale-cognition score. Secondary outcomes are changes in other cognitive scores (MMSE, Frontal Assessment Battery, Trail Making Test parts A and B), change in functional performance (Activities of Daily Living scale, and 4-item Instrumental Activities of Daily Living scale), posture and gait (Timed Up & Go, Five Time Sit-to-Stand, spatio-temporal analysis of walking), as well as the between-groups comparison of compliance to treatment and tolerance. These outcomes are assessed at baseline, 12 and 24 weeks, together with the serum concentrations of 25OHD, calcium and parathyroid hormone. Discussion The combination of memantine plus vitamin D may represent a new multi-target therapeutic class for the treatment of ADRD. The AD-IDEA Trial seeks to provide evidence on its efficacy in limiting cognitive and functional declines in ADRD. Trial Registration ClinicalTrials.gov number, NCT01409694
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