The Open Neurology Journal




ISSN: 1874-205X ― Volume 14, 2020
RESEARCH ARTICLE

Vitamin D Serum Level in Elderly Patients with Alzheimer’s Disease: Preliminary Analysis from Cilento Region



Vincenzo Pizza1, Silvana Montella1, Eugenio Luigi Iorio2, Anna Silvestro1, Anella Agresta1, Salvatore di Somma3, Anna Capasso4, *
1 Neurology Unit, S. Luca Hospital, Vallo della, Ospedale San Luca, Italy
2 International Oxidative Stress Center, Italy
3 Department of Medical-Surgery Sciences and Translational Medicine, La Sapienza University, Rome, Italy
4 Department of Pharmacy, University of Salerno, Fisciano, Italy

Abstract

Introduction:

It is estimated that 46 million people in the world live with dementia and it is estimated that this number will increase 3-fold by 2050, being a leading cause of disability worldwide and major welfare and economic problem. The aging of the general population increase these problems, especially in regions, such as Cilento (Southern Italy), where we can register higher longevity. Preserving cognitive health is one of the most important aims of the current research, also through the identification of possible preventative life-style strategies. Recent meta-analyses suggest that low serum vitamin D concentrations could be associated with Alzheimer's disease (AD) and cognitive impairment. The specific role of Vitamin D, however, is still controversial. There is a growing evidence of high rates of vitamin D deficiency in the elderly and there is still much uncertainty about the cause of AD and other forms of dementia. On the other hand, there is no definitive evidence is not conclusive and vitamin D could be involved in many other physiological and pathological mechanisms.

Objective:

Our aim is to investigate vitamin D serum levels in a small preliminary sample of AD patients from the Cilento area.

Materials and Methods:

Patients were recruited from the AD centre of the San Luca Hospital, in Vallo della Lucania (SA). We enrolled 25 consecutive patients, 13 women, and 12 men. The mean age was 78.5±8.3 years, the mean duration of the disease was 3.5±1.8 years. The average school-age of the patients was 6.1 +/- 3.5 years, the average disease age was 6.3 +/- 1.7 years, the average basal Mini-Mental Score Examination (MMSE) score was 17.6 +/- 3.6. We determined serum 25-hydroxyvitamin D (25[OH]D) in 25 consecutive AD patients.

Results:

The mean vitamin D serum level was 17.9+7.9 UI/ml, denoting a state of insufficiency. Among our 25 patients, only 3 had serum level above 30 UI/ml; most patients (17 out of 25) showed serum level among 10 and 30 UI, while in 5 patients, serum level was less than 10 UI.

Conclusion:

Our preliminary data showed that Vitamin D deficiency was, in our patients, independently associated with AD, even in a special population, high rate of centenarians, like Cilento people. However, our preliminary study has different limitations. The vitamin D deficiency has been evaluated through a single time-point of measurement (or in different periods of the year), that may be susceptible to bias. Even the differences in age and level of education should be taken into consideration. Nevertheless, these data in the Cilento region are original (there are no similar reports to our knowledge). However, our results confirm the necessity of other study, and this result is an important opportunity to introduce a modifiable risk fact and, consequently, a new treatment for AD.

Keywords: Alzheimer Disease, Cilento Region, Vitamin D, Cognitive impairment, Mini-Mental Score Examination (MMSE) score, Dementia.


Article Information


Identifiers and Pagination:

Year: 2020
Volume: 14
First Page: 63
Last Page: 67
Publisher Id: TONEUJ-14-63
DOI: 10.2174/1874205X02014010063

Article History:

Received Date: 13/4/2020
Revision Received Date: 16/6/2020
Acceptance Date: 17/6/2020
Electronic publication date: 08/09/2020
Collection year: 2020

© 2020 Pizza etal.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Department of Pharmacy, University of Salerno, Fisciano, Italy; E-mail: pharmacologyunisa@gmail.com





1. INTRODUCTION

Dementia is defined as the progressive decay of cognitive functions and behavioral changes capable of determining the reduction of an individual's functioning capacity. It is an acquired and progressive degenerative disease enough to impact on the activities of daily living. Everyday activities, in fact, are greatly impaired from dementia, that is a major cause of dependence, disability, and death. It mainly affects older people, with a mean age, at diagnosis of dementia, of 80 years of age [1Chai B, Gao F, Wu R, et al. Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: an updated meta-analysis. BMC Neurol 2019; 19(1): 284.
[http://dx.doi.org/10.1186/s12883-019-1500-6] [PMID: 31722673]
] although it is not a normal part of ageing [2World Health Organization. Mental health of older adult 2017. Available from: https://www.who.int/en/news-room/fact-sheets/detail/mental-health-of-older-adults].

Dementias are chronic, in most degenerative and require a complex management and the involvement of multiple healthcare professionals. The definition of dementia as we know now was established in 2011. Based on this definition, at least two neuropsychiatric or cognitive domains must be impaired without no better explanation by nondegenerative or primary psychiatric disorders, or other systemic conditions. The diagnosis of dementia is based on clinical characteristics, mostly reported by parents, and objective evaluation of cognitive loss through a neuropsychiatric and neuropsychological assessment [3McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3): 263-9.
[http://dx.doi.org/10.1016/j.jalz.2011.03.005] [PMID: 21514250]
].

In the last years, the World Health Organization (WHO) indicates dementia as a public health priority. About 50 million people worldwide are affected by dementia nowadays; among these patients, about 60% live in low- and middle-income countries. The total number of people with dementia is estimated to increase to 82 million in 2030 and 152 million in 2050 [2World Health Organization. Mental health of older adult 2017. Available from: https://www.who.int/en/news-room/fact-sheets/detail/mental-health-of-older-adults]. Every year, about 10 million people progress to dementia [1Chai B, Gao F, Wu R, et al. Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: an updated meta-analysis. BMC Neurol 2019; 19(1): 284.
[http://dx.doi.org/10.1186/s12883-019-1500-6] [PMID: 31722673]
]. These data imply a large expenditure of resources in terms of the direct costs of medical, social and informal care associated with dementia and indirect cost due to the constant commitment of patients’ family members. Assistance is needed from the health, social, financial and legal systems for both people with dementia and their parents, to support them from the economic and emotional point of view [2World Health Organization. Mental health of older adult 2017. Available from: https://www.who.int/en/news-room/fact-sheets/detail/mental-health-of-older-adults]. In the USA, the annual cost of dementia is estimated to be about $818 billion in 2015, an increase of 35% since 2010, and a $ 1 trillion threshold increase in 2018. It is an enormous sum. The global costs seem to be similar, in magnitude, to the GDP of countries like Indonesia, The Netherlands, and Turkey. These examples verify how enormous is the cost of dementia [4Wimo A, Guerchet M, Ali GC. Alzheimers Dement. 2017 Jan;13(1):1-7. The worldwide costs of dementia 2015 and comparisons with 2010, 5Prince M, Albanese E, Guerchet M, et al. World Alzheimer Report 2014. Dementia and risk reduction an analysis of protective and modifiable factors 2014.]. Dementia has huge economic impacts also in England, where about 690 000 people with dementia live at present and where the total annual cost of dementia is estimated to be £24.2 billion in 2015 [6Wittenberg R, Knapp M, Hu B, et al. The costs of dementia in England. Int J Geriatr Psychiatry 2019; 34(7): 1095-103. [The costs of dementia in England].
[http://dx.doi.org/10.1002/gps.5113] [PMID: 30950106]
]. In Italy, mean total monthly societal costs per patient is up to €2728 for patients and societal costs generally increased with increasing dementia severity [7Bruno G, Mancini M, Bruti G, Dell’Agnello G, Reed C. Costs and resource use associated with alzheimer’s disease in italy: Results from an observational study. J Prev Alzheimers Dis 2018; 5(1): 55-64.
[http://dx.doi.org/10.14283/jpad.2017.31] [PMID: 29405234]
].

In all forms of dementia, Alzheimer's disease (AD) is the most common and represents one of the most impactful diseases for public health with enormous health and economic implications for contemporary society. Countless progress in AD knowledge has been made in the last years but they were not sufficient to lead to the development of disease‐modifying treatments. AD is the most common type of dementia, accounting for 50%–75%, and is primarily a condition of later life [5Prince M, Albanese E, Guerchet M, et al. World Alzheimer Report 2014. Dementia and risk reduction an analysis of protective and modifiable factors 2014.]

AD is caused by the complex interplay of various genetic, environmental and lifestyle factors, whose consequence is the degeneration of neuronal cells over the period of time. Among genetic, the APOE gene seems to have a key role; moreover, genome-wide association studies using many thousands of samples have identified more than 20 genetic risk factors,

implicating inflammatory, cholesterol metabolism and endosomal vesicle recycling pathways that could be involved in AD pathogenesis [8Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol 2018; 25(1): 59-70.
[http://dx.doi.org/10.1111/ene.13439] [PMID: 28872215]
]. Genetic alteration can determine neuronal loss, abnormal accumulation of Amyloid-β (Aβ) and neurofibrillary tangles (NFTs) which lead to loss of synapses and neuronal death, macroscopic atrophy and, clinically, severe memory impairments and other cognitive dysfunctions and eventual demise of the individual. Other risk factors for AD could be overweight, smoking, diabetes. Vascular risk factors may increase the risk of clinical AD through a ‘double-hit’ with superimposed cerebrovascular damage, or vascular damage might influence the development of AD pathology directly [8Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol 2018; 25(1): 59-70.
[http://dx.doi.org/10.1111/ene.13439] [PMID: 28872215]
].

Recently, a potential role has been proposed also for vitamin D. During the last 25 years, vitamin D has been suggested as a candidate in nervous system development and function and a therapeutic tool in different neurological pathologies. Vitamin D could play an important role in the pathophysiology of dementia and therefore of Alzheimer’s disease and could be considered in this sense a potential risk factor.

The Cilento region is particularly interesting because, in this area we can record high longevity.

In particular, the centenarians of Cilento had a healthy metabolic profile and a low prevalence of clinical cardiovascular diseases and even in centenarians with structural cardiac anomalies, there is little evidence of objectionable symptoms [9Daniels LB, Antonini P, Marino R, et al. Cardiovascular health of nonagenarians in southern Italy: A cross-sectional, home-based pilot study of longevity. J Cardiovasc Med (Hagerstown) 2020; 21(2): 89-98.
[http://dx.doi.org/10.2459/JCM.0000000000000910] [PMID: 31789688]
].

Furthermore, in an over ninety year old population of Cilento it has been shown how the nutritional status and the oxidative balance are correlated to a better cognitive profile [10Pizza V, et al. Oxidative stress and aging. Current Neurobiology 2013; 4(1and2): 93-8.].

In our work, we have determined the serum values ​​of vitamin D in a population of patients with Alzheimer's disease, all of which are native and resident in Cilento.

2. MATERIALS AND METHODS

This cross-sectional study was conducted at the Alzheimer Disease Center of the San Luca Hospital, in Vallo della Lucania (SA), a village in the National Park of Cilento, Vallo di Diano and Alburni (Salerno, Sothern Italy). We enrolled 25 consecutive patients, 13 women and 12 men. The mean age is 78.5±8.3 years and the mean duration of the disease is 3.5±1.8 years. The average school age of the patients was 6.1 +/- 3.5 years, the average disease age 6.3 +/- 1.7 years, the average basal Mini Mental Score Examination (MMSE) score was 17.6 +/- 3.6. Each subject completed clinical and neuropsychological evaluations between January 2018 and June 2018. Subjects who fulfilled criteria for the diagnosis of AD were enrolled. For this study, we excluded subjects with a diagnosis of major depressive disorder, non-AD dementias, other neurological disorders affecting cognitive functions and vascular dementia. Subjects who were currently receiving Vitamin D supplements were also excluded. We also collected demographic information, specific geographical area of ​​origin, educational level, presence or absence of other pathologies, presence or absence, in the same family, of other people with AD. All patients underwent the neuropsychological evaluation with the mini-mental state examination (MMSE), functional capacity measured by Katz Index (Basic Activities of Daily Living) and Lawton-Brody (Instrumental Activities of Daily Living) scale. The diagnosis of probable AD was made according to the DSM-5 Criteria [11Sachs-Ericsson N, Blazer DG. The new DSM-5 diagnosis of mild neurocognitive disorder and its relation to research in mild cognitive impairment. Aging Ment Health 2015; 19(1): 2-12.
[http://dx.doi.org/10.1080/13607863.2014.920303] [PMID: 24914889]
].

Serum 25-hidroxyvitamin D [25(OH)D] levels were measured by MicroVueTM 25-OH Vitamin D EIA Kit (Quidel, San Diego, CA, US).

All patients provided written informed consent prior to enrolment in the study.

3. RESULTS AND CONCLUSION

We enrolled 25 consecutive patients, 13 women and 12 men. The mean age is 78.5 ± 8.3 years, the mean duration of the disease is 3.5 ± 1.8 years. Mean vitamin D serum level is 17.9+7.9 ng/ml, denoting a state of insufficiency. Among our 25 patients, only 3 had serum level above 30 ng/ml; most patients (17 out of 25) showed serum level among 10 and 30 ng/ml, while in 5 patients serum level is less than 10 ng/ml.

Vitamin D principal sources are fish, lipids and full-fat dairy products, as well as sunlight exposure, that can produce substantial amounts of vitamin D in the epidermis [12Anastasiou CA, Yannakoulia M, Scarmeas N. Vitamin D and cognition: an update of the current evidence. J Alzheimers Dis 2014; 42(Suppl. 3): S71-80.
[http://dx.doi.org/10.3233/JAD-132636] [PMID: 24820017]
]. After its production in the skin, vitamin D is subsequently metabolized to its hormonally active form, 1,25-dihydroxyvitamin D (1,25(OH)2D), in two steps: hydroxylation in the liver to 25-hydroxyvitamin D [25(OH)D] followed by 1a-hydroxylation in the renal proximal tubule to 1,25-dihydroxyvitamin D (1,25(OH)2D-calcitriol) [13Bikle D, Christakos S. New aspects of vitamin D metabolism and action - addressing the skin as source and target. Nat Rev Endocrinol 2020; 16(4): 234-52.
[http://dx.doi.org/10.1038/s41574-019-0312-5] [PMID: 32029884]
, 14Disorders in Vitamin D Action. Liberman UA SourceEndotext ].

Vitamin D has a key role in stimulating calcium absorption from the gut and promoting skeletal health, as well as many other important physiological functions, with effects on bone marrow, brain, colon, breast, malignant cells, and immune system [15Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab 2009; 94(1): 26-34.
[http://dx.doi.org/10.1210/jc.2008-1454] [PMID: 18854395]
].

Some authors define vitamin D as the “forgotten neurosteroid”, indicating the term vitamin as wrong [16Frye CA, Hirst JJ, Brunton PJ, Russell JA. Neurosteroids for a successful pregnancy. Stress 2011; 14(1): 1-5.
[http://dx.doi.org/10.3109/10253890.2010.540050] [PMID: 21166559]
].

Vitamin D deficiency could be implicated in different chronic pathologies. For example, it has been hypothesized that Vitamin D could have a role in age-related macular degeneration (AMD), a chronic, late-onset degeneration of the macula, that represents the first cause of vision loss in adults in developed countries [17Kan E, Kan EK, Yücel ÖE. The possible link between vitamin d levels and exudative age-related macular degeneration. Oman Med J 2020; 35(1)e83
[http://dx.doi.org/10.5001/omj.2020.01] [PMID: 31993223]
]. Among the etiopathogenetical hypothesis, it has been shown that 25(OH)D3 reduces the proliferation of cells of the immune system and the proliferation of endothelial cells and angiogenesis. Taken together, these data suggest a possible anti-inflammatory role and Vitamin D deficiency could be implicated in several conditions sharing, as a key role, inflammation [18Müller K, Gram J, Bollerslev J, et al. Down-regulation of monocyte functions by treatment of healthy adults with 1 alpha,25 dihydroxyvitamin D3. Int J Immunopharmacol 1991; 13(5): 525-30.
[http://dx.doi.org/10.1016/0192-0561(91)90072-F] [PMID: 1783465]
-20Shokravi MT, Marcus DM, Alroy J, Egan K, Saornil MA, Albert DM. Vitamin D inhibits angiogenesis in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci 1995; 36(1): 83-7.
[PMID: 7529753]
].

So, there is a negative relationship between 25(OH)D3 levels and several chronic conditions associated with inflammation, such as type 1 diabetes, cancer, heart diseases and rheumatoid arthritis [21Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004; 79(3):362-371 79(3): 362-71., 22Merlino LA, Curtis J, Mikuls TR, et al. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis RheumM 2004; 50(1): 72-7.].

Recently, a role has been proposed also in the development of depression [23Menon V, Kar SK, Suthar N, Nebhinani N. Vitamin D and depression: A critical appraisal of the evidence and future directions. Indian J Psychol Med 2020; 42(1): 11-21.
[http://dx.doi.org/10.4103/IJPSYM.IJPSYM_160_19] [PMID: 31997861]
]. Growing evidence, infact, points to the role of vitamin D in the pathobiology and treatment of depression. Serum vitamin D levels inversely correlate with clinical depression, but there is not enough evidence to suggest universal supplementation in depression. Enriching depression treatment trials with subjects having concurrent vitamin D deficiency appears to be a potential step forward in this field.

Recent studies indicate that vitamin D deficiency could have a role also in dementia pathogenesis. Vitamin D deficiency, in fact, is more frequent in patients with dementia, that have a lower level of vitamin D (25-hydroxyvitamin D (25 (OH) D)) compared with the control group healthy age-matched patients [24Zhao Y, Sun Y, Ji HF, Shen L. Vitamin D levels in Alzheimer’s and Parkinson’s diseases: a meta-analysis. Nutrition 2013; 29(6): 828-32.
[http://dx.doi.org/10.1016/j.nut.2012.11.018] [PMID: 23415143]
] However, we still do not know if vitamin D deficiency may be only a marker or potential risk factor for developing dementia [25Evatt ML, Delong MR, Khazai N, Rosen A, Triche S, Tangpricha V. Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol 2008; 65(10): 1348-52.
[http://dx.doi.org/10.1001/archneur.65.10.1348] [PMID: 18852350]
-27Littlejohns TJ, Henley WE, Lang IA, et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology 2014; 83(10): 920-8.
[http://dx.doi.org/10.1212/WNL.0000000000000755] [PMID: 25098535]
] Within the prospective Rotterdam Study, it has been evidenced that lower serum vitamin D concentrations are associated with a higher incidence of dementia [28Licher S, de Bruijn RFAG, Wolters FJ, Zillikens MC, Ikram MA, Ikram MK. Vitamin D and the risk of dementia: The rotterdam study. J Alzheimers Dis 2017; 60(3): 989-97.
[http://dx.doi.org/10.3233/JAD-170407] [PMID: 28984598]
]. This is a very interesting result, since vitamin D could be a potentially modifiable risk factor for dementia thanks to its possible neuroprotective action. However, different studies examining the association between vitamin D and dementia have provided conflicting results and further studies are needed.

Our preliminary data showed that Vitamin D deficiency was, in our patients, independently associated with AD. However, several studies do not agree on the role of vitamin d in dementia pathogenesis. The “Canadian Study of Health and Aging”, for example, is a 10-year cohort study that did not demonstrate a significant association found between Vitamin D level and cognitive decline, dementia or AD [29Duchaine CS. Vitamin D status, cognitive decline and incident dementia: the Canadian Study of Health and Aging. Can J Public Health 2020.]. On the contrary, these authors demonstrated that higher Vitamin D concentrations were associated with an increased risk of dementia and AD in women, but not in men. They conclude that, even if this study does not support a protective effect of vitamin D status on cognitive function, further research is needed, especially to clarify the relation by sex. Other studies, however, support a protective role of vitamin D in dementia development and a negative association between Vitamin D serum level and cognitive decline. Littlejons et al. [27Littlejohns TJ, Henley WE, Lang IA, et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology 2014; 83(10): 920-8.
[http://dx.doi.org/10.1212/WNL.0000000000000755] [PMID: 25098535]
] confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer's disease, adding to the ongoing debate about the role of vitamin D in nonskeletal conditions. Moreover, Low 25OHD concentrations were associated with mild cognitive impairment (MCI) status in older non-demented community-dwellers with a subjective memory complaint [30Annweiler C, Fantino B, Schott AM, Krolak-Salmon P, Allali G, Beauchet O. Vitamin D insufficiency and mild cognitive impairment: cross-sectional association. Eur J Neurol 2012; 19(7): 1023-9.
[http://dx.doi.org/10.1111/j.1468-1331.2012.03675.x] [PMID: 22339714]
].

Vitamin D deficiency has been classically associated with skeletal disorders, but it could play a role in different chronic disease since vitamin D receptors have been described on multiple types of cells. In 2005, Eyles and coll reported, for the first time, the distribution of the 1,25-dihydroxyvitamin D3 receptor (VDR), and 1alpha-hydroxylase (1alpha-OHase), the enzyme responsible for the formation of the active vitamin in the human brain. Multiple different areas of the brain, including hypothalamus and the large neurons within the substantia nigra, host both the receptor and enzyme, while the nucleus basalis of Meynert and the Purkinje cells in the cerebellum expressed 1alpha-OHase in the absence of VDR. The observed distribution of the VDR is consistent with the proposal that Vitamin D operates in a similar fashion to the known neurosteroids [31Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 2005; 29(1): 21-30.
[http://dx.doi.org/10.1016/j.jchemneu.2004.08.006] [PMID: 15589699]
].

In other words, the presence of the receptor and / or enzyme in specific areas related to memory could explain the possible association between vitamin d levels and dementia.

Our preliminary data showed that Vitamin D deficiency was, in our patients, independently associated with AD, even in a special population, high rate of centenarians, like Cilento people. However, our preliminary study has different limitations. The vitamin D deficiency has been evaluated through a single time-point of measurement (or in different periods of the year), that may be susceptible to bias. Even the differences in age and level of education should be taken into consideration. Nevertheless, these data in the Cilento region are original (there are no similar reports to our knowledge). However, our results confirm the necessity of other study and this result is an important opportunity to introduce a modifiable risk fact and, consequently, a new treatment for AD.

AUTHOR CONTRIBUTIONS

Study concept and design: Vincenzo Pizza.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Study supervision: Anna Capasso.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

Not applicable.

HUMAN AND ANIMAL RIGHTS

No animals were used in this research. All human research procedures were followed in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.

CONSENT FOR PUBLICATION

Informed consent has been obtained form all participants.

AVAILABILITY OF DATA AND MATERIALS

The data that support the findings of this study are available from the [V.P], upon reasonable request.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

The authors are grateful to Dr. Ileana Grimaldi for language revision.

REFERENCES

[1] Chai B, Gao F, Wu R, et al. Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: an updated meta-analysis. BMC Neurol 2019; 19(1): 284.
[http://dx.doi.org/10.1186/s12883-019-1500-6] [PMID: 31722673]
[2] World Health Organization. Mental health of older adult 2017. Available from: https://www.who.int/en/news-room/fact-sheets/detail/mental-health-of-older-adults
[3] McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3): 263-9.
[http://dx.doi.org/10.1016/j.jalz.2011.03.005] [PMID: 21514250]
[4] Wimo A, Guerchet M, Ali GC. Alzheimers Dement. 2017 Jan;13(1):1-7. The worldwide costs of dementia 2015 and comparisons with 2010
[5] Prince M, Albanese E, Guerchet M, et al. World Alzheimer Report 2014. Dementia and risk reduction an analysis of protective and modifiable factors 2014.
[6] Wittenberg R, Knapp M, Hu B, et al. The costs of dementia in England. Int J Geriatr Psychiatry 2019; 34(7): 1095-103. [The costs of dementia in England].
[http://dx.doi.org/10.1002/gps.5113] [PMID: 30950106]
[7] Bruno G, Mancini M, Bruti G, Dell’Agnello G, Reed C. Costs and resource use associated with alzheimer’s disease in italy: Results from an observational study. J Prev Alzheimers Dis 2018; 5(1): 55-64.
[http://dx.doi.org/10.14283/jpad.2017.31] [PMID: 29405234]
[8] Lane CA, Hardy J, Schott JM. Alzheimer’s disease. Eur J Neurol 2018; 25(1): 59-70.
[http://dx.doi.org/10.1111/ene.13439] [PMID: 28872215]
[9] Daniels LB, Antonini P, Marino R, et al. Cardiovascular health of nonagenarians in southern Italy: A cross-sectional, home-based pilot study of longevity. J Cardiovasc Med (Hagerstown) 2020; 21(2): 89-98.
[http://dx.doi.org/10.2459/JCM.0000000000000910] [PMID: 31789688]
[10] Pizza V, et al. Oxidative stress and aging. Current Neurobiology 2013; 4(1and2): 93-8.
[11] Sachs-Ericsson N, Blazer DG. The new DSM-5 diagnosis of mild neurocognitive disorder and its relation to research in mild cognitive impairment. Aging Ment Health 2015; 19(1): 2-12.
[http://dx.doi.org/10.1080/13607863.2014.920303] [PMID: 24914889]
[12] Anastasiou CA, Yannakoulia M, Scarmeas N. Vitamin D and cognition: an update of the current evidence. J Alzheimers Dis 2014; 42(Suppl. 3): S71-80.
[http://dx.doi.org/10.3233/JAD-132636] [PMID: 24820017]
[13] Bikle D, Christakos S. New aspects of vitamin D metabolism and action - addressing the skin as source and target. Nat Rev Endocrinol 2020; 16(4): 234-52.
[http://dx.doi.org/10.1038/s41574-019-0312-5] [PMID: 32029884]
[14] Disorders in Vitamin D Action. Liberman UA SourceEndotext
[15] Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab 2009; 94(1): 26-34.
[http://dx.doi.org/10.1210/jc.2008-1454] [PMID: 18854395]
[16] Frye CA, Hirst JJ, Brunton PJ, Russell JA. Neurosteroids for a successful pregnancy. Stress 2011; 14(1): 1-5.
[http://dx.doi.org/10.3109/10253890.2010.540050] [PMID: 21166559]
[17] Kan E, Kan EK, Yücel ÖE. The possible link between vitamin d levels and exudative age-related macular degeneration. Oman Med J 2020; 35(1)e83
[http://dx.doi.org/10.5001/omj.2020.01] [PMID: 31993223]
[18] Müller K, Gram J, Bollerslev J, et al. Down-regulation of monocyte functions by treatment of healthy adults with 1 alpha,25 dihydroxyvitamin D3. Int J Immunopharmacol 1991; 13(5): 525-30.
[http://dx.doi.org/10.1016/0192-0561(91)90072-F] [PMID: 1783465]
[19] Manolagas SC, Provvedini DM, Murray EJ, et al. The antiproliferative effect of calcitriol on human peripheral blood mononuclear cells. J Clin Endocrinol Metab 1986; 63(2): 394-400.
[20] Shokravi MT, Marcus DM, Alroy J, Egan K, Saornil MA, Albert DM. Vitamin D inhibits angiogenesis in transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci 1995; 36(1): 83-7.
[PMID: 7529753]
[21] Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004; 79(3):362-371 79(3): 362-71.
[22] Merlino LA, Curtis J, Mikuls TR, et al. Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women’s Health Study. Arthritis RheumM 2004; 50(1): 72-7.
[23] Menon V, Kar SK, Suthar N, Nebhinani N. Vitamin D and depression: A critical appraisal of the evidence and future directions. Indian J Psychol Med 2020; 42(1): 11-21.
[http://dx.doi.org/10.4103/IJPSYM.IJPSYM_160_19] [PMID: 31997861]
[24] Zhao Y, Sun Y, Ji HF, Shen L. Vitamin D levels in Alzheimer’s and Parkinson’s diseases: a meta-analysis. Nutrition 2013; 29(6): 828-32.
[http://dx.doi.org/10.1016/j.nut.2012.11.018] [PMID: 23415143]
[25] Evatt ML, Delong MR, Khazai N, Rosen A, Triche S, Tangpricha V. Prevalence of vitamin d insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol 2008; 65(10): 1348-52.
[http://dx.doi.org/10.1001/archneur.65.10.1348] [PMID: 18852350]
[26] Morley JE. Dementia: Does vitamin D modulate cognition? Nat Rev Neurol 2014; 10(11): 613-4.
[http://dx.doi.org/10.1038/nrneurol.2014.193] [PMID: 25330725]
[27] Littlejohns TJ, Henley WE, Lang IA, et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology 2014; 83(10): 920-8.
[http://dx.doi.org/10.1212/WNL.0000000000000755] [PMID: 25098535]
[28] Licher S, de Bruijn RFAG, Wolters FJ, Zillikens MC, Ikram MA, Ikram MK. Vitamin D and the risk of dementia: The rotterdam study. J Alzheimers Dis 2017; 60(3): 989-97.
[http://dx.doi.org/10.3233/JAD-170407] [PMID: 28984598]
[29] Duchaine CS. Vitamin D status, cognitive decline and incident dementia: the Canadian Study of Health and Aging. Can J Public Health 2020.
[30] Annweiler C, Fantino B, Schott AM, Krolak-Salmon P, Allali G, Beauchet O. Vitamin D insufficiency and mild cognitive impairment: cross-sectional association. Eur J Neurol 2012; 19(7): 1023-9.
[http://dx.doi.org/10.1111/j.1468-1331.2012.03675.x] [PMID: 22339714]
[31] Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 2005; 29(1): 21-30.
[http://dx.doi.org/10.1016/j.jchemneu.2004.08.006] [PMID: 15589699]
Track Your Manuscript:


Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents




Webmaster Contact: info@benthamopen.net
Copyright © 2020 Bentham Open