Microglia play a key role in the response to amyloid beta in Alzheimer's disease (AD). In this context, the major transcriptional response of microglia is the upregulation of APOE, the strongest late-onset AD risk gene. Of its three isoforms, APOE2 is thought to be protective, while APOE4 increases AD risk. We hypothesised that the isoforms change gene regulatory patterns that link back to biological function by shaping microglial transcriptomic and chromatin landscapes. We use RNA- and ATAC-sequencing to profile gene expression and chromatin accessibility of human microglia xenotransplantated into the brains of male APPNL-G-F mice. We identify widespread transcriptomic and epigenomic differences which are dependent on APOE genotype and are corroborated across the profiling assays. Our results indicate that impaired microglial proliferation, migration and immune responses may contribute to the increased risk for late-onset AD in APOE4 carriers, while increased phagocytic capabilities and DNA-binding of the vitamin D receptor in APOE2 microglia may contribute to the isoform's protective role.

As the world population ages, Alzheimer disease (AD) prevalence increases. However, understanding of AD etiology continues to evolve, and the pathophysiological processes involved are only partially elucidated. One compound suspected to play a role in the development and progression of AD is cholesterol. Several lines of evidence support this connection, yet it remains unclear whether cholesterol-modifying strategies have potential applications in the clinical management of AD.

A deep literature search using PubMed was performed to prepare this narrative review. The literature search, performed in early 2024, was inclusive of literature from 1990 to 2024. After providing an overview of cholesterol metabolism, this study summarizes key preclinical studies that have investigated cholesterol-modifying therapies in laboratory models of AD. It also summarizes past and current clinical trials testing specific targets modulated by anti-cholesterol therapies in AD patients.

Based on current epidemiological and mechanistic studies, cholesterol likely plays a role in AD etiology. The use of cholesterol-modifying therapies could be a promising treatment approach if administered at presymptomatic to early AD phases, but it is unlikely to be efficient in mild, moderate, and late AD stages. Several recommendations are provided for hypercholesterolemia management in AD patients.

Vitamins and minerals (micronutraceuticals) maintain good health. However, the specific effects of these micronutraceuticals on brain health are often overlooked, or not even known. In this review, an overview of the direct and indirect effects of micronutraceuticals on brain energy metabolism (neuroenergetics) and neuronal health is provided. Thereafter, a holistic summary of the existing studies that have shown the impact of micronutraceuticals on neurodegenerative diseases. Lastly, this review concludes by identifying several research gaps that remain and provides suggestions for future research on these hot topics.

Vitamin D deficiency is recognized as a significant public health concern, and it has been identified as one of the potentially modifiable risk factors for mild cognitive impairment (MCI). However, evidence regarding the relationship between vitamin D status and cognitive function remains conflicting.

Therefore, this study aimed to examine the prevalence of vitamin D deficiency in the Thai elderly population and an association between vitamin D status and cognitive function, adiposity, and insulin sensitivity.

This study enrolled participants aged 55-80 years with normal cognitive function (normal group) or MCI from the prospective cohort in the "Holistic approach of Alzheimer's disease in Thai people (HADThai study)". We used the baseline clinical data to determine the prevalence of vitamin D deficiency and its association between vitamin D status and cognitive function, adiposity, and insulin sensitivity.

A total of 718 subjects (71.9% women) with a mean age of 65.7 ± 5.8 years and a mean BMI of 23.9 ± 3.7 kg/m2 were enrolled. There were 470 (65.5%) participants with normal cognitive function and 248 (34.5%) with MCI. Vitamin D status did not differ significantly between individuals with normal cognitive function and those with MCI. The prevalence of vitamin D deficiency (<20 ng/mL) and vitamin D inadequacy (<30 ng/mL) in both normal cognitive function and MCI was around 6.5% and 40.0%, respectively. While serum 25(OH)D concentrations were inversely associated with body mass index (BMI), body fat, %body fat, and the homeostasis model assessment of insulin resistance (HOMA-IR), no relationship was found between vitamin D status and cognitive function.

Our study emphasized the high prevalence of vitamin D inadequacy among elderly individuals and an inverse association of vitamin D status and adiposity and insulin resistance. These findings emphasize the importance of addressing vitamin D deficiency in the elderly population to improve overall health outcomes. Nevertheless, our results do not support a direct role of vitamin D status in cognitive decline in this population. Further research, particularly studies with longer follow-up periods and the inclusion of patients with dementia with details of vitamin D supplementation, is needed to clarify the potential role of vitamin D in cognitive decline and neurodegenerative diseases.

Vitamin D plays a crucial role in neural differentiation, yet its precise mechanisms remain unclear. In this study, we investigated the effects of vitamin D metabolites, 25-hydroxyvitamin D3 (25D3) and 1α,25-dihydroxyvitamin D3 (1α,25D3), on neural differentiation using Cyp27b1-/- and Vdr-/- knockout mice-derived neural stem cells. We found that 1α,25D3 promotes neuronal differentiation via vitamin D receptor (VDR), whereas some of its effects occur independently of VDR. Additionally, 25D3 requires conversion to 1α,25D3 by CYP27B1 to induce neuronal differentiation. In contrast, both 25D3 and 1α,25D3 promoted astrocyte differentiation regardless of CYP27B1 expression but required VDR. Furthermore, using vitamin D derivatives, we demonstrated that VDR binding affinity does not directly correlate with neurogenic potential. These findings reveal distinct VDR-dependent and VDR-independent pathways in neural differentiation, highlighting a previously unrecognized role of vitamin D metabolism in neural fate determination.

In those with mild cognitive impairment (MCI) and dementia, nutritional intake decreases, increasing nutritional deficiency risk. Dietary supplements (DSs) may be an important source of nutrition, but recent insight into their use in those with normal cognition (NC), MCI or dementia is lacking.

A cross-sectional study design determined prevalence for reported use of 12 DS categories and 19 individual DSs based on co-participant report in 9517 older adult (≥ 55 years) National Alzheimer's Coordinating Center (NACC) participants diagnosed with NC (n = 5361), MCI (n = 1800) or dementia (n = 2347) in 2019. Multivariable binary logistic regression compared reported DS use prevalence between NC, MCI and dementia adjusting for demographics.

Reported use of any DS was highly prevalent (NC: 76.6%, MCI: 73.9% and dementia: 69.6%). For all DS categories and many DSs, reported use was significantly lower in dementia compared to NC. Prevalence of reported use progressively declined from NC, MCI and dementia for 8/12 DS categories, including any vitamin (NC: 71.2%, MCI: 68% and dementia: 62.4%) and any mineral (NC: 34.8% MCI: 28.2% and dementia: 23.5%). This trend was also observed for 4/19 DSs, including vitamin D (NC: 49.2%, MCI: 41.2% and dementia: 36.7%). For vitamin B12 (NC: 15.5%, MCI: 18.2% and dementia: 18.5%) and melatonin (NC: 6.0%, MCI: 7.3% and dementia: 7.9%), prevalence increased from NC to MCI and from NC to dementia.

For many DSs, prevalence was significantly lower in dementia compared to NC. Reported use of any DS was highly prevalent in NACC older adults with NC, MCI or dementia in 2019.

As the global population ages, neurodegenerative diseases, particularly Alzheimer's disease (AD), have become a major public health concern. AD is the most prevalent neurodegenerative disorder, accounting for 60-80% of cases, and is characterized by progressive cognitive and memory decline due to neuronal loss. Current pharmacological treatments primarily offer symptomatic relief rather than a cure. Recent research has highlighted the role of vitamin D in neuroprotection, owing to its antioxidant, anti-inflammatory, and neuroprotective properties, as well as its ability to maintain blood-brain barrier integrity and regulate amyloid-beta (Aβ) clearance. Another emerging noninvasive therapeutic approach is Low-Level Laser Therapy (LLLT), a form of photobiomodulation (PBM) that has been shown to enhance neuronal function, reduce oxidative stress, inflammation, and Aβ deposition, and potentially increase vitamin D levels. This review examines the interplay between LLLT, vitamin D, and oxidative stress in AD pathophysiology. Findings suggest that LLLT can stimulate mitochondrial function, enhance synaptic plasticity, and improve cognitive performance in preclinical and clinical studies. Furthermore, LLLT has been reported to modulate immune responses, promote neurogenesis, and facilitate vitamin D synthesis by activating cytochrome c oxidase (CCO), which plays a crucial role in mitochondrial energy production. However, while promising, further in vivo and clinical trials are required to optimize treatment protocols and establish standardized guidelines for LLLT application, particularly in enhancing vitamin D levels, in AD patients. CLINICAL TRIAL NUMBER: Not applicable.

To investigate whether exposure to secondhand smoke (SHS) aggravates the detrimental effect of vitamin D deficiency (VDD) on cognitive performance in the elderly.

Based on National Health and Nutrition Examination Surveys (NHANES) 2011-2014, 1,446 non-smoking participants (≥ 60 years old) with detailed serum 25-hydroxyvitamin D [25(OH)D], concentration of cotinine and tests score of cognitive function were included. Cognitive impairment was defined as having a cognitive score in the lowest quartile. The possible synergistic effect of SHS with VDD on cognitive impairment was evaluated by using a multivariable logistic regression model.

VDD was independently associated with risk of low the Digit Symbol Substitution Test (DSST) scores, increased by nearly 60% [< 34, adjusted odds ratio (aOR) = 1.62, 95% CI: 1.03 ~ 2.53]. Although it only had an association with cognitive impairment indicated by DSST and the Animal Fluency test (AFT) in the crude model, SHS exposure showed significant synergistic effects with VDD on DSST (aOR: 3.03, 95% CI: 1.57 ~ 5.83, Pinteraction = 0.001) and AFT (aOR: 2.40, 95% CI: 1.34 ~ 4.29, Pinteraction = 0.003), respectively, after adjusting for the possible confounders. In further stratified analysis, a more obvious synergistic effect of SHS with VDD on DSST (aOR: 4.73, 95%CI:1.77 ~ 12.68, Pinteraction = 0.002) and AFT (aOR: 5.30, 95%CI: 1.63 ~ 17.24, Pinteraction = 0.006) was found in obese and overweight subjects, respectively.

SHS exposure had synergistic effect with VDD on cognitive impairment among elderly and the interaction effect was more obvious in overweight and obese individuals.

The impact of vitamin D deficiency (VDD) on cognition remains controversial. Evidences suggest that variability based on apolipoprotein E (APOE) ε4 status and gender, given APOE ε4's influence on vitamin D metabolism and women's heightened vitamin D sensitivity. We investigated the interplay between APOE ε4, gender, and VDD in cognitive decline among older adults.

In a population-based cohort of 1547 cognitively normal Koreans aged ≥60 years, Mini Mental State Examination (MMSE) changes were tracked biennially (2010-2020). VDD was defined as serum 25-hydroxyvitamin D < 10 ng/mL. Linear mixed models analyzed VDD effects, with subgroup analyses for APOE ε4 status and gender.

VDD was present in 21.3 % at baseline and was linked to faster MMSE decline (estimate = -0.054, 95 % CI [-0.091, -0.017], p = 0.004), particularly in APOE ε4 non-carriers (estimate = -0.070, 95 % CI [-0.112, -0.029], p = 0.001). A gender-based analysis revealed that this effect was significant only in female non-carriers (estimate = -0.097, 95 % CI [-0.156, -0.038], p = 0.001). Conversely, male non-carriers demonstrated an absence of a statistically significant association (estimate = -0.017, 95 % CI [-0.076, 0.041], p = 0.562).

VDD accelerates cognitive decline in cognitively normal APOE ε4 non-carriers, particularly women, underscoring the importance of tailored prevention strategies.

Vitamin D offers numerous under-recognized health benefits beyond its well-known role in musculoskeletal health. It is vital for extra-renal tissues, prenatal health, brain function, immunity, pregnancy, cancer prevention, and cardiovascular health. Existing guidelines issued by governmental and health organizations are bone-centric and largely overlook the abovementioned extra-skeletal benefits and optimal thresholds for vitamin D. In addition, they rely on randomized controlled trials (RCTs), which seldom show benefits due to high baseline 25-hydroxyvitamin D [25(OH)D] concentrations, moderate supplementation doses, and flawed study designs. This review emphasizes the findings from prospective cohort studies showing that higher 25(OH)D concentrations reduce the risks of major diseases and mortality, including pregnancy and birth outcomes. Serum concentrations > 30 ng/mL (75 nmol/L) significantly lower disease and mortality risks compared to <20 ng/mL. With 25% of the U.S. population and 60% of Central Europeans having levels <20 ng/mL, concentrations should be raised above 30 ng/mL. This is achievable through daily supplementation with 2000 IU/day (50 mcg/day) of vitamin D3, which prevent diseases and deaths. Furthermore, a daily dose between 4000 and 6000 IU of vitamin D3 to achieve serum 25(OH)D levels between 40 and 70 ng/mL would provide greater protection against many adverse health outcomes. Future guidelines and recommendations should integrate the findings from observational prospective cohort studies and well-designed RCTs to improve public health and personalized care.

Wilson's disease is a metabolic disorder affecting the liver, brain, skin and osteo-muscular organs. Refractory rickets is an unusual phenomenon in Wilson's disease. This 27-year-old man was primarily treated for rickets for 20 years without success and later developed features of tremulousness of limbs and dysphonia when he was evaluated for Wilson's disease. On treatment with a chelating agent, he showed clinical improvement neurologically. This case report emphasises on the consideration of Wilson's disease early in a case of rickets for better clinical outcome.

This study explores the complex link between vitamin D and neurological illnesses, focusing on how vitamin D affects possible risk factors, therapeutic applications, and the trajectory of the disease. An epidemiological study has linked vitamin D insufficiency to several neurological conditions, including Parkinson's disease, Alzheimer's disease, and multiple sclerosis. It is hypothesized that immunomodulatory and anti-inflammatory properties of vitamin D contribute to its neuroprotective effects. Two major mechanisms in dementia include neuroinflammation and oxidative stress. Adequate levels of vitamin D have been shown in both animal models and human studies to enhance both clinical outcomes and the duration of illness in those who have it. Other ways that vitamin D contributes to its therapeutic potential include the production of neurotrophic factors, control over neurotransmitter synthesis, and preservation of the blood-brain barrier. Despite the encouraging outcomes, research is still being conducted to determine the optimal dosage and long-term benefits of vitamin D supplementation on brain function. In order to furnish precise directives and clarify the processes behind the neuroprotective impacts of vitamin D, future research must focus on large-scale randomized controlled studies. . This study highlights the significance of maintaining adequate levels of vitamin D as a modifiable risk factor for neurological disorders. Further study is also required to comprehend the possible medical benefits of this vitamin fully.

This study investigates the global impact of ambient ultraviolet radiation (UVR) on dementia incidence, addressing its controversial association with dementia risk. UVR, through both vitamin D-dependent and independent mechanisms, influences physiological processes essential for brain health, such as reducing neuroinflammation, improving sleep regulation, and enhancing neuroplasticity. This study aims to clarify the relationship between UVR and dementia incidence and evaluate its role in public health strategies for dementia prevention.

An ecological analysis across 204 countries was conducted using country-specific data on UVR levels and dementia incidence rates. Bivariate analysis, partial correlation, and multiple linear regression models were employed to assess the relationship between UVR and dementia incidence. Confounding factors, including aging, economic affluence, genetic predisposition, and urbanization, were controlled to ensure robust results. Subgroup analyses were performed to explore differences across income classifications, regional groupings, and developmental statuses, based on World Bank and United Nations criteria.

A significant inverse correlation between UVR and dementia incidence was identified (r = -0.764, p < 0.001), which persisted after adjusting for confounding factors. UVR emerged as the strongest predictor of dementia incidence, explaining a substantial portion of the variance, followed by aging as the second strongest predictor. Subgroup analyses revealed that the protective effects of UVR were particularly pronounced in developing countries, where limited access to vitamin D supplementation, combined with greater exposure to natural sunlight may enhance its influence.

Lower ambient UVR levels are associated with higher dementia incidence rates worldwide, suggesting a critical role for UVR in mitigating dementia risk. Public health strategies should consider environmental factors like UVR, particularly in regions with limited sunlight. Incorporating interventions to optimize UVR exposure could offer a cost-effective approach to reducing the global dementia burden and improving brain health outcomes.

In this study, we extended a previously developed one-pot double derivatization reaction to establish the first routine isotope-coded multiplex derivatization for vitamin D and its metabolites for application in clinical environments, using commercial reagents, without the need for specialized reagents and advanced synthesis requirements. The original derivatization process consisted of using both a Cookson-type reagent and derivatization of hydroxyl groups. Initially, the analytes are derivatized by a Diels-Alder reaction using 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD), followed by acetylation using acetic anhydride, catalyzed by 4-dimethylaminopyridine at room temperature. To enable sample multiplexing, we utilized acetic anhydride as well as the d 3- isotopologue of acetic anhydride, generating d 3- and d 6-products of the investigated vitamin D3 metabolites. This approach not only allowed for the simultaneous measurement of two samples within a single LC-MS/MS run but also improved the LC separation of the important 25-hydroxyvitamin D3 epimers (3α-25(OH)D3 and 3β-25(OH)D3) on a conventional C-18 column, addressing a significant challenge in vitamin D analysis. Typically, the separation of these epimers after PTAD derivatization cannot be performed on C-18 columns, necessitating the use of pentafluorophenylpropyl (PFP) stationary phases. However, PFP columns are not as stable as C-18 in long-term use, wherein the acetylation of the C-3 hydroxyl group provided a solution by enhancing chromatographic selectivity and achieving the baseline separation of the metabolites 24,25(OH)2D3, 3α-25(OH)D3, 3β-25(OH)D3, and vitamin D3 using a C-18 column with methanol/water gradient elution. The described duplex derivatization was tested on 40 serum samples of patients with chronic liver diseases (CLD). Additionally, the method was evaluated in terms of linearity, accuracy, precision, and interferences between heavy and light tag samples using both commercial quality control samples and in-house quality control and calibration samples.

The rate of suicide attempts by patients with bipolar disorder is high. In addition to patient and country specific factors, environmental factors may contribute to suicidal behavior. Sunlight has multiple diverse impacts on human physiology and behavior. Solar insolation is defined as the electromagnetic energy from the sun striking a surface area on earth. We previously found that a large change in solar insolation between the minimum and maximum monthly values was associated with an increased risk of suicide attempts in patients with bipolar I disorder.

The association between solar insolation and a history of suicide attempts in bipolar disorder was again investigated using an international database with 15% more data and more sites at diverse locations and countries.

Data were available from 5641 patients with bipolar I disorder living at a wide range of latitudes in 41 countries in both hemispheres. A large change in solar insolation between the minimum and maximum monthly values was associated with a history of suicide attempts in patients with bipolar I disorder, a replication of our prior analysis. The estimated model also associated state sponsored religion in the onset country, female gender, a history of alcohol or substance abuse, and being part of a younger birth cohort with a history of suicide attempts.

A large change between the minimum and maximum monthly values of solar insolation was associated with a history of suicide attempts in bipolar I disorder, replicating our prior research. Physicians should be aware that daylight has wide ranging physiological and psychiatric impacts, and that living with large changes in solar insolation may be associated with an increased suicide risk.

Background/Objectives: Vitamin D receptor (VDR) agonists are commonly used in clinical practice for their roles in calcium regulation and potential benefits in various diseases. However, their safety profiles, particularly for compounds available as food supplements, remain underexplored in real-world settings. This study aimed to analyze the safety profiles of VDR agonists using the EudraVigilance database, focusing on adverse drug reactions (ADRs) reported between 1 January 2004 and 23 June 2024. Methods: Data for ten VDR agonists were collected, de-duplicated, and analyzed to identify specific safety signals. Risk factors for specific ADRs were assessed using multiple logistic regression. Results: This study analyzed 5,369,581 reports in the EudraVigilance system, from which 17,947 reports (0.33%) involving 80,050 ADRs were linked to VDR agonists. The most-reported drugs were cholecalciferol (12,944 cases) and calcitriol (1355 cases). Serious ADRs were more prevalent with paricalcitol, alfacalcidol, and calcitriol than with cholecalciferol (p < 0.05). Hypercalcemia was a hallmark ADR for all VDR agonists, with the highest risk linked to dihydrotachysterol (ROR = 5668; 95%CI = 3332 to 9641; p < 0.0001), alfacalcidol (ROR = 965.7; 95%CI = 843.6 to 1106; p < 0.0001), and calcitriol (ROR = 726.0; 95%CI = 634.6 to 830.5; p < 0.0001). Logistic regression highlighted dehydration, overdose, and concomitant administration of calcium salts as major predictors of hypercalcemia. The co-administration of multiple VDR agonists was also found to increase hypercalcemia risk. However, the disproportionality analysis showed that only active VDR agonists (e.g., calcitriol, alfacalcidol) were associated with severe complications like renal and urinary disorders and cardiac issues due to hypercalcemia. Natural precursors (cholecalciferol, ergocalciferol) were more often linked to non-calcemic ADRs such as gastrointestinal symptoms, which were more prevalent in infants and children compared to adults. Conclusions: The safety profiles of VDR agonists differ significantly between compounds. Active derivatives require close monitoring for serious calcemia-related complications, whereas cholecalciferol is associated with less severe ADRs, primarily in at-risk populations. These findings highlight the need for targeted safety monitoring and further research into the real-world uses of VDR agonists.

Previous studies have reported that vitamin D deficiency increased the risk of Alzheimer's disease (AD) dementia in older adults. However, little is known about how vitamin D is involved in the pathophysiology of AD. Thus, this study aimed to examine the association and interaction of serum vitamin D levels with in vivo AD pathologies including cerebral beta-amyloid (Aβ) deposition and neurodegeneration in nondemented older adults.

428 Nondemented older adults were recruited from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease, a prospective cohort that began in 2014. All participants underwent comprehensive clinical assessments, measurement of serum 25-hydroxyvitamin D (25[OH]D), and multimodal brain imaging including Pittsburgh compound B (PiB) positron emission tomography and magnetic resonance imaging. Global PiB deposition was measured for the Aβ biomarker. Intracranial volume-adjusted hippocampal volume (HVa) was used as a neurodegeneration biomarker.

Overall, serum 25(OH)D level was not associated with either Aβ deposition or HVa after controlling for age, sex, apolipoprotein E ε4 positivity, and vascular risk factors. However, serum 25(OH)D level had a significant moderating effect on the association between Aβ and neurodegeneration, with lower serum 25(OH)D level significantly exacerbating cerebral Aβ-associated hippocampal volume loss (B = 34.612, p = 0.008).

Our findings indicate that lower serum vitamin D levels may contribute to AD by exacerbating Aβ-associated neurodegeneration in nondemented older adults. Further studies to explore the potential therapeutic effect of vitamin D supplementation on the progression of AD pathology will be necessary.

This study aims to investigate the connection between 25-hydroxyvitamin D (25(OH)D) levels and the prognosis of breast cancer with various estrogen receptor (ER) statuses. The summary statistics of 25(OH)D levels was obtained from a GWAS of 441,291 individuals and the information of breast cancer was collected from the Breast Cancer Association Consortium. We analyzed the causal association between 25(OH)D levels and breast cancer prognosis using a number of approaches, including inverse variance weighting (IVW). The heterogeneity test was performed using Cochran Q test. IVW, Mendelian randomization (MR)-Egger, and MR Pleiotropy RESidual Sum and Outlier methods were used for sensitivity analysis. In addition, a multivariate MR adjusted for total triglycerides, total cholesterol, and body mass index was used for further analysis. Two-sample MR results showed that 25(OH)D levels were not associated with prognosis in overall breast cancer (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.73-1.19, IVW exam) and estrogen receptor positive (ER+) breast cancers (OR = 1.12, 95% CI = 0.77-1.63, IVW exam) and were protective associated with prognosis in estrogen receptor negative (ER-) breast cancers (OR = 0.55, 95% CI = 0.34-0.87, IVW exam). Sensitivity analysis did not observe the presence of heterogeneity and horizontal pleiotropy. In multivariate MR analysis, after adjusting for total triglycerides, total cholesterol, and body mass index, the correlation between the protective relationship between 25(OH)D levels and the prognosis for ER- breast cancer remained and became increasingly significant (OR = 0.51, 95% CI = 0.31-0.83, P = .007). This study demonstrated a protective relationship between 25(OH)D levels and the prognosis of ER- breast cancer, but there was no connection between 25(OH)D levels and the prognosis of ER+ breast cancer.

The identification of novel acetylcholinesterase inhibitors holds significant relevance in the treatment of Alzheimer's disease (AD), the prevailing form of dementia. The exploration of alternative inhibitors to the conventional acetylcholinesterase inhibitors is steadily gaining prominence. Quinones, categorized as plant metabolites, represent a specific class of compounds. In this study, the inhibitory effects of various naphthoquinone derivatives, along with anthraquinone and its derivatives, on the acetylcholinesterase (AChE) enzyme were investigated for this purpose. An in vitro investigation was conducted to examine the effects of these compounds in order to clarify the possible mechanism of inhibition in the interaction between the enzyme and chemicals. In addition, an in silico investigation was carried out to understand the conceivable inhibitor binding process to the enzyme's active site. The acquired outcomes corroborated the in vitro results. The AChE enzyme was found to be effectively inhibited by both naphthoquinones and anthraquinones, with inhibition constant (KI) values ranging from 0.014 to 0.123 μM (micormolar). The AChE enzyme was inhibited differently by this quinone and its derivatives. Although derivatives of naphthoquinone and anthraquinone exhibited a competitive inhibitory effect, derivatives of anthraquinone exhibited a noncompetitive inhibition effect. Furthermore, because it had the lowest KI value of any of these substances, 1,5-dihydroxyanthraquinone (1c) was shown to be the most potent inhibitor. The findings will add to the body of knowledge on the creation of fresh, potent, and successful treatment approaches.

Vitamin D's effect on risk health outcomes is often evaluated using prospective cohort studies. For vitamin D, risk ratios (RRs) are based on health outcomes with respect to serum 25-hydroxyvitamin D [25(OH)D] concentrations measured at time of enrollment. Serum 25(OH)D concentrations vary over time, thereby diluting the effect of 25(OH)D for long follow-up periods. Inverse relationships between RR and follow-up period have been reported for all-cause mortality rate and cancer incidence rates. Here, the effect for neurological outcomes is evaluated.

The analysis examines how follow-up period affected results from nine cohort studies of all-cause dementia, six studies of Alzheimer's disease, and nine for cognitive impairment with respect to vitamin D deficiency.

For all-cause dementia, Alzheimer's disease, and cognitive impairment, respectively, the linear regression fits are RR = 2.9 - 0.14 × years, r = 0.73, p = 0.02; RR = 2.9 - 0.14 × years, r = 0.69, p = 0.13; and RR = 1.8 - 0.066 × years, r = 0.72, p = 0.03. The regression fit to RR for the shortest follow-up period for each outcome is considered the best estimate of vitamin D deficiency's effect on risk. Those values are approximately twice that found by averaging all RRs without considering the effect of follow-up period.

Vitamin D's effect on risk of neurological conditions is inversely correlated with mean follow-up period in prospective cohort studies. This effect should be considered in the design and analysis of such studies. Additional studies should also be conducted regarding raising serum 25(OH)D concentrations to reduce risk of brain function decline.

Parkinson's disease (PD) is a chronic neurodegenerative disease (NDD) due to the degeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). PD is characterized by diverse motor symptoms such as rigidity, resting tremors, and bradykinesia, and non-motor symptoms such as cognitive dysfunction and sleep disturbances. Vitamin D (VD), VD receptor (VDR), and VD metabolites are present in the brain and play a role in maintaining the development, differentiation, and functions of the DNs. VDRs exert protective effects against PD neuropathology by modulating functional capacity and DNs neurotransmission in the SN. In virtue of its anti-inflammatory and antioxidant activities, VD could be effective in the prevention and treatment of PD. VD exerts a neuroprotective effect by reducing oxidative stress and mitochondrial dysfunction, and by increasing autophagy and brain-derived neurotrophic factor (BDNF). Low VD serum level is connected with cognitive dysfunction and the development of dementia in PD. The VD-mediated cognitive augmenting effect is interrelated to the safeguarding of synaptic plasticity and modulation of neurotransmitter release. VD deficiency is linked with the severity of olfactory dysfunction which precedes the progression of symptomatic PD. However, the precise role of VD in PD remains unidentified, and there is a conflict about whether treatment with VD can ameliorate PD or not.

Vitamin D deficiency (VDD) is widespread around the world and has been extensively documented to affect various health conditions, including the cognitive functioning of the brain. Serum 25-hydroxylated forms of vitamin D are traditionally used to determine vitamin D status. However, there is now evidence that cholecalciferol activation can occur and be controlled by locally expressed enzymes in the brain. This study aimed to investigate the effects of cholecalciferol supplementation on cognitive function in rats who underwent transient VDD in adulthood. Thirty-six adult Wistar rats were administered paricalcitol (seven doses of 32 ng injected every other day) along with a "vitamin D-free" diet to induce VDD, which was confirmed using a LC-MS/MS serum analysis of the cholecalciferol and 25-hydroxyvitamin D3 levels. Treatment was performed by including 1000 IU/kg and 10,000 IU/kg cholecalciferol in the diet. Cognitive performance was evaluated using the novel object recognition (NOR), Morris water maze (MWM), and radial arm maze (RAM) tests. An immunohistochemical analysis of the brain regions involved in learning and memory was performed by quantifying the neurons, astrocytes, and microglia labelled with anti-neuronal nuclei (NeuN), glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1) antibodies, respectively. The vitamin D deficient group showed the lowest performance in both the MWM and RAM tests. In contrast, the cholecalciferol-treated groups exhibited a faster learning curve. However, no difference was detected between the groups in the NOR test. On the other hand, differences in the cellular organization of the hippocampus and amygdala were observed between the groups. Cholecalciferol supplementation decreased the density of the Iba-1- and GFAP-labeled cells in the hilus and cornu Ammonis 3 (CA3) regions of the hippocampus and in the amygdala. These results support vitamin D's substantial role in learning and memory. They also highlight that subtle changes of cognitive function induced by transient VDD could be reversed by cholecalciferol supplementation. Further studies are needed to better understand VDD and cholecalciferol's effects on the brain structure and function.

Vitamin D, obtained from diet or synthesized internally as cholecalciferol and ergocalciferol, influences bodily functions through its most active metabolite and the vitamin D receptor. Recent research has uncovered multiple roles for vitamin D in the central nervous system, impacting neural development and maturation, regulating the dopaminergic system, and controlling the synthesis of neural growth factors. This review thoroughly examines these connections and investigates the consequences of vitamin D deficiency in neurological disorders, particularly neurodegenerative diseases. The potential benefits of vitamin D supplementation in alleviating symptoms of these diseases are evaluated alongside a discussion of the controversial findings from previous intervention studies. The importance of interpreting these results cautiously is emphasised. Furthermore, the article proposes that additional randomised and well-designed trials are essential for gaining a deeper understanding of the potential therapeutic advantages of vitamin D supplementation for neurological disorders. Ultimately, this review highlights the critical role of vitamin D in neurological well-being and highlights the need for further research to enhance our understanding of its function in the brain.

Alzheimer's disease (AD), the most common cause of dementia, is a complex and multifactorial condition without cure at present. The latest treatments, based on anti-amyloid monoclonal antibodies, have only a modest effect in reducing the progression of cognitive decline in AD, whereas the possibility of preventing AD has become a crucial area of research. In fact, recent studies have observed a decrease in dementia incidence in developed regions such as the US and Europe. However, these trends have not been mirrored in non-Western countries (Japan or China), and the contributing factors of this reduction remain unclear. The Lancet Commission has delineated a constrained classification of 12 risk factors across different life stages. Nevertheless, the scientific literature has pointed to over 200 factors-including sociodemographic, medical, psychological, and sociocultural conditions-related to the development of dementia/AD. This narrative review aims to synthesize the risk/protective factors of dementia/AD. Essentially, we found that risk/protective factors vary between individuals and populations, complicating the creation of a unified prevention strategy. Moreover, dementia/AD explanatory mechanisms involve a diverse array of genetic and environmental factors that interact from the early stages of life. In the future, studies across different population-based cohorts are essential to validate risk/protective factors of dementia. This evidence would help develop public health policies to decrease the incidence of dementia.

Low vitamin D (VD) has been associated with poor clinical course in several neurological diseases. Supplementation has been suggested to improve outcomes. Severe acquired brain injury (sABI) subjects have low VD levels and disabling conditions requiring rehabilitation. The aim of the present study was to evaluate if VD supplementation produced a better clinical course and a better functional outcome in sABI during rehabilitation. A randomized single-blind study was performed. sABI subjects were randomized to the VD supplementation group (VDsG) (initial dose of 50.000 UI and 1.000 daily) and usual care control group (CG). Disability Rating Scale (DRS), Glasgow Outcome Scale (GOS), and Level of Cognitive Functioning (LCF) were used in assessing disability. A total of 73 subjects (42 M and 31 F; mean age 53.2 ± 15.7) were randomized: 36 (21 M and 15 F; mean age 57.52 ± 14.88) to VDsG and 37 (20 M and 17 F; mean age 48.28 ± 17.47) to CG. Both groups significantly improved after rehabilitation, and no between-group difference was observed. The mean score values for DRS, GOS, and LCF in VDsG were 18.83 ± 4.27 and 9.42 ± 5.83; 2.89 ± 0.32 and 3.78 ± 0.80; and 4.81 ± 1.70 and 7.53 ± 1.28, at admission and discharge, respectively. Likewise, mean values for DRS, GOS, and LCF in CG were 18.57 ± 4.80 and 9.84 ± 6.34; 2.84 ± 0.37 and 3.81 ± 0.94; and 4.97 ± 2.01 and 7.41 ± 1.32, respectively. VD supplementation did not improve functional outcomes in sABI during rehabilitation treatment.

Mitochondrial one-carbon metabolism provides carbon units to several pathways, including nucleic acid synthesis, mitochondrial metabolism, amino acid metabolism, and methylation reactions. Late-onset Alzheimer's disease is the most common age-related neurodegenerative disease, characterised by impaired energy metabolism, and is potentially linked to mitochondrial bioenergetics. Here, we discuss the intersection between the molecular pathways linked to both mitochondrial one-carbon metabolism and Alzheimer's disease. We propose that enhancing one-carbon metabolism could promote the metabolic processes that help brain cells cope with Alzheimer's disease-related injuries. We also highlight potential therapeutic avenues to leverage one-carbon metabolism to delay Alzheimer's disease pathology.

This study aims to explore the potential of osteoporosis as a modifiable risk factor for dementia and investigate whether treatments like estrogen supplementation and bisphosphonates can reduce the risk of dementia in the Thai population. This study aimed to evaluate the risk of dementia in patients with osteoporosis.

A cross-sectional analysis was conducted. Participants aged <50 years and those with a history of dementia at baseline were excluded. Clinical variables were analyzed using the chi-squared test. Logistic regression analysis was conducted to determine independent factors of dementia after adjusting for potential confounders.

The cohort was conducted on 54,399 participants, of whom 9763 (17.9%) had osteoporosis. The results indicated that individuals with osteoporosis had an odds ratio (OR) of 1.62-fold higher risk of developing dementia compared to those without osteoporosis (95% confidence interval (CI) 1.37-1.92, p-value < 0.001). Furthermore, compared to patients with osteoporosis not undergoing any treatment, those receiving estrogen supplementation and bisphosphonate treatment showed reduced associations with dementia, with an OR of 0.84 (95% CI 0.73-0.98, p-value = 0.023) and 0.66 (95% CI 0.60-0.73, p-value < 0.001), respectively.

The study findings suggest an elevated risk of dementia in patients with osteoporosis and contribute substantially to our understanding of the link between osteoporosis and dementia in the Thai population.

Hippocampal neurogenesis (HN) occurs throughout the life course and is important for memory and mood. Declining with age, HN plays a pivotal role in cognitive decline (CD), dementia, and late-life depression, such that altered HN could represent a neurobiological susceptibility to these conditions. Pertinently, dietary patterns (e.g., Mediterranean diet) and/or individual nutrients (e.g., vitamin D, omega 3) can modify HN, but also modify risk for CD, dementia, and depression. Therefore, the interaction between diet/nutrition and HN may alter risk trajectories for these ageing-related brain conditions. Using a subsample (n = 371) of the Three-City cohort-where older adults provided information on diet and blood biobanking at baseline and were assessed for CD, dementia, and depressive symptomatology across 12 years-we tested for interactions between food consumption, nutrient intake, and nutritional biomarker concentrations and neurogenesis-centred susceptibility status (defined by baseline readouts of hippocampal progenitor cell integrity, cell death, and differentiation) on CD, Alzheimer's disease (AD), vascular and other dementias (VoD), and depressive symptomatology, using multivariable-adjusted logistic regression models. Increased plasma lycopene concentrations (OR [95% CI]  =  1.07 [1.01, 1.14]), higher red meat (OR [95% CI]  =  1.10 [1.03, 1.19]), and lower poultry consumption (OR [95% CI]  =  0.93 [0.87, 0.99]) were associated with an increased risk for AD in individuals with a neurogenesis-centred susceptibility. Increased vitamin D consumption (OR [95% CI]  =  1.05 [1.01, 1.11]) and plasma γ-tocopherol concentrations (OR [95% CI]  =  1.08 [1.01, 1.18]) were associated with increased risk for VoD and depressive symptomatology, respectively, but only in susceptible individuals. This research highlights an important role for diet/nutrition in modifying dementia and depression risk in individuals with a neurogenesis-centred susceptibility.

Sunlight is closely intertwined with daily life. It remains unclear whether there are associations between sunlight exposure and brain structural markers. General linear regression analysis was used to compare the differences in brain structural markers among different sunlight exposure time groups. Stratification analyses were performed based on sex, age, and diseases (hypertension, stroke, diabetes). Restricted cubic spline was performed to examine the dose-response relationship between natural sunlight exposure and brain structural markers, with further stratification by season. A negative association of sunlight exposure time with brain structural markers was found in the upper tertile compared to the lower tertile. Prolonged natural sunlight exposure was associated with the volumes of total brain (β: - 0.051, P < 0.001), white matter (β: - 0.031, P = 0.023), gray matter (β: - 0.067, P < 0.001), and white matter hyperintensities (β: 0.059, P < 0.001). These associations were more pronounced in males and individuals under the age of 60. The results of the restricted cubic spline analysis showed a nonlinear relationship between sunlight exposure and brain structural markers, with the direction changing around 2 h of sunlight exposure. This study demonstrates that prolonged exposure to natural sunlight is associated with brain structural markers change.

Prior studies on vitamin D and dementia outcomes yielded mixed results and had several important limitations.

We aimed to assess the associations of both serum vitamin D status and supplementation with all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD) incidence.

With a prospective cohort study design, we comprehensively assessed the associations of vitamin D and multivitamin supplementation, as well as vitamin D deficiency {25-hydroxyvitamin D [25(OH)D] <30 nmol/L}, and insufficiency [25(OH)D 30 to <50 nmol/L], with the 14-year incidence of all-cause dementia, AD, and VD in 269,229 participants, aged 55 to 69, from the UK Biobank.

Although 5.0% reported regular vitamin D use and 19.8% reported multivitamin use, the majority of participants exhibited either vitamin D deficiency (18.3%) or insufficiency (34.0%). However, vitamin D deficiency was less prevalent among users of vitamin D (6.9%) or multivitamin preparations (9.5%) than among nonusers (21.5%). Adjusted Cox regression models demonstrated 19% to 25% increased risk of all 3 dementia outcomes for those with vitamin D deficiency [hazard ratio (HR) 95% confidence interval (CI)]: 1.25 (1.16, 1.34) for all-cause dementia; 1.19 (1.07-1.31) for AD; 1.24 (1.08-1.43) for VD] and 10% to 15% increased risk of those with vitamin D insufficiency [HR (95% CI): 1.11 (1.05, 1.18) for all-cause dementia; 1.10 (1.02-1.19) for AD; 1.15 (1.03-1.29) for VD]. Regular users of vitamin D and multivitamins had 17% and 14% lower risk of AD [HR (95% CI): 0.83 (0.71, 0.98)] and VD [HR (95% CI): 0.86 (0.75, 0.98)] incidence, respectively.

Although our findings indicate the potential benefits of vitamin D supplementation for dementia prevention, randomized controlled trials are essential for definitive evidence.