Using optical coherence tomography and optical coherence tomography angiography to delineate neurovascular homeostasis in migraine: a review.

Migraine is one of the world's most debilitating disorders, and it has recently been shown that changes in the retina can be a potential biomarker for the disease. These changes can be detected by optical coherence tomography (OCT), which measures retinal thickness, and optical coherence tomography angiography (OCTA), which measures vessel density. We searched the databases Google Scholar, ProQuest, Scopus, and Web of Science for studies in English using OCT and OCTA in migraineurs, using the search terms "optical coherence tomography," "OCT," "optical coherence tomography angiography," "OCTA" and "migraine." We found 73 primary studies, 11 reviews, and 8 meta-analyses pertaining to OCT and OCTA findings in migraineurs. They showed that migraineurs had reduced retinal thickness (via OCT), retinal vessel density, and greater foveal avascular zone area (via OCTA) than controls. OCTA changes reflect a perfusion compromise occurring in migraineurs as opposed to in healthy controls. OCT and OCTA deficits were worse in migraine-with-aura and chronic migraine than in migraine-without-aura and episodic migraine. Certain areas of the eye, such as the fovea, may be more vulnerable to these perfusion changes than other parts. Direct comparison between study findings is difficult because of the heterogeneity between the studies in terms of both methodology and analysis. Moreover, as almost all case-control studies were cross-sectional, more longitudinal cohort studies are needed to determine cause and effect between migraine pathophysiology and OCT/OCTA findings. Current evidence suggests both OCT and OCTA may serve as retinal markers for migraineurs, and further research in this field will hopefully enable us to better understand the vascular changes associated with migraine, perhaps also providing a new diagnostic and therapeutic biomarker.

Peripheral Administration of the Kv1.3-Blocking Peptide HsTX1[R14A] Improves Cognitive Performance in Senescence Accelerated SAMP8 Mice.

Increased expression of the voltage-gated potassium channel Kv1.3 in activated microglia, and the subsequent release of pro-inflammatory mediators, are closely associated with the progression of Alzheimer's disease (AD). Studies have shown that reducing neuroinflammation through the non-selective blockade of microglial Kv1.3 has the potential to improve cognitive function in mouse models of familial AD. We have previously demonstrated that a potent and highly-selective peptide blocker of Kv1.3, HsTX1[R14A], not only entered the brain parenchyma after peripheral administration in a lipopolysaccharide (LPS)-induced mouse model of inflammation, but also significantly reduced pro-inflammatory mediator release from activated microglia. In this study, we show that microglial expression of Kv1.3 is increased in senescence accelerated mice (SAMP8), an animal model of sporadic AD, and that subcutaneous dosing of HsTX1[R14A] (1 mg/kg) every other day for 8 weeks provided a robust improvement in cognitive deficits in SAMP8 mice. The effect of HsTX1[R14A] on the whole brain was assessed using transcriptomics, which revealed that the expression of genes associated with inflammation, neuron differentiation, synapse function, learning and memory were altered by HsTX1[R14A] treatment. Further study is required to investigate whether these changes are downstream effects of microglial Kv1.3 blockade or a result of alternative mechanisms, including any potential effect of Kv1.3 blockade on other brain cell types. Nonetheless, these results collectively demonstrate the cognitive benefits of Kv1.3 blockade with HsTX1[R14A] in a mouse model of sporadic AD, demonstrating its potential as a therapeutic candidate for this neurodegenerative disease.

Plasma Amyloid-ß Homeostasis Is Associated with Body Mass Index and Weight Loss in People with Overweight and Obesity.

BACKGROUND: Obesity is linked to a higher incidence of Alzheimer's disease (AD). Studies show that plasma amyloid-ß (Aß) dyshomeostasis, particularly low 42/40 ratio indicates a heightened risk for developing AD. However, the relationship between body mass index (BMI) and circulating plasma Aß has not been extensively studied. OBJECTIVE: We hypothesized that people with a high BMI have altered plasma Aß homeostasis compared with people with a lower BMI. We also tested whether reducing BMI by calorie-restriction could normalize plasma concentrations of Aß. METHODS: Plasma concentrations of Aß40, Aß42, and Aß42/40 ratio were measured in 106 participants with BMIs classified as lean, overweight, or obese. From this cohort, twelve participants with overweight or obese BMIs entered a 12-week calorie-restriction weight loss program. We then tested whether decreasing BMI affected plasma Aß concentrations. RESULTS: Plasma Aß42/40 ratio was 17.54% lower in participants with an obese BMI compared to lean participants (p < 0.0001), and 11.76% lower compared to participants with an overweight BMI (p < 0.0001). The weight loss regimen decreased BMI by an average of 4.02% (p = 0.0005) and was associated with a 6.5% decrease in plasma Aß40 (p = 0.0425). However, weight loss showed negligible correlations with plasma Aß40, Aß42, and Aß42/40 ratio. CONCLUSION: Obesity is associated with aberrant plasma Aß homeostasis which may be associated with an increased risk for AD. Weight loss appears to lower Aß40, but large-scale longitudinal studies in addition to molecular studies are required to elucidate the underlying mechanisms of how obesity and weight loss influence plasma Aß homeostasis.

L-arginine and aged garlic extract for the prevention of migraine: a study protocol for a randomised, double-blind, placebo-controlled, phase-II trial (LARGE trial).

BACKGROUND: Migraine is a common and distressing neurological condition characterised by recurrent throbbing headaches, nausea and heightened sensitivity to light and sound. Accumulating evidence suggests that cerebral arteries dilate during migraine, causing distal microvessels to constrict, which could activate nociceptors and cause onset of headache pain. If so, preventing or attenuating chronic microvascular constriction, and promoting a dilatory phenotype, may reduce frequency and/or severity of migraines. The primary aim of the L-Arginine and Aged Garlic Extract (LARGE) trial is to investigate whether oral treatment with dietary nutraceuticals, L-arginine and aged garlic extract (AGE), both systemic vasodilatory agents, will alleviate migraine frequency, duration and severity in adults with chronic frequent episodic migraines. METHODS: The study is a randomised double-blind placebo-controlled phase-II single-site clinical trial conducted in Perth, Australia. The target sample is to recruit 240 participants diagnosed with chronic frequent episodic migraines between 18 and 80 years of age. Participants will be randomised to one of four treatment groups for 14 weeks (placebo induction for 2 weeks, followed by 12 weeks on one of the respective treatment arms): placebo, L-arginine, AGE, or a combination of L-arginine and AGE. The doses of L-arginine and AGE are 1.5 g and 1 g daily, respectively. The primary outcome is to assess migraine response using change in migraine frequency and intensity between baseline and 12 weeks. Secondary outcomes include the impact of L-arginine and/or AGE on photosensitivity, retinal vessel changes, and blood biomarker concentrations of vascular tone, following a 12-week intervention. DISCUSSION: The protocol describes the oral administration of 2 nutraceutical-based interventions as possible prophylactic treatments for chronic frequent episodic migraines, with potential for direct clinical translation of outcomes. Potential limitations of the study include the fixed-dose design of each treatment arm and that in vivo neuroimaging methods, such as magnetic resonance imaging (MRI), will not be conducted to determine putative cerebro-vasodilatory changes to coincide with the outcome measures. Dose-response studies may be indicated. TRIAL REGISTRATION: The trial was retrospectively registered with the Australian New Zealand Clinical Trials Registry ACTRN12621001476820 (Universal Trial Number: U1111-1268-1117) on 04/08/2021. This is protocol version 1, submitted on 25/11/2022.

Is type 2 diabetes associated dementia a microvascular early-Alzheimer's phenotype induced by aberrations in the peripheral metabolism of lipoprotein-amyloid?

There is increasing evidence of a positive association of type 2 diabetes with Alzheimer's disease (AD), the most prevalent form of dementia. Suggested pathways include cerebral vascular dysfunction; central insulin resistance, or exaggerated brain abundance of potentially cytotoxic amyloid-ß (Aß), a hallmark feature of AD. However, contemporary studies find that Aß is secreted in the periphery by lipogenic organs and secreted as nascent triglyceride-rich lipoproteins (TRL's). Pre-clinical models show that exaggerated abundance in blood of TRL-Aß compromises blood-brain barrier (BBB) integrity, resulting in extravasation of the TRL-Aß moiety to brain parenchyme, neurovascular inflammation and neuronal degeneration concomitant with cognitive decline. Inhibiting secretion of TRL-Aß by peripheral lipogenic organs attenuates the early-AD phenotype indicated in animal models, consistent with causality. Poorly controlled type 2 diabetes commonly features hypertriglyceridemia because of exaggerated TRL secretion and reduced rates of catabolism. Alzheimer's in diabetes may therefore be a consequence of heightened abundance in blood of lipoprotein-Aß and accelerated breakdown of the BBB. This review reconciles the prevailing dogma of amyloid associated cytotoxicity as a primary risk factor in late-onset AD, with substantial evidence of a microvascular axis for dementia-in-diabetes. Consideration of potentially relevant pharmacotherapies to treat insulin resistance, dyslipidaemia and by extension plasma amyloidemia in type 2 diabetes are discussed.

Peripheral metabolism of lipoprotein-amyloid beta as a risk factor for Alzheimer's disease: potential interactive effects of APOE genotype with dietary fats.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by brain parenchymal abundance of amyloid-beta (Aß) and the accumulation of lipofuscin material that is rich in neutral lipids. However, the mechanisms for aetiology of AD are presently not established. There is increasing evidence that metabolism of lipoprotein-Aß in blood is associated with AD risk, via a microvascular axis that features breakdown of the blood-brain barrier, extravasation of lipoprotein-Aß to brain parenchyme and thereafter heightened inflammation. A peripheral lipoprotein-Aß/capillary axis for AD reconciles alternate hypotheses for a vascular, or amyloid origin of disease, with amyloidosis being probably consequential. Dietary fats may markedly influence the plasma abundance of lipoprotein-Aß and by extension AD risk. Similarly, apolipoprotein E (Apo E) serves as the primary ligand by which lipoproteins are cleared from plasma via high-affinity receptors, for binding to extracellular matrices and thereafter for uptake of lipoprotein-Aß via resident inflammatory cells. The epsilon APOE ε4 isoform, a major risk factor for AD, is associated with delayed catabolism of lipoproteins and by extension may increase AD risk due to increased exposure to circulating lipoprotein-Aß and microvascular corruption.

Association between ageing, brain chemistry and white matter volume revealed with complementary MRI and FTIR brain imaging.

Magnetic resonance imaging (MRI) is the gold standard method to study brain anatomy in vivo. Using MRI, subtle alterations to white matter structures in the brain are observed prior to cognitive decline associated with the ageing process, and neurodegenerative diseases such as Alzheimer's disease. Detection of such alterations provides hope for early clinical diagnosis. While MRI is essential to detect subtle alterations to brain structure in vivo, the technique is less suited to study and image the distribution of biochemical markers within specific brain structures. Consequently, the chemical changes that drive, or are associated with MRI-detectable alterations to white matter are not well understood. Herein, we describe (to the best of our knowledge) the first application of a complementary imaging approach that incorporates in vivo MRI with ex vivo Fourier transform infrared (FTIR) spectroscopic imaging on the same brain tissue. The combined workflow is used to detect and associate markers of altered biochemistry (FTIR) with anatomical changes to brain white matter (MRI). We have applied this combination of techniques to the senescence accelerated murine prone strain 8 (SAMP8) mouse model (n = 6 animals in each group, analysed across two ageing time points, 6 and 12 months). The results have demonstrated alterations to lipid composition and markers of disturbed metabolism during ageing are associated with loss of white matter volume.

Diabetic hypertriglyceridaemia and Alzheimer's disease: causal or not?

PURPOSE OF REVIEW: To summarize recent findings considering type II diabetes, or metabolic syndrome dyslipidaemia with risk for Alzheimer's disease. RECENT FINDINGS: Population, genetic, clinical and preclinical studies support the hypothesis of increased risk for Alzheimer's disease in type 2 diabetes mellitus. The mechanisms are unclear. However, recent studies suggest that aberrations in the peripheral metabolism of triglyceride-rich-lipoproteins compromise the brain microvasculature. SUMMARY: We review the literature of prediabetic metabolic syndrome and type 2 diabetes mellitus as a risk factor for Alzheimer's disease. We focus on a potential association with aberrations in the systemic metabolism of triglyceride-rich-lipoproteins reported over 18 months.

The Effects of Chronic Consumption of Lipid-Rich and Delipidated Bovine Dairy Milk on Brown Adipose Tissue Volume in Wild-Type Mice.

Brown adipose tissue (BAT) activation is associated with increased energy expenditure by inducing non-shivering thermogenesis. The ingestion of a milk fat globule membrane (MFGM) supplement and a high calorie diet are reported gateways into BAT activation. However, little is known about the effect of the MFGM and high calorie diets on BAT volume. To gain insight into this, mice were maintained on a high-fat (HF) or low-fat (LF) diet in conjunction with either full-cream (FC) or skim bovine dairy milk (BDM). After being maintained on their respective diets for 13 weeks, their body composition, including BAT volume, was measured using X-ray microtomography. A high calorie diet resulted in an increase in the BAT volume and mice consuming an HF diet in conjunction with FC BDM had a significantly greater BAT volume than all the other groups. Conversely, mice consuming an HF diet in addition to skim milk had a lower BAT volume compared to the HF control. The data presented suggest that the consumption of a high calorie diet in conjunction with FC BDM increases the BAT volume in wild-type mice. This study may provide valuable insight into future studies investigating BAT volume and BAT activity in relation to environmental factors, including diet.

Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

Sodium alginate microencapsulation improves the short-term oral bioavailability of cannabidiol when administered with deoxycholic acid.

BACKGROUND: Cannabidiol (CBD) confers therapeutic effects in some neurological disorders via modulation of inflammatory, oxidative and cell-signalling pathways. However, CBD is lipophilic and highly photooxidative with low oral bioavailability in plasma and brain. In this study, we aimed to design and test a CBD microencapsulation method as a drug delivery strategy to improve the absorption of CBD. Additionally, we evaluated the brain uptake of CBD capsules when administered alongside capsules containing a permeation-modifying bile acid, deoxycholic acid (DCA). METHODS: Microcapsules containing either CBD or DCA were formed using the ionic gelation method with 1.5% sodium alginate formulations and 100 mM calcium chloride. C57BL/6J wild type mice randomly assigned to three treatment groups (3-4 mice per group) were administered CBD in the following preparations: 1) CBD capsules, 2) CBD capsules + DCA capsules and 3) naked CBD oil (control). To assess the short-term bioavailability of CBD, plasma and brain samples were collected at 0.3, 1 and 3 hours post administration and CBD levels were analysed with liquid chromatography mass spectrometer. RESULTS: We produced spherical capsules at 400 ± 50 µm in size. The CBD capsules were calculated to have a drug loading of 2% and an encapsulation efficiency of 23%. Mice that received CBD capsules + DCA capsules showed a 40% and 47% increase in CBD plasma concentration compared to mice on CBD capsules and naked CBD oil, respectively. Furthermore, the CBD capsules + DCA capsules group showed a 48% and 25% increase in CBD brain concentration compared to mice on CBD capsules and naked CBD oil, respectively. In mice treated with CBD capsules + DCA capsules, the brain CBD concentration peaked at 0.3 hours with a 300% increased availability compared to CBD capsules and naked CBD oil groups, which peaked at 1 hour after administration. CONCLUSIONS: The microencapsulation method combined with a permeation enhancer, DCA increased the short-term bioavailability of CBD in plasma and brain.

[Mapping the Metallo-maze to Memory Loss: Does Neuronal Metal Ion Deficiency Contribute to Dementia?]

Dementia has no cure and is an international health crisis. In addition to the immeasurable loss of QOL caused by dementia, the global economic cost is predicted to reach $2 trillion (USD) by 2030. Although much remains unknown about the biochemical pathways driving cognitive decline and memory loss during dementia, metals have been implicated in neurodegenerative disease. For example, total levels of Fe and Cu increase, which has been proposed to drive oxidative stress; and Fe, Cu, and Zn can bind amyloid-ß, catalysing aggregation and formation of amyloid plaques. Unfortunately, despite these known facets through which metal ions may induce pathology, studies in greater detail have been hampered by a lack of microscopy methods to directly visualise metal ions, and their chemical form, within brain cells. Herein we report the use of synchrotron X-ray fluorescence microscopy to simultaneously image Fe, Cu, and Zn within neurons in ex vivo brain tissue sections. Using animal models of dementia, we now demonstrate for the first time that despite global increases in brain metal content and metal ion accumulation within amyloid plaques, key brain regions may also become metal ion deficient. Such deficiency could contribute to cognitive decline because of the essential roles metal ions play in neurotransmitter synthesis and energy metabolism. These recent findings are discussed in the context of memory loss, and the impact that metal ion dis-homeostasis may have on diagnostic and therapeutic development.

The Consumption of Energy Drinks Induces Blood-Brain Barrier Dysfunction in Wild-Type Mice.

Energy drinks containing significant quantities of caffeine and sugar are increasingly consumed, particularly by adolescents and young adults. Chronic ingestion of energy drinks may potentially regulate vascular risk factors. This study investigated the effects of chronic ingestion of energy drinks on blood-brain barrier (BBB) integrity and neuroinflammation. Male C57BL/6J mice were maintained on water (control), MotherTM (ED), sugar-free MotherTM (sfED), or Coca ColaTM soft drink (SD) for 13 weeks. The BBB integrity and neuroinflammation were analyzed with semi-quantitative immunofluorescent microscopy. Blood pressure, plasma inflammatory cytokine levels and blood glucose were also considered. Following 13 weeks of intervention, mice treated with ED, sfED, and SD showed significant disruption of BBB. However, marked neuroinflammation was observed only in sfED group mice. The consumption of ED and sfED significantly altered the blood pressure and plasma concentrations of inflammatory cytokines, TNF-a, IL-4, IL-6, and IL-10, and both increased plasma glucose. Correlation analyses showed significant associations between BBB dysfunction and hypotension, hyperglycaemia and cytokine dyshomeostasis. The intake of energy drink, particularly the sugar free formulation, may compromise the integrity of BBB and induce neuroinflammation via hypotension, hyperglycaemia and inflammatory pathways.

Chronic Intake of Energy Drinks and Their Sugar Free Substitution Similarly Promotes Metabolic Syndrome.

Energy drinks containing significant quantities of caffeine, taurine and sugar are increasingly consumed, particularly by adolescents and young adults. The putative effects of chronic ingestion of either standard energy drink, MotherTM (ED), or its sugar-free formulation (sfED) on metabolic syndrome were determined in wild-type C57BL/6J mice, in comparison to a soft drink, Coca-Cola (SD), a Western-styled diet enriched in saturated fatty acids (SFA), and a combination of SFA + ED. Following 13 weeks of intervention, mice treated with ED were hyperglycaemic and hypertriglyceridaemic, indicating higher triglyceride glucose index, which was similar to the mice maintained on SD. Surprisingly, the mice maintained on sfED also showed signs of insulin resistance with hyperglycaemia, hypertriglyceridaemia, and greater triglyceride glucose index, comparable to the ED group mice. In addition, the ED mice had greater adiposity primarily due to the increase in white adipose tissue, although the body weight was comparable to the control mice receiving only water. The mice maintained on SFA diet exhibited significantly greater weight gain, body fat, cholesterol and insulin, whilst blood glucose and triglyceride concentrations remained comparable to the control mice. Collectively, these data suggest that the consumption of both standard and sugar-free forms of energy drinks induces metabolic syndrome, particularly insulin resistance.

Blood-brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts over 2 weeks.

Repeated sub-concussive impact (e.g. soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood-brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion 3 days per week for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippocampal formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippocampus and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits.

Chronic high fat feeding paradoxically attenuates cerebral capillary dysfunction and neurovascular inflammation in Senescence-Accelerated-Murine-Prone Strain 8 mice.

Background: A body of epidemiological, clinical and preclinical studies suggest increased risk for cerebro- and cardio-vascular disease associated with dietary ingestion of long-chain saturated fatty acids (LCSFA). In wild-type rodent models, chronic ingestion of LCSFA diets are associated with increased cerebral capillary permeability, heightened neurovascular inflammation and poorer cognitive performance. However, recent studies suggest that diets enriched in fat may paradoxically attenuate elements of the ageing phenotype via a caloric support axis.Objective: The purpose of this study was to explore the effects of dietary LCSFA on cerebral capillary integrity and neurovascular inflammation in an established model of accelerated ageing, Senescence-Accelerated-Murine-Prone Strain 8 (SAMP8) mice.Methods: From 6 weeks of age, SAMP8 mice and age-matched controls were randomised to either normal chow, or to an LCSFA-enriched diet, for either 12 or 34 weeks. An additional group of SAMP8 mice were provided the LCSFA-enriched diet for 12 weeks followed by the provision of ordinary low-fat chow for 22 weeks. Ex vivo measures of cerebrovascular integrity, neurovascular inflammation and astrocytic activation, were determined via 3-dimensional immunofluorescent confocal microscopy methodologies.Results: LCSFA-fed SAMP8 mice had markedly attenuated cerebral capillary dysfunction concomitant with reduced microglial activation. In SAMP8 mice transiently maintained on an LCSFA diet for 12 weeks, suppression of neurovascular inflammation persisted. Marked hippocampal astrogliosis was evident in LCSFA-fed mice when compared to SAMP8 mice maintained on ordinary chow.Conclusion: The findings from this study support the notion that high-fat, potentially ketogenic diets, may confer neuroprotection in SAMP8 mice through a vascular-support axis.

Revealing differences in the chemical form of zinc in brain tissue using K-edge X-ray absorption near-edge structure spectroscopy.

Zinc is a prominent trace metal required for normal memory function. Memory loss and cognitive decline during natural ageing and neurodegenerative disease have been associated with altered brain-Zn homeostasis. Yet, the exact chemical pathways through which Zn influences memory function during health, natural ageing, or neurodegenerative disease remain unknown. The gap in the literature may in part be due to the difficulty to simultaneously image, and therefore, study the different chemical forms of Zn within the brain (or biological samples in general). To this extent, we have begun developing and optimising protocols that incorporate X-ray absorption near-edge structure (XANES) spectroscopic analysis of tissue at the Zn K-edge as an analytical tool to study Zn speciation in the brain. XANES is ideally suited for this task as all chemical forms of Zn are detected, the technique requires minimal sample preparation that may otherwise redistribute or alter the chemical form of Zn, and the Zn K-edge has known sensitivity to coordination geometry and ligand type. Herein, we report our initial results where we fit K-edge spectra collected from micro-dissected flash-frozen brain tissue, to a spectral library prepared from standard solutions, to demonstrate differences in the chemical form of Zn that exist between two brain regions, the hippocampus and cerebellum. Lastly, we have used an X-ray microprobe to demonstrate differences in Zn speciation within sub-regions of thin air-dried sections of the murine hippocampus; but, the corresponding results highlight that the chemical form of Zn is easily perturbed by sample preparation such as tissue sectioning or air-drying, which must be a critical consideration for future work.

Chronic Consumption of Bovine Dairy Milk Attenuates Dietary Saturated Fatty Acid-Induced Blood-Brain Barrier Dysfunction.

Ingestion of Western-diets enriched in long chain saturated fatty acids (LCSFA) are associated with increased risk of blood-brain barrier (BBB) dysfunction and neurovascular inflammation. Potential mechanisms include vascular insult as a consequence of metabolic aberrations, or changes in capillary permeability resulting in brain parenchymal extravasation of pro-inflammatory molecules. Bovine dairy milk (BDM) is potentially a significant source of dietary LCSFA, however, BDM contains an array of bioactive molecules purported to have vascular anti-inflammatory properties. This study investigated the effects of full cream (4% total fat) and delipidated (skim) BDM on BBB integrity and neuroinflammation in wild-type mice. Mice consuming substantial amounts of full cream or skim BDM with LCSFA-enriched chow were dyslipidemic compared to control mice provided with standard chow and water. However, there was no evidence of BBB dysfunction or neuroinflammation indicated by parenchymal abundance of immunoglobulin G and microglial recruitment, respectively. Positive control mice maintained on an LCSFA-enriched diet derived from cocoa-butter and water, had marked BBB dysfunction, however, co-provision of both full cream and skim milk solutions effectively attenuated LCSFA-induced BBB dysfunction. In mice provided with low-fat chow and full cream BDM drinking solutions, there were substantial favorable changes in the concentration of plasma anti-inflammatory cytokines. This study suggests that consumption of BDM may confer potent vascular benefits through the neuroprotective properties exuded by the milk-fat globule membrane moiety of BDM.

Genetic, environmental and biomarker considerations delineating the regulatory effects of vitamin D on central nervous system function.

Studies show that vitamin D (vit-D) (25(OH)D), the bioactive metabolite (1,25(OH)2D3) and vit-D receptors (vit-D receptor; protein disulphide isomerase, family A member 3) are expressed throughout the brain, particularly in regions pivotal to learning and memory. This has led to the paradigm that avoiding vit-D deficiency is important to preserve cognitive function. However, presently, it is not clear if the common clinical measure of serum 25(OH)D serves as a robust surrogate marker for central nervous system (CNS) homeostasis or function. Indeed, recent studies report CNS biosynthesis of endogenous 25(OH)D, the CNS expression of the CYP group of enzymes which catalyse conversion to 1,25(OH)2D3 and thereafter, deactivation. Moreover, in the periphery, there is significant ethnic/genetic heterogeneity in vit-D conversion to 1,25(OH)2D3 and there is a paucity of studies which have actually investigated vit-D kinetics across the cerebrovasculature. Compared with peripheral organs, the CNS also has differential expression of receptors that trigger cellular response to 1,25(OH)2D3 metabolites. To holistically consider the putative association of peripheral (blood) abundance of 25(OH)D on cognitive function, herein, we have reviewed population and genetic studies, pre-clinical and clinical intervention studies and moreover have considered potential confounders of vit-D analysis.