Data-driven analysis of regional brain metabolism in behavioral frontotemporal dementia and late-onset primary psychiatric diseases with frontal lobe syndrome: A PET/MRI study.

Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose metabolism in bvFTD and late-onset PPD and investigate the metabolic correlates of cognitive and behavioral disturbances through FDG-PET/MRI. We studied 37 bvFTD and 20 late-onset PPD with a mean clinical follow-up of three years. At baseline evaluation, metabolism of the dorsolateral, ventrolateral, orbitofrontal regions and caudate could classify the patients with a diagnostic accuracy of 91% (95% CI: 0.81-0.98%). 45% of PPD showed low-grade hypometabolism in the anterior cingulate and/or parietal regions. Frontal lobe metabolism was normal in 32% of genetic bvFTD and bvFTD with motor neuron signs. Hypometabolism of the frontal and caudate regions could help in distinguishing bvFTD from PPD, except in cases with motor neuron signs and/or genetic bvFTD for which brain metabolism may be less informative.

MRI abnormalities in Creutzfeldt-Jakob disease and other rapidly progressive dementia.

OBJECTIVE: To investigate brain MRI abnormalities in a cohort of patients with rapidly progressive dementia (RPD) with and without a diagnosis of Creutzfeldt-Jakob disease (CJD). METHODS: One hundred and seven patients with diagnosis of prion disease (60 with definite sCJD, 33 with probable sCJD and 14 with genetic prion disease) and 40 non-prion related RPD patients (npRPD) underwent brain MRI including DWI and FLAIR. MRIs were evaluated with a semiquantitative rating score, which separately considered abnormal signal extent and intensity in 22 brain regions. Clinical findings at onset, disease duration, cerebrospinal-fluid 14-3-3 and t-tau protein levels, and EEG data were recorded. RESULTS: Among patients with definite/probable diagnosis of CJD or genetic prion disease, 2/107 had normal DWI-MRI: in one patient a 2-months follow-up DWI-MRI showed CJD-related changes while the other had autopsy-proven CJD despite no DWI abnormalities 282 days after clinical onset. CJD-related cortical changes were detected in all lobes and involvement of thalamus was common. In the npRPD groups, 6/40 patients showed DWI alterations that clustered in three different patterns: (1) minimal/doubtful signal alterations (limbic encephalitis, dementia with Lewy bodies); (2) clearly suggestive of alternative diagnoses (status epilepticus, Wernicke or metabolic encephalopathy); (3) highly suggestive of CJD (mitochondrial disease), though cortical swelling let exclude CJD. CONCLUSIONS: In the diagnostic work-up of RPD, negative/doubtful DWI makes CJD diagnosis rather unlikely, while specific DWI patterns help differentiating CJD from alternative diagnoses. The pulvinar sign is not exclusive of the variant form.

Episodic Memory in Amnestic Behavioral Frontotemporal Dementia and Alzheimer's Disease.

Behavioral frontotemporal dementia (bvFTD) may present with episodic memory deficits. In 38 patients with bvFTD and 61 with Alzheimer's disease (AD) specific measures of verbal memory (learning curves and serial position effects) were studied through the Rey Auditory Verbal Learning test. Forty-two percent of bvFTD showed deficits of delayed recall memory similar to that found in AD including the serial position effects. Amnestic bvFTD had more severe atrophy in the left mesial temporal lobe than non-amnestic bvFTD. AD-like memory deficits are not infrequent in bvFTD and may be in part related to mesial temporal lobe atrophy.

PET/MR in recurrent glioblastoma patients treated with regorafenib: [18F]FET and DWI-ADC for response assessment and survival prediction.

OBJECTIVE: The use of regorafenib in recurrent glioblastoma patients has been recently approved by the Italian Medicines Agency (AIFA) and added to the National Comprehensive Cancer Network (NCCN) 2020 guidelines as a preferred regimen. Given its complex effects at the molecular level, the most appropriate imaging tools to assess early response to treatment is still a matter of debate. Diffusion-weighted imaging and O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography ([18F]FET PET) are promising methodologies providing additional information to the currently used RANO criteria. The aim of this study was to evaluate the variations in diffusion-weighted imaging/apparent diffusion coefficient (ADC) and [18F]FET PET-derived parameters in patients who underwent PET/MR at both baseline and after starting regorafenib. METHODS: We retrospectively reviewed 16 consecutive GBM patients who underwent [18F]FET PET/MR before and after two cycles of regorafenib. Patients were sorted into stable (SD) or progressive disease (PD) categories in accordance with RANO criteria. We were also able to analyze four SD patients who underwent a third PET/MR after another four cycles of regorafenib. [18F]FET uptake greater than 1.6 times the mean background activity was used to define an area to be superimposed on an ADC map at baseline and after treatment. Several metrics were then derived and compared. Log-rank test was applied for overall survival analysis. RESULTS: Percentage difference in FET volumes correlates with the corresponding percentage difference in ADC (R = 0.54). Patients with a twofold increase in FET after regorafenib showed a significantly higher increase in ADC pathological volume than the remaining subjects (p = 0.0023). Kaplan-Meier analysis, performed to compare the performance in overall survival prediction, revealed that the percentage variations of FET- and ADC-derived metrics performed at least as well as RANO criteria (p = 0.02, p = 0.024 and p = 0.04 respectively) and in some cases even better. TBR Max and TBR mean are not able to accurately predict overall survival. CONCLUSION: In recurrent glioblastoma patients treated with regorafenib, [18F]FET and ADC metrics, are able to predict overall survival and being obtained from completely different measures as compared to RANO, could serve as semi-quantitative independent biomarkers of response to treatment. ADVANCES IN KNOWLEDGE: Simultaneous evaluation of [18F]FET and ADC metrics using PET/MR allows an early and reliable identification of response to treatment and predict overall survival.

Cognitive correlates and baseline predictors of future development of visual hallucinations in dementia with Lewy bodies.

Visual hallucinations (VH) are common in dementia with Lewy bodies (DLB), and are among the core symptoms for its clinical diagnosis. VH have been associated with cognitive alterations, although research findings in this area are still limited. The present study aimed at investigating the cognitive correlates of VH in DLB, and the baseline neuropsychological features predicting the future development of VH. A cross sectional study compared the cognitive profile of 18 DLB patients with VH with that of 32 DLB without VH. A longitudinal study involved 34 DLB patients with no VH at baseline, among whom 17 developed VH and 17 remained without VH at follow-up. Logistic regression analyses were carried out to investigate what baseline cognitive variables independently predicted the development of VH at follow-up. DLB patients with VH had worse performance on the copy of the Rey complex figure, assessing visual construction/perception, than those without VH in the cross-sectional study (p = .001). Significant impairments in attention and visual memory delayed recall were also present. Baseline performance on the immediate prose memory was the only significant predictor of VH development in the longitudinal study (p = .03). DLB patients are more at risk of developing VH if presenting more severe immediate verbal memory impairment, and this might be related to a combination of (a) DMN-related dysfunctions, (b) impairment in medial temporal lobe-related functions, and (c) frontal abilities including long-term encoding of information and working memory. Differences between hallucinating and non-hallucinating patients in visual construction/perception, typical of DLB symptomatology, may be essential for VH to emerge in individuals with an at risk cognitive profile.

Functional Brain Connectivity Patterns Associated with Visual Hallucinations in Dementia with Lewy Bodies.

BACKGROUND: The presence of recurrent, complex visual hallucinations (VH) is among the core clinical features of dementia with Lewy bodies (DLB). It has been proposed that VH arise from a disrupted organization of functional brain networks. However, studies are still limited, especially investigating the resting-state functional brain features underpinning VH in patients with dementia. OBJECTIVE: The aim of the present pilot study was to investigate whether there were any alterations in functional connectivity associated with VH in DLB. METHODS: Seed-based analyses and independent component analysis (ICA) of resting-state fMRI scans were carried out to explore differences in functional connectivity between DLB patients with and without VH. RESULTS: Seed-based analyses reported decreased connectivity of the lateral geniculate nucleus, the superior parietal lobule and the putamen with the medial frontal gyrus in DLB patients with VH. Visual areas showed a pattern of both decreased and increased functional connectivity. ICA revealed between-group differences in the default mode network (DMN). CONCLUSION: Functional connectivity analyses suggest dysfunctional top-down and bottom-up processes and DMN-related alterations in DLB patients with VH. This impairment might foster the generation of false visual images that are misinterpreted, ultimately resulting in VH.

White matter abnormalities of right hemisphere attention networks contribute to visual hallucinations in dementia with Lewy bodies.

OBJECTIVE: Functional alterations of the visual attention networks in a setting of impaired visual information processing have a role in the genesis of visual hallucinations (VH) in dementia with Lewy bodies (DLB). This multimodal MRI study aims at exploring structural and functional basis of VH. METHODS: 23 DLB patients (10 with and 13 without VH) and 13 healthy controls were studied. They underwent MRI with T1-w sequences to measure cortical thickness, DTI for whole-brain and single tract microstructural properties and rs-fMRI of the default mode, dorsal and ventral attention, and visual networks. RESULTS: In DLB with VH, whole-brain DTI revealed a lower fractional anisotropy and a greater mean diffusivity in the right frontal and temporo-parietal white matter tracts. Tracts dissection showed lower fractional anisotropy in the right inferior and superior (ventral part) longitudinal fasciculi (ILF and SLF) (p < .05, corrected), and greater mean diffusivity (p < .05). The extent of white matter microstructural alterations involving the right ILF and SLF correlated with the severity of VH (r = .55, p < .01; r = .42, p < .05, respectively), and with performance in the visual attention task (r = -.56 and r = -.61; p < .01, respectively). Cortical thickness in the projection areas of the right SLF was significantly reduced (p < .05). Patients with VH also showed an altered functional connectivity in the ventral attention network, connected by the ventral portion of the SLF (p < .05). CONCLUSIONS: Our findings suggest that a combination of microstructural and functional alterations involving the attention networks in the right hemisphere may be important in the genesis of VH.

Changes of Metabolic Connectivity in Dementia with Lewy Bodies with Visual Hallucinations: A 18F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Study.

Background: Recurrent complex visual hallucinations (VHs) are common in dementia with Lewy bodies (DLB). Previous investigations suggest that VHs are associated with connectivity changes within and between large scale networks involved in visual processing and attention. Aim: To examine more directly whether VH in DLB reflects direct changes in neuronal activity between cortical regions assessing metabolic connectivity with 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/magnetic resonance and graph theory. Methods: Twenty-six patients with probable DLB (13 VHs and 13 no-VHs; mean age: 72.9 ± 6.87 years vs. 70.2 ± 7.96 years) were enrolled. T1-weighted 3T-MR images and FDG-PET data were coacquired using an integrated PET/MR scanner. MR images defined cortical parcels of the Shaefer-Yeo atlas for multiple functional networks. We computed in each parcel the regional standardized-uptake-values (SUV) corrected for partial volume and normalized to the cerebellar cortex. Strength degree, clustering coefficient, characteristic path length, and hubs were analyzed with graph analysis. Results: The mean 18F-FDG-PET SUVr of parcels belonging to the visual and dorsal attention networks (DANs) were significantly lower in the VH group (p = 0.01). Metabolism in the right temporoparietal cortex correlated with VH severity (R = -0.58; p < 0.01). VH patients showed weaker metabolic connectivity in the parietal, temporal, and occipital cortex of the default mode network, DAN, and visual networks, but more robust connectivity in the right insula and orbitofrontal cortex. A lower global efficiency characterized the VH group, except for ventral attention network and limbic network. Conclusions: VHs in DLB correlate with lower glucose metabolism and weaker metabolic connectivity in the parietal-occipital cortex, but stronger connectivity in the limbic system. Impact statement This study shows that application of the graph theory to 18F-fluorodeoxyglucose-positron emission tomography data, commonly acquired during the diagnostic workflow in neurodegenerative diseases, could be used to obtain information of functional connectivity at a group level, with results that are consistent with other data commonly used in brain functional investigation (e.g., electroencephalography or functional magnetic resonance). New network-based methods of metabolic image analyses, such as graph analysis, are a recent area of research with a potential capacity to extract information on alterations of metabolic connectivity that may become pharmacological and neuromodulation targets of the physiopathology of recurrent complex visual hallucinations.

Psychiatric Phenocopy Syndrome of Behavioral Frontotemporal Dementia: Behavioral and Cognitive Fingerprint.

Behavioral and cognitive variables predicting behavioral frontotemporal dementia (bvFTD) versus primary psychiatric disorders mimicking bvFTD (phenocopy syndrome: bvFTD-PS) were studied. Forty-one probable/definite bvFTD and 16 bvFTD-PS patients were evaluated with cognitive battery, Neuropsychiatric Inventory, and Stereotypic and Ritualistic Behavior-revised questionnaires. Twenty-seven healthy subjects served as control. Severity of cognitive impairment/behavioral symptoms and profile of cognitive deficits were similar, with bvFTD-PS showing impaired executive abilities and memory. However, phonemic fluency was impaired only in bvFTD (p < 0.001). Depression was worse in bvFTD-PS, while apathy, disinhibition, and dietary changes characterized bvFTD. Phonemic fluency and depression accounted for the best predictive diagnostic model. A structured psychiatric screening of bvFTD mimickers may often yield a psychiatric diagnosis with predominant depressive symptoms and therefore a potentially treatable condition.

Quercetin and 3-O-methylquercetin in vitro skin layers permeation/retention from hydrogels: why only a methoxy group difference determines different behaviors?

OBJECTIVES: The present study was designed to verify if quercetin (QCT), a flavonoid with antioxidant and antiviral activity, and 3-O-methylquercetin (3OMQ), a quercetin C3-methoxylated derivative, present differences in their behavior against complexation with ß-cyclodextrin (ß-CD) and the corresponding permeation/retention trhough porcine ear skin, when incorporated into hydroxypropyl methylcellulose (HPMC) or chitosan (CS) hydrogels. METHODS: The influence of ß-CD on the skin permeation/retention of QCT and 3OMQ from hydrogels is comparatively evaluated for both flavonoids using porcine ear skin in Franz cells model. The properties of the two flavonoids using the semi-empirical method Recife Model was studied. KEY FINDINGS: Quercetin presented higher skin retention compared with its C3-methoxy derivative 3OMQ. The best permeation/retention of QCT was observed when it was incorporated into CS hydrogel containing 5% ß-CD, whereas, for 3OMQ, the HPMC hydrogel containing 5% ß-CD was the best formulation. The flavonoids complexation with ß-CD in water occurred preferentially with the insertion of the B ring through the secondary OH rim. CONCLUSIONS: The dynamic molecular modeling revealed that the methyl group at C3 in 3OMQ molecule determined significant difference in its complexation with ß-CD, in comparison to its analogous QCT and that difference is coincident with the permeation behavior of these flavonoids, denoting a possible relationship with their molecular dynamics.

Box Behnken design of siRNA-loaded liposomes for the treatment of a murine model of ocular keratitis caused by Acanthamoeba.

Acanthamoeba keratitis is an ophthalmic disease with no specific treatment that specially affects contact lens users. The silencing of serine phosphatase (SP) and glycogen phosphorylase (GP) proteins produced by Acanthamoeba has been shown to significantly reduce the cytopathic effect, although no vehicle was proposed yet to deliver the siRNA sequences to the trophozoites. In this study, PEGylated cationic liposomes were proposed and optimized using Box-Behnken design. The influence of DOTAP:DOPE ratio, DSPE-PEG concentration, and siRNA/DOTAP charge ratio were evaluated over both biological response and physicochemical properties of liposomes. The ratio of DOTAP:DOPE had an effect in the trophozoite activity whereas the charge ratio influenced both size and protease activity. The predicted values were very close to the observed values, yielding a formulation with good activity and toxicity profile, which was used in the following experiments. A murine model of ocular keratitis was treated with siGP + siSP-loaded liposomes, as well as their respective controls, and combined treatment of liposomes and chlorhexidine. After 15 days of eight daily administrations, the liposomal complex combined with chlorhexidine was the only treatment able to reverse the more severe lesions associated with keratitis. There was 60% complete regression in corneal damage, with histological sections demonstrating the presence of an integral epithelium, without lymphocytic infiltrate. The set of results demonstrate the efficacy of a combined therapy based on siRNA with classical drugs for a better prognosis of keratitis caused by Acanthamoeba.

Testing Hippocampal Memory in Prodromal Dementia with Lewy Bodies.

The Free and Cued Selective Reminding test (FCSRT) was used to assess memory in 19 patients with prodromal dementia with Lewy bodies (DLB) and 25 Alzheimer's disease (AD) patients. DLB scored better than AD in selective measures of the FCSRT: immediate total recall (p = 0.01) and index of sensitivity of cueing (p = 0.001), while free delayed and total memory scores were similarly impaired. The index of sensitivity of cueing held a sensitivity of 76% and specificity of 79% in distinguishing DLB. FCSRT could help in disentangling hippocampal memory deficits from memory impairment due to ineffective recall strategies.

Cationic nanoemulsions as nucleic acids delivery systems.

Since the first clinical studies, knowledge in the field of gene therapy has advanced significantly, and these advances led to the development and subsequent approval of the first gene medicines. Although viral vectors-based products offer efficient gene expression, problems related to their safety and immune response have limited their clinical use. Thus, design and optimization of nonviral vectors is presented as a promising strategy in this scenario. Nonviral systems are nanotechnology-based products composed of polymers or lipids, which are usually biodegradable and biocompatible. Cationic liposomes are the most studied nonviral carriers and knowledge about these systems has greatly evolved, especially in understanding the role of phospholipids and cationic lipids. However, the search for efficient delivery systems aiming at gene therapy remains a challenge. In this context, cationic nanoemulsions have proved to be an interesting approach, as their ability to protect and efficiently deliver nucleic acids for diverse therapeutic applications has been demonstrated. This review focused on cationic nanoemulsions designed for gene therapy, providing an overview on their composition, physicochemical properties, and their efficacy on biological response in vitro and in vivo.

Specific Verbal Memory Measures May Distinguish Alzheimer's Disease from Dementia with Lewy Bodies.

BACKGROUND: Standard measures of commonly used memory tests may not be appropriate to distinguish different neurodegenerative diseases affecting memory. OBJECTIVE: To study whether specific measures of verbal memory obtained with the Rey Auditory Verbal Learning test (RAVLT) could help distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). METHODS: Twenty-nine DLB and 32 AD patients participated in the study and were followed longitudinally for 3 years until the diagnosis was confirmed according to standard clinical criteria. Twenty-eight healthy elderly subjects served as controls. The following verbal memory measures were evaluated: verbal learning (VL), verbal forgetting (VF), percentage of verbal forgetting (VF%), and serial position effects of the immediate recall performance. RESULTS: DLB and AD groups have comparable performances at the RAVLT immediate and delayed recall tasks. However, VL was higher in DLB than AD while VF% was greater in AD. With a VF% cut-off ≥75%, AD and DLB patients were differently distributed, with 58% of AD versus 21% of DLB above this cut-off. The recency effect was significant higher in AD than DLB. DISCUSSION: DLB patients had a better performance in VL than AD, but worse VF and recency effect. These specific measures of verbal memory could be used as cognitive markers in the differential diagnosis between these two conditions.

siRNA-loaded liposomes: Inhibition of encystment of Acanthamoeba and toxicity on the eye surface.

Current treatments for Acanthamoeba keratitis are unspecific. Because of the presence of the resilient cyst form of the parasite, the infection is persistent. Silencing the key protein of cyst formation, glycogen phosphorylase, has shown potential for reducing encystment processes of the Acanthamoeba trophozoite. However, a suitable carrier to protect and deliver siRNA sequences is still needed. DOTAP: DOPE:DSPE-PEG liposomes were prepared by three different techniques and used to associate a therapeutic siRNA sequence. Liposomes prepared by film hydration followed by membrane extrusion were considered the most adequate ones with average size of 250 nm and zeta potential of +45 mV, being able to associate siRNA for at least 24 hr in culture medium. siRNA-liposomes could inhibit up to 66% of the encystment process. Cell viability studies demonstrated MTT reduction capacity higher than 80% after 3 hr incubation with this formulation. After 24 hr of incubation, LDH activity ranged for both the formulations from around 4% to 40%. In vivo tolerance studies in mice showed no macroscopic alteration in the eye structures up to 24 hr after eight administrations during 1 day. Histological studies showed regular tissue architecture without any morphological alteration. Overall, these results suggest that the formulations developed are a promising new strategy for the treatment of ocular keratitis caused by Acanthamoeba spp.

Nanoemulsions Containing a Coumarin-Rich Extract from Pterocaulon balansae (Asteraceae) for the Treatment of Ocular Acanthamoeba Keratitis.

This study describes the incorporation of a coumarin-rich extract from Pterocaulon balansae into nanoemulsions intended for the local treatment of ocular keratitis caused by Acanthamoeba. The n-hexane dewaxed extract of P. balansae was characterized by HPLC/PDA and UPLC/MS. The presence of four major coumarins was detected, where 5-methoxy-6,7-methylenedioxycoumarin was selected as a chemical marker. This extract was then incorporated into nanoemulsions composed of medium chain triglycerides and egg-lecithin, through spontaneous emulsification. Such a procedure yielded the formation of monodisperse nanoemulsions in a sub-300-nm range, regardless of the amount of extract incorporated (1.0-5.0 mg/mL). The amoebicidal activity against Acanthamoeba castellanii was both dose-dependent and incubation time-dependent. A reduction of 95% of trophozoite viability was detected after 24 h of incubation with a nanoemulsion at 1.25 mg/mL of coumarins, being a similar effect detected for chlorhexidine. These results suggest a potential of the formulations developed in this study as a new strategy for the treatment of ocular keratitis caused by Acanthamoeba.

Structural analysis of nanosystems: Solid Sorbitan esters Nanoparticles (SSN) as a case study.

Innovative approaches in nanotechnology can provide drug delivery systems with a high potential in different fields. To avoid trial and error assays as a main driving force governing new designs and, furthermore, to develop successful nanosystem optimization strategies, it is of the greatest importance to develop specific characterisation techniques beyond conventional determinations of size, zeta potential and morphology. However, the application of techniques able to determine some key characteristics, such as nanostructure (i.e., solid structure vs vesicular), and the way in which the reorganization of components takes place on these structures has been scarcely explored. The present work has been devoted to provide some insights about the potential offered by some NMR techniques to those scientists working on nanotechnological approaches. For this purpose, we selected our nanosystems based on sorbitan monooleate as a case study. We used (1)H NMR methods, including a recently proposed method relying in the well-known Saturation Transfer Difference (STD) experiment for the observation of 'invisible signals' in large aggregates (Invisible State STD or ISSTD). Overall, these techniques revealed the presence in these nanosystems of a gradient of flexibility from an internal rigid core towards a more flexible region located on their surface, as well as the absence of water content in both regions. Such structure, corresponding to a solid nanostructure rather than a vesicular one, can explain some of the interesting properties previously observed for these innovative nanosystems, such as their high stability, and allows us to refer to these nanosystems with the term "Solid Sorbitan esters Nanoparticles" (SSN). On the basis of the valuable information provided by the mentioned characterisation techniques, it is our understanding that they could facilitate the future design of new drug delivery nanosystems as well as the improvement of existing ones and/or the development of new applications for classical drug delivery concepts.

Antioxidant Effect of Nanoemulsions Containing Extract of Achyrocline satureioides (Lam) D.C.-Asteraceae.

Ethanolic extracts of Achyrocline satureioides have pronounced antioxidant activity mainly due to the presence of the flavonoid quercetin. However, direct topical application of the extract is not possible due to the presence of high amounts of ethanol. In this sense, nanoemulsions arise as an alternative for topical formulation associating molecules with limited aqueous solubility. This article describes the development of topical nanoemulsions containing either A. satureioides extract or one of its most abundant flavonoid, quercetin. Nanoemulsions composed of octyldodecanol, egg lecithin, water and extract (NEE), or quercetin (NEQ) were prepared by spontaneous emulsification. This process led to monodisperse nanoemulsions presenting a mean droplet size of approximately 200-300 nm, negative zeta potential, and high association efficiency. A study of quercetin skin retention using porcine skin which was performed using a Franz diffusion cell revealed a higher accumulation of quercetin in skin for NEE when compared to NEQ. Finally, the antioxidant activity of formulations was measured by thiobarbituric acid-reactive species and the APPH model. A lower lipoperoxidation for the extract in respect to quercetin solution was observed. However, no difference between NEQ and NEE lipoperoxidation could be seen. The protection against lipoperoxidation by the formulations was also measured in the skin, where lower formation of reactive species was observed after treatment with NEE. In conclusion, this study shows the formulation effect on the physicochemical properties of nanoemulsions as well as on the skin retention and antioxidant activity of quercetin.