Introduction
Limbic age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) is common in advanced age and can underlie a clinical presentation mimicking Alzheimer's disease (AD). We ...studied whether an autopsy‐derived fluorodeoxyglucose positron emission tomography (FDG‐PET) signature of LATE‐NC provides clinical utility for differential diagnosis of amnestic dementia patients.
Methods
Ante mortem FDG‐PET patterns from autopsy‐confirmed LATE‐NC (N = 7) and AD (N = 23) patients were used to stratify an independent cohort of clinically diagnosed AD dementia patients (N = 242) based on individual FDG‐PET profiles.
Results
Autopsy‐confirmed LATE‐NC and AD groups showed markedly distinct temporo‐limbic and temporo‐parietal FDG‐PET patterns, respectively. Clinically diagnosed AD dementia patients showing a LATE‐NC–like FDG‐PET pattern (N = 25, 10%) were significantly older, showed less abnormal AD biomarker levels, lower APOE ε4, and higher TMEM106B risk allele load. Clinically, they exhibited a more memory‐predominant profile and a generally slower disease course.
Discussion
An autopsy‐derived temporo‐limbic FDG‐PET signature identifies older amnestic patients whose clinical, genetic, and molecular biomarker features are consistent with underlying LATE‐NC.
Heart rate (HR) is an essential indicator of health in the human body. It measures the number of times per minute that the heart contracts or beats. An irregular heartbeat can signify a severe health ...condition, so monitoring heart rate periodically can help prevent heart complications. This paper presents a novel wearable sensing approach for remote HR measurement by a compact resistance-to-microcontroller interface circuit. A heartbeat’s signal can be detected by a Force Sensing Resistor (FSR) attached to the body near large arteries (such as the carotid or radial), which expand their area each time the heart expels blood to the body. Depending on how the sensor interfaces with the subject, the FSR changes its electrical resistance every time a pulse is detected. By placing the FSR in a direct interface circuit, those resistance variations can be measured directly by a microcontroller without using either analog processing stages or an analog-to-digital converter. In this kind of interface, the self-heating of the sensor is avoided, since the FSR does not require any voltage or bias current. The proposed system has a sampling rate of 50 Sa/s, and an effective resolution of 10 bits (200 mΩ), enough for obtaining well-shaped cardiac signals and heart rate estimations in real time by the microcontroller. With this approach, the implementation of wearable systems in health monitoring applications is more feasible.
The association between white matter hyperintensities (WMH) and amyloid accumulation over time in cognitively normal, amyloid-negative elderly people remains largely unexplored. In order to study ...whether baseline WMH were associated with longitudinal subthreshold amyloid accumulation, 159 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative who were amyloid-negative at baseline were examined. All the participants underwent a T1 and a Fluid-Attenuated Inversion Recovery MRI scan at baseline. Amyloid PET imaging was performed at baseline and follow-up visits in 2-year intervals for up to 8 years. Partial volume correction was applied for quantifying cortical Standardised Uptake Value Ratios (SUVR). The associations between global and regional WMH burden and amyloid accumulation were assessed using linear mixed models adjusted by demographic characteristics and baseline SUVR. Partial volume correction increased the measured annual rate of change (+2.4%) compared to that obtained from non-corrected data (+0.5%). There were no significant correlations between baseline WMHs and baseline subthreshold cortical amyloid uptake. In a longitudinal analysis, increased baseline cortical SUVR and increased baseline burden of global (p = 0.006), frontal (p = 0.006), and parietal WMH (p = 0.003) were associated with faster amyloid accumulation. WMH-related amyloid accumulation occurred in parietal, frontal, and, to a lesser extent, cingulate cortices. These results remained unchanged after a sensitivity analysis excluding participants with the highest cortical SUVRs. This is the first study to identify a specific spatial distribution of WMH which is associated with future amyloid accumulation in cognitively normal elderly subjects without PET-detectable amyloid pathology. These findings may have important implications in prevention trials for the early identification of amyloid accumulation.
•The relation between white matter lesions and amyloid accumulation is unclear.•Longitudinal Aβ-PET scans in Aβ-negative, normal elderly for up to 8 years.•A spatial pattern of WMH relates to amyloid accrual in Aβ-negative, normal elderly.•WMH patterns might help identify amyloid “accumulators”.
High standards regarding Listeria monocytogenes control and consumer demands for food products without synthetic additives represent a challenge to food industry. We determined the antilisterial ...properties of an enriched acetogenin extract (EAE) from avocado seed, compared it to two commercial antimicrobials (one enriched in avocado acetogenins), and tested purified molecules. Acetogenin composition in pulp and seed of Hass avocado was quantified. EAE were obtained by two sequential centrifuge partition chromatography separations and molecules purified by preparative chromatography and quantified by HPLC‐MS‐TOF and HPLC‐PDA. Avocado seed extracts which are the following two: 1) EAE and 2) the commercially available antimicrobial Avosafe®, presented similar inhibition zones and chemical profiles. Minimum inhibitory concentration (MIC) values of extracts and two isolated acetogenins varied between 7.8 and 15.6 mg/L, were effective at 37 and 4 °C, and showed a bactericidal effect probably caused by increased membrane permeability and lytic effects, evidenced by flow cytometry at 10 and 100× MIC. Activity was comparable to Mirenat®. Most potent acetogenins were Persenone C (5) and A (6), and AcO‐avocadenyne (1), the latter exclusively present in seed. Common features of bioactive molecules were the acetyl moiety and multiple unsaturations (2 to 3) in the aliphatic chain, some persenones also featured a trans‐enone group. Seeds contained 1.6 times higher levels of acetogenins than pulp (5048.1 ± 575.5 and 3107.0 ± 207.2 mg/kg fresh weight, respectively), and total content in pulp was 199 to 398 times higher than MIC values. Therefore, acetogenin levels potentially consumed by humans are higher than inhibitory concentrations. Results document properties of avocado seed acetogenins as natural antilisterial food additives.
Practical Application
Avocado acetogenins possess antilisterial activity comparable to that of synthetic commercial antimicrobials, indicating that enriched extracts or isolated compounds from avocado fruit can potentially be incorporated into ready‐to‐eat (RTE) foods as natural additives to control Listeria monocytogenes. As a waste product of the industry, avocado seeds represent a good source of these molecules. Humans already consume acetogenins from avocado pulp above antilisterial levels; however, bioavailability and safety of the enriched extracts and isolated compounds needs further assessment.
The lack of standardization of intensity normalization methods and its unknown effect on the quantification output is recognized as a major drawback for the harmonization of brain FDG-PET ...quantification protocols. The aim of this work is the ground truth-based evaluation of different intensity normalization methods on brain FDG-PET quantification output.
Realistic FDG-PET images were generated using Monte Carlo simulation from activity and attenuation maps directly derived from 25 healthy subjects (adding theoretical relative hypometabolisms on 6 regions of interest and for 5 hypometabolism levels). Single-subject statistical parametric mapping (SPM) was applied to compare each simulated FDG-PET image with a healthy database after intensity normalization based on reference regions methods such as the brain stem (RRBS), cerebellum (RRC) and the temporal lobe contralateral to the lesion (RRTL), and data-driven methods, such as proportional scaling (PS), histogram-based method (HN) and iterative versions of both methods (iPS and iHN). The performance of these methods was evaluated in terms of the recovery of the introduced theoretical hypometabolic pattern and the appearance of unspecific hypometabolic and hypermetabolic findings.
Detected hypometabolic patterns had significantly lower volumes than the introduced hypometabolisms for all intensity normalization methods particularly for slighter reductions in metabolism . Among the intensity normalization methods, RRC and HN provided the largest recovered hypometabolic volumes, while the RRBS showed the smallest recovery. In general, data-driven methods overcame reference regions and among them, the iterative methods overcame the non-iterative ones. Unspecific hypermetabolic volumes were similar for all methods, with the exception of PS, where it became a major limitation (up to 250 cm3) for extended and intense hypometabolism. On the other hand, unspecific hypometabolism was similar far all methods, and usually solved with appropriate clustering.
Our findings showed that the inappropriate use of intensity normalization methods can provide remarkable bias in the detected hypometabolism and it represents a serious concern in terms of false positives. Based on our findings, we recommend the use of histogram-based intensity normalization methods. Reference region methods performance was equivalent to data-driven methods only when the selected reference region is large and stable.
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•The white matter and CSF are the main contributors to PVE in longitudinal tau PET quantification for all cortical regions. All other off-target regions showed neglibile contributions to cortical ...PVE.•PVC showed succesful at atenuating PVE contributions to longitudinal tau PET quantification. However, residual correlations due to biological or tracer-related factors remained after PVC.•PVC showed very limited benefits in increasing statistical power in group-level-style analysis of longitudinal tau PET metrics.
18Fflortaucipir (FTP) tau PET quantification is known to be affected by non-specific binding in off-target regions. Although partial volume correction (PVC) techniques partially account for this effect, their inclusion may also introduce noise and variability into the quantification process. While the impact of these effects has been studied in cross-sectional designs, the benefits and drawbacks of PVC on longitudinal FTP studies is still under scrutiny. The aim of this work was to study the performance of the most common PVC techniques for longitudinal FTP imaging.
A cohort of 247 individuals from the Alzheimer's Disease Neuroimaging Initiative with concurrent baseline FTP-PET, amyloid-beta (Aβ) PET and structural MRI, as well as with follow-up FTP-PET and MRI were included in the study. FTP-PET scans were corrected for partial volume effects using Meltzer's, a simple and popular analytical PVC, and both the region-based voxel-wise (RBV) and the iterative Yang (iY) corrections. FTP SUVR values and their longitudinal rates of change were calculated for regions of interest (ROI) corresponding to Braak Areas I-VI, for a temporal meta-ROI and for regions typically displaying off-target FTP binding (caudate, putamen, pallidum, thalamus, choroid plexus, hemispheric white matter, cerebellar white matter, and cerebrospinal fluid). The longitudinal correlation between binding in off-target and target ROIs was analysed for the different PVCs. Additionally, group differences in longitudinal FTP SUVR rates of change between Aβ-negative (A-) and Aβ-positive (A+), and between cognitively unimpaired (CU) and cognitively impaired (CI) individuals, were studied. Finally, we compared the ability of different partial-volume-corrected baseline FTP SUVRs to predict longitudinal brain atrophy and cognitive decline.
Among off-target ROIs, hemispheric white matter showed the highest correlation with longitudinal FTP SUVR rates from cortical target ROIs (R2=0.28–0.82), with CSF coming in second (R2=0.28–0.42). Application of voxel-wise PVC techniques minimized this correlation, with RBV performing best (R2=0.00–0.07 for hemispheric white matter). PVC also increased group differences between CU and CI individuals in FTP SUVR rates of change across all target regions, with RBV again performing best (No PVC: Cohen's d = 0.26–0.66; RBV: Cohen's d = 0.43–0.74). These improvements were not observed for differentiating A- from A+ groups. Additionally, voxel-wise PVC techniques strengthened the correlation between baseline FTP SUVR and longitudinal grey matter atrophy and cognitive decline.
Quantification of longitudinal FTP SUVR rates of change is affected by signal from off-target regions, especially the hemispheric white matter and the CSF. Voxel-wise PVC techniques significantly reduce this effect. PVC provided a significant but modest benefit for tasks involving the measurement of group-level longitudinal differences. These findings are particularly relevant for the estimations of sample sizes and analysis methodologies of longitudinal group studies.
18FFlortaucipir (FTP) PET quantification is usually hindered by spill-in counts from off-target binding (OFF) regions. The present work aims to provide an in-depth analysis of the impact of OFF in ...FTP PET quantification, as well as to identify optimal partial volume correction (PVC) strategies to minimize this problem.
309 amyloid-beta (Aβ) negative cognitively normal subjects were included in the study. Additionally, 510 realistic FTP images with different levels of OFF were generated using Monte Carlo simulation (MC). Images were corrected for PVC using both a simple two-compartment and a multi-region method including OFF regions. FTP standardized uptake value ratio (SUVR) was quantified in Braak Areas (BA), the hippocampus (which was not included in Braak I/II) and different OFF regions (caudate, putamen, pallidum, thalamus, choroid plexus (ChPlex), cerebellar white matter (cerebWM), hemispheric white matter (hemisWM) and cerebrospinal fluid (CSF)) using the lower portion of the cerebellum as a reference region. The correlations between OFF and cortical SUVRs were studied both in real and in simulated PET images, with and without PVC.
In-vivo, we found correlations between all OFF and target regions, especially strong for the hemisWM (slope>0.63, R2>0.4). All the correlations were attenuated but remained significant after applying PVC, except for the ChPlex. In MC simulations, the hemisWM and CSF were the main contributors to PVE in all BA (slopes 0.15-0.26 and 0.13-0.21 respectively). The hemisWM (slope=0.2), as well as the ChPlex (slope=0.02), influenced SUVRs in the hippocampus. The CerebWM was negatively correlated with all target regions (slope<-0.02, R2>0.8). While no other correlations between OFF and target regions were found, hemisWM was correlated with all OFF regions but the cerebWM (slopes 0.06-0.33). HemisWM correlations attenuated (slopes<0.06) when applying two-compartment PVC, but the hippocampus-ChPlex and the cerebWM correlations required more complex PVC with dedicated compartments for these regions. In-vivo, PVC removed a notably higher fraction of the correlation between OFF regions found to be affected by PVE in the simulation studies and BA (≈50%) than for OFF regions not affected by PVE (16%).
HemisWM is the main driver of spill-in effects in FTP PET, affecting both target regions and the rest of OFF regions. PVC successfully reduces PVE, even when using a simple two-compartment method. Despite PVC, non-zero correlations were still observed between target and OFF regions in vivo, which suggests the existence of biological or tracer-related contributions to these correlations.
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Urea is a hygroscopic molecule (capable of absorbing water) present in the epidermis as a component of the natural moisturizing factor (NMF) and is essential for the adequate hydration and integrity ...of the stratum corneum. Urea improves skin barrier function including antimicrobial defense by regulating gene expression in keratinocytes relevant for their differentiation and antimicrobial peptide production. It also plays a fundamental role in regulating keratinocyte proliferation. One of the first uses of urea in modern medicine was the topical treatment of wounds due to its proteolytic and antibacterial properties. At present, urea is widely used in dermatology to improve skin barrier function and as one of the most common moisturizers and keratolytic agents. Urea-containing formulations are available in diverse formulations and concentrations. Multiple clinical trials on the use of urea-containing formulations have shown significant clinical improvement in many of the dermatosis presenting with scaly and dry skin such as atopic dermatitis, ichthyosis, xerosis, seborrheic dermatitis and psoriasis, among others. Furthermore, urea can increase skin penetration and optimize the action of topical drugs. Urea-based products are well tolerated; their side effects are mild and are more frequent at high concentration. Here, we present a review of the use of urea in dermatology, discussing its mechanism of action, safety profile and frequent indications.
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