Development of an organic polymer monolith column for the nano liquid chromatography fast analysis of monoclonal antibody in infusion bags prepared in a hospital pharmacy.

Poly(butyl methacrylate-co-ethylene dimethacrylate) monolith was in situ prepared in a liquid chromatography capillary column with a 75 µm internal diameter. This monolith offered high permeability (5.3 ± 10-14 m2) and good peak capacity (140 for a 15 cm column length at 300 nl/min with a 20 min gradient time). This is exemplified by its separation ability in reversed mode for subunit analysis of monoclonal antibodies after IdeS digestion (middle-up analysis). The potential of this column was also illustrated for the fast analytical control of therapeutic monoclonal antibodies in standardized infusion bags prepared in advance in a pharmacy department. Linearity analysis revealed the column's capability for accurate quantification analysis of the different dose bandings (in mg) of monoclonal antibodies in <2 min. In addition, lifetime analysis data indicated that the column can be highly reproducible and has a long lifetime with stable and low back pressure. The variations observed on the peak shape and area between unstressed (intact) and stressed monoclonal antibodies indicated that our nano liquid chromatographic method was stability indicating. In addition, using a gradient elution mode, the presence of minor components in the infusion bags was visualized.

Cerebral grey matter may not explain sleep slow-wave characteristics after severe brain injury.

Sleep slow waves are the hallmark of deeper non-rapid eye movement sleep. It is generally assumed that grey matter properties predict slow-wave density, morphology, and spectral power in healthy adults. Here, we tested the association between grey matter volume (GMV) and slow-wave characteristics in 27 moderate to severe traumatic brain injury patients (TBI; 32.0 ± 12.2 years old, eight women) compared to 32 healthy controls (29.2 ± 11.5 years old, nine women). Participants underwent overnight polysomnography and cerebral MRI with a 3-tesla scanner. A whole-brain voxel-wise analysis was performed to compare GMV between groups. Slow-wave density, morphology, and spectral power (0.4-6  Hz) were computed, and GMV was extracted from the thalamus, cingulate, insula, precuneus, and orbitofrontal cortex to test the relationship between slow waves and grey matter in regions implicated in the generation and/or propagation of slow waves. Compared to controls, TBI patients had significantly lower frontal and temporal GMV and exhibited a subtle decrease in slow-wave frequency. Moreover, higher GMV in the orbitofrontal cortex, insula, cingulate cortex, and precuneus was associated with higher slow-wave frequency and slope, only in healthy controls. Higher orbitofrontal GMV was also associated with higher slow-wave density in healthy participants. While we observed the expected associations between GMV and slow-wave characteristics in healthy controls, no such associations were observed in the TBI group despite lower GMV. This finding challenges the presumed role of GMV in slow-wave generation and morphology.Significance Statement Because sleep slow waves play a key role in cognition, synaptic plasticity, and restorative sleep, understanding how they relate to cerebral matter integrity is especially important in the context of brain atrophy following moderate to severe traumatic brain injury (TBI). We found that higher grey matter volume (GMV) in regions involved in slow-wave generation and propagation was associated with faster and steeper slow waves in healthy individuals. However, these associations were not observed in TBI participants, raising questions about the degree of contribution of GMV to slow-wave properties in patients with lower grey matter relative to controls. These findings challenge our current understanding of the link between grey matter integrity and slow waves, highlighting the complexity of this relationship.

Altered fornix integrity is associated with sleep apnea-related hypoxemia in mild cognitive impairment.

INTRODUCTION: The limbic system is critical for memory function and degenerates early in the Alzheimer's disease continuum. Whether obstructive sleep apnea (OSA) is associated with alterations in the limbic white matter tracts remains understudied. METHODS: Polysomnography, neurocognitive assessment, and brain magnetic resonance imaging (MRI) were performed in 126 individuals aged 55-86 years, including 70 cognitively unimpaired participants and 56 participants with mild cognitive impairment (MCI). OSA measures of interest were the apnea-hypopnea index and composite variables of sleep fragmentation and hypoxemia. Microstructural properties of the cingulum, fornix, and uncinate fasciculus were estimated using free water-corrected diffusion tensor imaging. RESULTS: Higher levels of OSA-related hypoxemia were associated with higher left fornix diffusivities only in participants with MCI. Microstructure of the other white matter tracts was not associated with OSA measures. Higher left fornix diffusivities correlated with poorer episodic verbal memory. DISCUSSION: OSA may contribute to fornix damage and memory dysfunction in MCI. HIGHLIGHTS: Sleep apnea-related hypoxemia was associated with altered fornix integrity in MCI. Altered fornix integrity correlated with poorer memory function. Sleep apnea may contribute to fornix damage and memory dysfunction in MCI.

Reduced rapid eye movement sleep in late middle-aged and older apolipoprotein E ɛ4 allele carriers.

STUDY OBJECTIVES: Apolipoprotein E ɛ4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD). In addition, APOE4 carriers may exhibit sleep disturbances, but conflicting results have been reported, such that there is no clear consensus regarding which aspects of sleep are impacted. Our objective was to compare objective sleep architecture between APOE4 carriers and non-carriers, and to investigate the modulating impact of age, sex, cognitive status, and obstructive sleep apnea (OSA). METHODS: A total of 198 dementia-free participants aged >55 years old (mean age: 68.7 ± 8.08 years old, 40.91% women, 41 APOE4 carriers) were recruited in this cross-sectional study. They underwent polysomnography, APOE4 genotyping, and a neuropsychological evaluation. ANCOVAs assessed the effect of APOE4 status on sleep architecture, controlling for age, sex, cognitive status, and the apnea-hypopnea index. Interaction terms were added between APOE4 status and covariates. RESULTS: Rapid eye movement (REM) sleep percentage (F = 9.95, p = .002, ηp2 = 0.049) and duration (F = 9.23, p = .003, ηp2 = 0.047) were lower in APOE4 carriers. The results were replicated in a subsample of 112 participants without moderate-to-severe OSA. There were no significant interactions between APOE4 status and age, sex, cognitive status, and OSA in the whole sample. CONCLUSIONS: Our results show that APOE4 carriers exhibit lower REM sleep duration, including in cognitively unimpaired individuals, possibly resulting from early neurodegenerative processes in regions involved in REM sleep generation and maintenance.

Associations Between Repetitive Negative Thinking and Objective and Subjective Sleep Health in Cognitively Healthy Older Adults.

Objective: Poor sleep and high levels of repetitive negative thinking (RNT), including future-directed (ie, worry) and past-directed (ie, brooding) negative thoughts, have been associated with markers of dementia risk. The relationship between RNT and sleep health in older adults is unknown. This study aimed to investigate this association and its specificities including multiple dimensions of objective and subjective sleep. Methods: This study used a cross sectional quantitative design with baseline data from 127 cognitively healthy older adults (mean age 69.4 ± 3.8 years; 63% female) who took part in the Age-Well clinical trial, France. RNT (ie, worry and brooding) levels were measured using the Penn State Worry Questionnaire and the Rumination Response Scale (brooding subscale). Polysomnography was used to assess sleep objectively, and the Pittsburgh Sleep Quality Index and the St. Mary's Hospital Sleep Questionnaire were used to measure sleep subjectively. In primary analyses the associations between RNT and sleep (ie, objective sleep duration, fragmentation and efficiency and subjective sleep disturbance) were assessed via adjusted regressions. Results: Higher levels of RNT were associated with poorer objective sleep efficiency (worry: ß=-0.32, p<0.001; brooding: ß=-0.26, p=0.002), but not objective sleep duration, fragmentation, or subjective sleep disturbance. Additional analyses, however, revealed differences in levels of worry between those with short, compared with typical and long objective sleep durations (p < 0.05). Conclusion: In cognitively healthy older adults, RNT was associated with sleep characteristics that have been implicated in increased dementia risk. It will take additional research to ascertain the causal link between RNT and sleep characteristics and how they ultimately relate to the risk of developing dementia.

Multimodal neuroimaging correlates of spectral power in NREM sleep delta sub-bands in cognitively unimpaired older adults.

STUDY OBJECTIVES: In aging, reduced delta power (0.5-4 Hz) during N2 and N3 sleep has been associated with gray matter (GM) atrophy and hypometabolism within frontal regions. Some studies have also reported associations between N2 and N3 sleep delta power in specific sub-bands and amyloid pathology. Our objective was to better understand the relationships between spectral power in delta sub-bands during N2-N3 sleep and brain integrity using multimodal neuroimaging. METHODS: In-home polysomnography was performed in 127 cognitively unimpaired older adults (mean age ±â€…SD: 69.0 ±â€…3.8 years). N2-N3 sleep EEG power was calculated in delta (0.5-4 Hz), slow delta (0.5-1 Hz), and fast delta (1-4 Hz) frequency bands. Participants also underwent magnetic resonance imaging and Florbetapir-PET (early and late acquisitions) scans to assess GM volume, brain perfusion, and amyloid burden. Amyloid accumulation over ~21 months was also quantified. RESULTS: Higher delta power was associated with higher GM volume mainly in fronto-cingular regions. Specifically, slow delta power was positively correlated with GM volume and perfusion in these regions, while the inverse association was observed with fast delta power. Delta power was neither associated with amyloid burden at baseline nor its accumulation over time, whatever the frequency band considered. CONCLUSIONS: Our results show that slow delta is particularly associated with preserved brain structure, and highlight the importance of analyzing delta power sub-bands to better understand the associations between delta power and brain integrity. Further longitudinal investigations with long follow-ups are needed to disentangle the associations among sleep, amyloid pathology, and dementia risk in older populations. CLINICAL TRIAL INFORMATION: Name: Study in Cognitively Intact Seniors Aiming to Assess the Effects of Meditation Training (Age-Well). URL: https://clinicaltrials.gov/ct2/show/NCT02977819?term=Age-Well&draw=2&rank=1. See STROBE_statement_AGEWELL in supplemental materials. REGISTRATION: EudraCT: 2016-002441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819.

Age- and sex-specific associations between obstructive sleep apnea risk and cognitive decline in middle-aged and older adults: A 3-year longitudinal analysis of the Canadian longitudinal study on aging.

BACKGROUND: Whether obstructive sleep apnea (OSA) increases the risk of cognitive decline and how sex and age influence this association is not clear. Here, we characterized the sex- and age-specific associations between OSA risk and 3-year cognitive change in middle-aged and older adults. METHODS: We included 24,819 participants aged 45-85 (52% women) from the Canadian Longitudinal Study on Aging. OSA risk was measured at baseline using the STOP combined to body mass index (STOP-B). Neuropsychological tests assessed memory, executive functioning, and psychomotor speed at baseline and at 3-year follow-up. We conducted age- and sex-specific linear mixed models to estimate the predictive role of baseline STOP-B score on 3-year cognitive change. RESULTS: Men at high-risk for OSA aged 45-59 years showed a steeper decline in psychomotor speed (+13.2 [95% CI: -1.6, 27.9]) compared to men at low-risk. Men at high-risk for OSA aged 60-69 showed a steeper decline in mental flexibility (-1.2 [-1.9, -0.5]) and processing speed (+0.6 [0.3, 0.9]) than those at low-risk. Women at high-risk for OSA aged 45-59 showed a steeper decline in processing speed (+0.1 [-0.2, 0.4]) than women at low-risk, while women at high-risk ≥70 years had a steeper decline in memory (-0.2 [-0.6, 0.1]) and processing speed (+1.0 [0.4, 1.5]). CONCLUSIONS: Associations between OSA risk and cognitive decline over 3 years depend on age and sex. Being at high-risk for OSA is associated with a generalized cognitive decline in attention and processing speed, while a memory decline is specific to older women (≥70 years).

REM sleep is associated with the volume of the cholinergic basal forebrain in aMCI individuals.

BACKGROUND: Rapid-eye movement (REM) sleep highly depends on the activity of cholinergic basal forebrain (BF) neurons and is reduced in Alzheimer's disease. Here, we investigated the associations between the volume of BF nuclei and REM sleep characteristics, and the impact of cognitive status on these links, in late middle-aged and older participants. METHODS: Thirty-one cognitively healthy controls (66.8 ± 7.2 years old, 13 women) and 31 participants with amnestic Mild Cognitive Impairment (aMCI) (68.3 ± 8.8 years old, 7 women) were included in this cross-sectional study. All participants underwent polysomnography, a comprehensive neuropsychological assessment and Magnetic Resonance Imaging examination. REM sleep characteristics (i.e., percentage, latency and efficiency) were derived from polysomnographic recordings. T1-weighted images were preprocessed using CAT12 and the DARTEL algorithm, and we extracted the gray matter volume of BF regions of interest using a probabilistic atlas implemented in the JuBrain Anatomy Toolbox. Multiple linear regressions were performed between the volume of BF nuclei and REM sleep characteristics controlling for age, sex and total intracranial volume, in the whole cohort and in subgroups stratified by cognitive status. RESULTS: In the whole sample, lower REM sleep percentage was significantly associated to lower nucleus basalis of Meynert (Ch4) volume (ß = 0.32, p = 0.009). When stratifying the cohort according to cognitive status, lower REM sleep percentage was significantly associated to both lower Ch4 (ß = 0.48, p = 0.012) and total BF volumes (ß = 0.44, p = 0.014) in aMCI individuals, but not in cognitively unimpaired participants. No significant associations were observed between the volume of the BF and wake after sleep onset or non-REM sleep variables. DISCUSSION: These results suggest that REM sleep disturbances may be an early manifestation of the degeneration of the BF cholinergic system before the onset of dementia, especially in participants with mild memory deficits.

Effect of cognitive reserve on the association between slow wave sleep and cognition in community-dwelling older adults.

Sleep, especially slow wave sleep (SWS), is essential for cognitive functioning and is reduced in aging. The impact of sleep quality on cognition is variable, especially in aging. Cognitive reserve (CR) may be an important modulator of these effects. We aimed at investigating this question to better identify individuals in whom sleep disturbances might have greater behavioral consequences. Polysomnography and neuropsychological assessments were performed in 135 cognitively intact older adults (mean age ± SD: 69.4 ± 3.8y) from the Age-Well randomized controlled trial (baseline data). Two measures of cognitive engagement throughout life were used as CR proxies. Linear regression analyses were performed between the proportion of SWS, and executive function and episodic memory composite scores. Then, interaction analyses between SWS and CR proxies on cognition were conducted to assess the possible impact of CR on these links. SWS was positively associated with episodic memory, but not with executive function. CR proxies modulated the associations between SWS and both executive and episodic memory performance. Specifically, individuals with higher CR were able to maintain cognitive performance despite low amounts of SWS. This study provides the first evidence that CR may protect against the deleterious effects of age-related sleep changes on cognition.

The Potential of Social Policies in Preventing Dementia: An Ecological Study Using Systematic Review and Meta-Analysis.

Social policies determine the distribution of factors (e.g. education, cardiovascular health) protecting against the development of dementia in Alzheimer's disease (AD). However, the association between social policies and the likelihood of AD without dementia (ADw/oD) has yet to be evaluated. We estimated this association in an ecological study using systematic review and meta-analysis. Four reference databases were consulted; 18 studies were included in the final analysis. ADw/oD was defined as death without dementia in people with clinically significant AD brain pathology. The indicators of social policy were extracted from the Organisation for Economic Co-operation and Development database (OECD). The probability of ADw/oD with moderate AD brain pathology was inversely associated with the Gini index for disposable income, poverty rate, and certain public expenditures on healthcare. ADw/oD with advanced AD brain pathology was only associated with public expenditures for long-term care. Social policies may play a role in maintaining and sustaining cognitive health among older people with AD.

Altered resting-state functional connectivity patterns in late middle-aged and older adults with obstructive sleep apnea.

Introduction: Obstructive sleep apnea (OSA) is increasingly recognized as a risk factor for cognitive decline, and has been associated with structural brain alterations in regions relevant to memory processes and Alzheimer's disease. However, it is unclear whether OSA is associated with disrupted functional connectivity (FC) patterns between these regions in late middle-aged and older populations. Thus, we characterized the associations between OSA severity and resting-state FC between the default mode network (DMN) and medial temporal lobe (MTL) regions. Second, we explored whether significant FC changes differed depending on cognitive status and were associated with cognitive performance. Methods: Ninety-four participants [24 women, 65.7 ± 6.9 years old, 41% with Mild Cognitive Impairment (MCI)] underwent a polysomnography, a comprehensive neuropsychological assessment and a resting-state functional magnetic resonance imaging (MRI). General linear models were conducted between OSA severity markers (i.e., the apnea-hypopnea, oxygen desaturation and microarousal indices) and FC values between DMN and MTL regions using CONN toolbox. Partial correlations were then performed between OSA-related FC patterns and (i) OSA severity markers in subgroups stratified by cognitive status (i.e., cognitively unimpaired versus MCI) and (ii) cognitive scores in the whole sample. All analyzes were controlled for age, sex and education, and considered significant at a p < 0.05 threshold corrected for false discovery rate. Results: In the whole sample, a higher apnea-hypopnea index was significantly associated with lower FC between (i) the medial prefrontal cortex and bilateral hippocampi, and (ii) the left hippocampus and both the posterior cingulate cortex and precuneus. FC patterns were not associated with the oxygen desaturation index, or micro-arousal index. When stratifying the sample according to cognitive status, all associations remained significant in cognitively unimpaired individuals but not in the MCI group. No significant associations were observed between cognition and OSA severity or OSA-related FC patterns. Discussion: OSA severity was associated with patterns of lower FC in regions relevant to memory processes and Alzheimer's disease. Since no associations were found with cognitive performance, these FC changes could precede detectable cognitive deficits. Whether these FC patterns predict future cognitive decline over the long-term needs to be investigated.

Sleep Location and Its Association with Caregiver Sleep Quality During Patient Hospital Admission.

During acute hospitalization, many caregivers decide to stay at the care recipient's bedside over the course of several days or months, coping with a stressful situation and a poor sleeping environment. Our objective was to characterize caregiver sleep-wake cycles during care recipient hospital admission and test the association between sleep location (home versus hospital) and caregiver sleep. Eighty-six informal caregivers (78.8% female; age 55.47 ± 12.43 years) were recruited. For seven consecutive days, caregivers wore actigraphy devices and filled a sleep diary indicating whether they had slept at the hospital or at home. Caregiver insomnia symptoms, anxiety, and depression along with patient dependence were also assessed. Nighttime total sleep time, wake after sleep onset, sleep efficiency, sleep latency, and fragmentation index were described. Mixed-model analyses were used to evaluate the effect of the overnight location (home versus hospital) on caregiver sleep quality. In total, 38.4% of caregivers exhibited poor objective sleep efficiencies (< 80%), and 43% of caregivers reported having moderate to severe insomnia symptoms. Caregivers mostly slept at the hospital (n = 53), but some slept at home (n = 14) or between both locations (n = 19). Mixed-model analyses using actigraphy showed that caregivers had significantly better sleep quality when resting at home regarding wake after sleep onset, fragmentation index, and sleep efficiency (p < .05). Caregivers experienced poor sleep quality during care recipients' hospitalization, specifically when sleeping at the hospital versus sleeping at home. Healthcare workers should ensure caregivers' well-being and strongly encourage caregivers to rest at home whenever possible.

New liquid chromatography columns for highlighting the interaction of ligand candidates with humic acid.

Humic acid was the main compound in soil and reduced the availability of some organic compounds in soils. In this work, humic acid was immobilized for the first time on a homemade neutravidin poly(glycidyl methacrylate-co-ethylene dimethacrylate) capillary column with a 20 µm i.d. for the screening of potential ligands to humic acid and the evaluation of their molecular recognition mechanism. This homemade humic acid column enabling it to work at very low backpressure (0.60 MPa at 20 nl/min flow rate), had a long lifetime, excellent repeatability, and negligible non-specific binding sites. The performance of this affinity humic acid column was demonstrated by the evaluation of recognition assay for a series of known ligands of humic acid (a series of rodenticide molecules) which is the heart of the fragment-based drug design. In addition, this column was used successfully for highlighting the binding mechanism to humic acid of the severe acute respiratory syndrome coronavirus-2-spike protein. As well this new humic acid miniaturized liquid chromatography column developed in this work could be used in the feature for another solute molecule-humic acid binding studies or for a separative mode.

Association of Sleep-Disordered Breathing and Medial Temporal Lobe Atrophy in Cognitively Unimpaired Amyloid-Positive Older Adults.

BACKGROUND AND OBJECTIVES: Sleep disordered breathing (SDB) has been related to amyloid deposition and an increased dementia risk. However, how SDB relates to medial temporal lobe neurodegeneration and subsequent episodic memory impairment is unclear. Our objective was to investigate the impact of amyloid positivity on the associations between SDB severity, medial temporal lobe subregions, and episodic memory performance in cognitively unimpaired older adults. METHODS: Data were acquired between 2016 and 2020 in the context of the Age-Well randomized controlled trial of the Medit-Aging European project. Participants older than 65 years who were free of neurologic, psychiatric, or chronic medical diseases were recruited from the community. They completed a neuropsychological evaluation, in-home polysomnography, a Florbetapir PET, and an MRI, including a specific high-resolution assessment of the medial temporal lobe and hippocampal subfields. Multiple linear regressions were conducted to test interactions between amyloid status and SDB severity on the volume of MTL subregions, controlling for age, sex, education, and the ApoE4 status. Secondary analyses aimed at investigating the links between SDB, MTL subregional atrophy, and episodic memory performance at baseline and at a mean follow-up of 20.66 months in the whole cohort and in subgroups stratified according to amyloid status. RESULTS: We included 122 cognitively intact community-dwelling older adults (mean age ± SD: 69.40 ± 3.85 years, 77 women, 26 Aß+ individuals) in baseline analyses and 111 at follow-up. The apnea-hypopnea index interacted with entorhinal (ß = -0.81, p < 0.001, pη2 = 0.19), whole hippocampal (ß = -0.61, p < 0.001, pη2 = 0.10), subiculum (ß = -0.56, p = 0.002, pη2 = 0.08), CA1 (ß = -0.55, p = 0.002, pη2 = 0.08), and DG (ß = -0.53, p = 0.003, pη2 = 0.08) volumes such that a higher sleep apnea severity was related to lower MTL subregion volumes in amyloid-positive individuals, but not in those who were amyloid negative. In the whole cohort, lower whole hippocampal (r = 0.27, p = 0.005) and CA1 (r = 0.28, p = 0.003) volumes at baseline were associated with worse episodic memory performance at follow-up. DISCUSSION: Overall, we showed that SDB was associated with MTL atrophy in cognitively asymptomatic older adults engaged in the Alzheimer continuum, which may increase the risk of developing memory impairment over time. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02977819.

Distinct Sleep Alterations in Alcohol Use Disorder Patients with and without Korsakoff's Syndrome: Relationship with Episodic Memory.

Alcohol Use Disorder (AUD) results in sleep disturbances that may have deleterious impacts on cognition, especially on memory. However, little is known about the sleep architecture in patients with Korsakoff's syndrome (KS). This study aims at characterizing sleep disturbances in KS compared to AUD without KS and at specifying the relationships with cognitive impairments. Twenty-nine AUD patients (22 without KS and 7 with KS) and 15 healthy controls underwent a neuropsychological assessment and a polysomnography. The severity of sleep-disordered breathing and sleep fragmentation was similar in AUD and KS patients compared to controls. Sleep architecture differed between both patient groups: the proportion of slow-wave sleep was reduced in AUD patients only, while a lower proportion of rapid-eye movement (REM) sleep was specifically observed in KS patients. The proportion of REM sleep correlated with the severity of episodic memory deficits when AUD and KS were examined together. These data provide evidence for both similarities and specificities regarding sleep alterations in AUD patients with and without KS. They also indicate that altered sleep architecture may contribute to the pathophysiology of alcohol-related memory disorders.

Development of a new heparan sulfate proteoglycan (HSPG) chromolith LC column to study the pH dependence binding of peptide vaccines to HSPG and role of human serum albumin on its binding.

Heparan sulfate proteoglycan (HSPG) expressed on immune cell surface participate in antitumor T-cell responses generated in the acidic lymph node (LN) microenvironment. In this work, HSPG was immobilized for the first time on a HPLC chromolith support for studying the effect of extra cellular acidosis in LNs on the binding to HSPG of two peptide vaccines (universal cancer peptide UCP2 and UCP4). This home-made HSPG column enabling to work at high flow-rates, was resistance to change in pH, had a long - life time, an excellent repeatability and negligible non-specific binding sites. The performance of this affinity HSPG column was confirmed by the evaluation of recognition assay for a series of known ligand of HSPG. It was shown that at 37 °C, the UCP2 binding to HSPG versus pH described a sigmoidal shape while UCP4 remained relatively constant in the pH range 5.0-7.5 and lower than the one of UCP2. By the use of an HSA HPLC column, it was shown at 37 °C and in acidic conditions a loss of affinity of UCP2 and UCP4 to HSA. It was demonstrated that upon UCP2/HSA binding, the protonation of the histidine residue in the cluster R(arg) Q(Gln) Hist (H) of the UCP2 peptide allowed to expose more favorably than UCP4 its polar and cationic groups to the negative net charge of HSPG on immune cells. Acidic pHs led to the protonation of the UCP2 residue histidine by flipping the His switch to the on position with a concomitant increase in affinity for the negative net charge of HSPG confirming that UCP2 was more immunogenic than UCP4. As well this HSPG chromolith LC column developed in this work could be used in the feature for other protein - HSPG binding studies or for a separative mode.

Performance evaluation of the HPLC diode array and evaporative light scattering detection for the implementation of dose-banded gemcitabine infusion bags.

BACKGROUND: Dose banding (DB) was used to optimise the individualisation of patient treatments with gemcitabine (Gem) in order to improve workload planning at the pharmacy of the University Hospital Centre of Besançon (UHCB). A new simple and fast high-performance liquid chromatographic (HPLC) method was also developed for the quantification of Gem without dilution of the infusion bags. METHODS: Individual doses of Gem preparations were retrospectively analysed over a 1-year period to determine the frequency of prepared doses. Using a maximum gap of 7.5% around the doses chosen, the selected Gem standard doses were 1400 mg, 1600 mg, 1800 mg and 2000 mg. Following the DB scheme, the frequency of prescription of standard and individualised Gem doses was analysed over a period of 10 months. The four selected Gem standard doses were aseptically prepared in polyolefin infusion bags. Each series of 20 bags was stocked under refrigerated storage conditions (4°C) for up to 84 days. The quantification of Gem without dilution of the infusion bags was obtained by the development of a HPLC method coupled to a diode array detector (DAD) or an evaporative light scattering detector (ELSD). RESULTS: During the 10-month period following implementation of the DB, 75.6% of the 1266 prescribed doses were covered by the four standardised preparations. The number of different Gem doses was reduced from 183 to 55. Concerning the Gem quantification, both heteroscedasticity and non-linearity were observed with DAD. Using an ELSD, the trueness values were between 98.59% and 101.52% with excellent repeatability values between 0.66% and 1.42%. CONCLUSION: A new HPLC method has been developed for the quantification of Gem without dilution of the infusion bags prepared in advance as a result of a target DB scheme successfully implemented in our pharmacy department.

Rapid Eye Movement Sleep, Neurodegeneration, and Amyloid Deposition in Aging.

OBJECTIVE: Rapid eye movement (REM) sleep is markedly altered in Alzheimer's disease (AD), and its reduction in older populations is associated with AD risk. However, little is known about the underlying brain mechanisms. Our objective was to investigate the relationships between REM sleep integrity and amyloid deposition, gray matter volume, and perfusion in aging. METHODS: We included 121 cognitively unimpaired older adults (76 women, mean age 68.96 ± 3.82 years), who underwent a polysomnography, T1-weighted magnetic resonance imaging, early and late Florbetapir positron emission tomography scans to evaluate gray matter volume, perfusion, and amyloid deposition. We computed indices reflecting REM sleep macro- and microstructural integrity (ie, normalized electroencephalographic spectral power values). Voxel-wise multiple regression analyses were conducted between REM sleep indices and neuroimaging data, controlling for age, sex, education, the apnea-hypopnea index, and the apolipoprotein E ε4 status. RESULTS: Lower perfusion in frontal, anterior and posterior cingulate, and precuneus areas was associated with decreased delta power and electroencephalographic slowing (slow/fast frequencies ratio), and increased alpha and beta power. To a lower extent, similar results were obtained between gray matter volume and delta, alpha, and beta power. In addition, lower REM sleep theta power was more marginally associated with greater diffuse amyloid deposition and lower gray matter volume in fronto-temporal and parieto-occipital areas. INTERPRETATION: These results suggest that alterations of REM sleep microstructure are associated with greater neurodegeneration and neocortical amyloid deposition in older adults. Further studies are warranted to replicate these findings, and determine whether older adults exhibiting REM sleep alterations are more at risk of cognitive decline and belonging to the Alzheimer's continuum. ANN NEUROL 2023;93:979-990.

Age-related changes in fast spindle clustering during non-rapid eye movement sleep and their relevance for memory consolidation.

Sleep plays a crucial role in memory consolidation. Recent data in rodents and young adults revealed that fast spindle band power fluctuates at a 0.02-Hz infraslow scale during non-rapid eye movement (NREM) sleep. These fluctuations result from a periodic temporal clustering of spindles and may modulate sleep maintenance and memory consolidation. With age, sleep undergoes substantial changes but age-related changes in spindle clustering have never been investigated. Polysomnography data were collected in 147 older (mean age ±â€…SD: 69.3 ±â€…4.1 years) and 32 young-middle aged (34.5 ±â€…10.9 years) adults. Sleep-dependent memory consolidation was assessed in a subsample of 57 older adults using a visuospatial memory task. We analyzed power fluctuations in fast spindle frequency band, detected fast spindles, and quantified their clustering during the night separating encoding and retrieval. Fast spindle band power fluctuated at a 0.02-Hz infraslow scale in young-middle aged and older adults. However, the proportion of clustered fast spindles decreased non-linearly with age (p < .001). This effect was not mediated by NREM sleep fragmentation. The clustering level of fast spindles modulated their characteristics (p < .001). Finally, the mean size of spindle clusters was positively associated with memory consolidation (p = .036) and negatively with NREM sleep micro-arousal density (p = .033). These results suggest that clusters of fast spindles may constitute stable sleep periods promoting off-line processes such as memory consolidation. We emphasize the relevance of considering spindle dynamics, obviously impaired during aging, to understand the impact of age-related sleep changes on memory. Clinical Trial Information: Name: Study in Cognitively Intact Seniors Aiming to Assess the Effects of Meditation Training (Age-Well). URL: https://clinicaltrials.gov/ct2/show/NCT02977819?term=Age-Well&draw=2&rank=1. See STROBE_statement_AGEWELL.doc in supplementary material. Registration: EudraCT: 2016-002441-36; IDRCB: 2016-A01767-44; ClinicalTrials.gov Identifier: NCT02977819.

Social class and the risk of dementia: A systematic review and meta-analysis of the prospective longitudinal studies.

BACKGROUND: The association between belonging to a disadvantaged socio-economic status or social class and health outcomes has been consistently documented during recent decades. However, a meta-analysis quantifying the association between belonging to a lower social class and the risk of dementia has yet to be performed. In the present work, we sought to summarise the results of prospective, longitudinal studies on this topic. METHODS: We conducted a systematic review and meta-analysis of prospective, longitudinal studies measuring the association between indicators of social class and the risk of all-cause/Alzheimer's dementia. The search was conducted in four databases (Medline, Embase, Web of Science and PsychInfo). Inclusion criteria for this systematic review and meta-analysis were: (a) longitudinal prospective study, (b) aged ⩾60 years at baseline, (c) issued from the general population, (d) no dementia at baseline and (e) mention of social class as exposure. Exclusion criteria were: (a) study of rare dementia types (e.g. frontotemporal dementia), (b) abstract-only papers and (c) articles without full text available. The Newcastle-Ottawa scale was used to assess the risk of bias in individual studies. We calculated the overall pooled relative risk of dementia for different social class indicators, both crude and adjusted for sex, age and the year of the cohort start. RESULTS: Out of 4548 screened abstracts, 15 were included in the final analysis (76,561 participants, mean follow-up 6.7 years (2.4-25 years), mean age at baseline 75.1 years (70.6-82.1 years), mean percentage of women 58%). Social class was operationalised as levels of education, occupational class, income level, neighbourhood disadvantage and wealth. Education (relative risk (RR)=2.48; confidence interval (CI) 1.71-3.59) and occupational class (RR=2.09; CI 1.18-3.69) but not income (RR=1.28; CI 0.81-2.04) were significantly associated with the risk of dementia in the adjusted model. Some of the limitations of this study are the inclusion of studies predominantly conducted in high-income countries and the exclusion of social mobility in our analysis. CONCLUSIONS: We conclude that there is a significant association between belonging to a social class and the risk of dementia, with education and occupation being the most relevant indicators of social class regarding this risk. Studying the relationship between belonging to a disadvantaged social class and dementia risk might be a fruitful path to diminishing the incidence of dementia over time. However, a narrow operationalisation of social class that only includes education, occupation and income may reduce the potential for such studies to inform social policies.