In vivo marker of brainstem myelin is associated to quantitative sleep parameters in healthy young men.

The regional integrity of brain subcortical structures has been implicated in sleep-wake regulation, however, their associations with sleep parameters remain largely unexplored. Here, we assessed association between quantitative Magnetic Resonance Imaging (qMRI)-derived marker of the myelin content of the brainstem and the variability in the sleep electrophysiology in a large sample of 18-to-31 years healthy young men (N = 321; ~ 22 years). Separate Generalized Additive Model for Location, Scale and Shape (GAMLSS) revealed that sleep onset latency and slow wave energy were significantly associated with MTsat estimates in the brainstem (pcorrected ≤ 0.03), with overall higher MTsat value associated with values reflecting better sleep quality. The association changed with age, however (MTsat-by-age interaction-pcorrected ≤ 0.03), with higher MTsat value linked to better values in the two sleep metrics in the younger individuals of our sample aged ~ 18 to 20 years. Similar associations were detected across different parts of the brainstem (pcorrected ≤ 0.03), suggesting that the overall maturation and integrity of the brainstem was associated with both sleep metrics. Our results suggest that myelination of the brainstem nuclei essential to regulation of sleep is associated with inter-individual differences in sleep characteristics during early adulthood. They may have implications for sleep disorders or neurological diseases related to myelin.

Association between sleep slow-wave activity and in-vivo estimates of myelin in healthy young men.

Sleep has been suggested to contribute to myelinogenesis and associated structural changes in the brain. As a principal hallmark of sleep, slow-wave activity (SWA) is homeostatically regulated but also differs between individuals. Besides its homeostatic function, SWA topography is suggested to reflect processes of brain maturation. Here, we assessed whether interindividual differences in sleep SWA and its homeostatic response to sleep manipulations are associated with in-vivo myelin estimates in a sample of healthy young men. Two hundred twenty-six participants (18-31 y.) underwent an in-lab protocol in which SWA was assessed at baseline (BAS), after sleep deprivation (high homeostatic sleep pressure, HSP) and after sleep saturation (low homeostatic sleep pressure, LSP). Early-night frontal SWA, the frontal-occipital SWA ratio, as well as the overnight exponential SWA decay were computed over sleep conditions. Semi-quantitative magnetization transfer saturation maps (MTsat), providing markers for myelin content, were acquired during a separate laboratory visit. Early-night frontal SWA was negatively associated with regional myelin estimates in the temporal portion of the inferior longitudinal fasciculus. By contrast, neither the responsiveness of SWA to sleep saturation or deprivation, its overnight dynamics, nor the frontal/occipital SWA ratio were associated with brain structural indices. Our results indicate that frontal SWA generation tracks inter-individual differences in continued structural brain re-organization during early adulthood. This stage of life is not only characterized by ongoing region-specific changes in myelin content, but also by a sharp decrease and a shift towards frontal predominance in SWA generation.

Genetic risk for insomnia is associated with objective sleep measures in young and healthy good sleepers.

Insomnia disorder (ID) is the second most common neuropsychiatric disorder. Its socioeconomic burden is enormous while diagnosis and treatment are difficult. A novel approach that reveals associations between insomnia genetic propensity and sleep phenotypes in youth may help understand the core of the disease isolated from comorbidities and pave the way for new treatments. We obtained quantitative nocturnal sleep electroencephalogram (EEG) features in 456 participants (18-31y, 49 women). Sleep EEG was recorded during a baseline night following at least 7 days of regular sleep times. We then assessed daytime sleep onset latency in a subsample of N = 359 men exposed to manipulations affecting sleep pressure. We sampled saliva or blood for polygenic risk score (PRS) determination. The PRS for ID was computed based on genome-wide common single nucleotide polymorphism assessments. Participants also completed a battery of behavioral and cognitive tests. The analyses revealed that the PRS for ID was negatively associated with cumulated EEG power in the delta (0.5-4 Hz) and theta (4-8 Hz) bands across rapid eye movement (REM) and non-REM sleep (p ≤ .0026; ß ≥ -0.13) controlling for age, sex and BMI. The PRS for ID was also negatively associated with daytime likelihood of falling asleep (ß = -0.19, p = .0009). Other explorations for associations with non-baseline-nights, cognitive measures, and mood did not yield significant results. These results propose that the need or the ability to fall asleep and to generate slow brain activity during sleep may constitute the core sleep-related risk factors for developing ID.

Exercise against cocaine sensitization in mice: a [18F]fallypride micro-PET study.

Wheel-running exercise in laboratory rodents (animal model useful to study the neurobiology of aerobic exercise) decreases behavioural markers of vulnerability to addictive properties of various drugs of abuse including cocaine. However, neurobiological mechanisms underpinning this protective effect are far from fully characterized. Here, 28-day-old female C57BL/6J mice were housed with (n = 48) or without (n = 48) a running wheel for 6 weeks before being tested for acute locomotor responsiveness and initiation of locomotor sensitization to intraperitoneal injections of 8 mg/kg cocaine. The long-term expression of sensitization took place 3 weeks after the last session. On the day after, all mice underwent a micro-PET imaging session with [18F]fallypride radiotracer (dopamine 2/3 receptors antagonist). Exercised mice were less sensitive to acute and sensitized cocaine hyperlocomotor effects, such attenuation being particularly well marked for long-term expression of sensitization (η 2 P = 0.262). Chronic administration of cocaine was associated with a clear-cut increase of [18F]fallypride binding potential in mouse striatum (η 2 P = 0.170) while wheel-running exercise was associated with a moderate decrease in dopamine 2/3 receptors density in striatum (η 2 P = 0.075), a mechanism that might contribute to protective properties of exercise against drugs of abuse vulnerability.

Monitoring of a progressive functional dopaminergic deficit in the A53T-AAV synuclein rats by combining 6-[18F]fluoro-L-m-tyrosine imaging and motor performances analysis.

With the emergence of disease-modifying therapies for Parkinson's disease, reliable longitudinal markers are needed to quantify pathology and demonstrate disease progression. We developed the A53T-AAV rat model of synucleinopathy by combining longitudinal measures over 12 weeks. We first characterized the progression of the motor and dopaminergic deficits. Then, we monitored the disease progression using the [18F]FMT Positron Emission Tomography (PET) radiotracer. The nigral injection of A53T-AAV led to an increase in phosphorylated α-synuclein on S129, a progressive accumulation of α-synuclein aggregates, and a decrease of dopaminergic function associated with a deterioration of motor activity. The longitudinal monitoring of A53T-AAV rats with [18F]FMT PET showed a progressive reduction of the Kc outcome parameter in the caudate putamen from the lesioned side. Interestingly, the progressive reduction in the [18F]FMT PET signal correlated with defects in the stepping test. In conclusion, we established a progressive rat model of α-synuclein pathology which monitors the deficit longitudinally using both the [18F]FMT PET tracer and behavioral parameters, 2 features that have strong relevance for translational approaches.

In vivo exploration of synaptic projections in frontotemporal dementia.

The purpose of this exploratory research is to provide data on synaptopathy in the behavioral variant of frontotemporal dementia (bvFTD). Twelve patients with probable bvFTD were compared to 12 control participants and 12 patients with Alzheimer's disease (AD). Loss of synaptic projections was assessed with [18F]UCBH-PET. Total distribution volume was obtained with Logan method using carotid artery derived input function. Neuroimages were analyzed with SPM12. Verbal fluency, episodic memory and awareness of cognitive impairment were equally impaired in patients groups. Compared to controls, [18F]UCBH uptake tended to decrease in the right anterior parahippocampal gyrus of bvFTD patients. Loss of synaptic projections was observed in the right hippocampus of AD participants, but there was no significant difference in [18F]UCBH brain uptake between patients groups. Anosognosia for clinical disorder was correlated with synaptic density in the caudate nucleus and the anteromedial prefrontal cortex. This study suggests that synaptopathy in bvFTD targets the temporal social brain and self-referential processes.

Associations Between Cognitive Complaints, Memory Performance, Mood, and Amyloid-ß Accumulation in Healthy Amyloid Negative Late-Midlife Individuals.

BACKGROUND: Cognitive complaints are gaining more attention as they may represent an early marker of increased risk for AD in individuals without objective decline at standard neuropsychological examination. OBJECTIVE: Our aim was to assess whether cognitive complaints in late middle-aged individuals not seeking medical help are related to objective cognitive outcomes known as early markers for AD risk, concomitant affective state, and amyloid-ß (Aß) burden. METHODS: Eighty-seven community-based cognitively normal individuals aged 50-69 years underwent neuropsychological assessment for global cognition, using Preclinical Alzheimer's Cognitive Composite 5 (PACC5) score, and a more specific episodic memory measure. Affective state was based on self-assessment questionnaires for depression and anxiety. Aß PET burden was assessed via [18F]Flutemetamol (N = 84) and [18F]Florbetapir (N = 3) uptake. Cognitive complaints were evaluated using Cognitive Difficulties Scale. RESULTS: Higher cognitive complaints were significantly associated with lower episodic memory performance and worse affective state. Moreover, higher level of cognitive complaints was related to higher (but still sub-clinical) global Aß accumulation (at uncorrected significance level). Importantly, all three aspects remained significant when taken together in the same statistical model, indicating that they explained distinct parts of variance. CONCLUSION: In healthy Aß negative late middle-aged individuals, a higher degree of cognitive complaints is associated with lower episodic memory efficiency, more anxiety and depression, as well as, potentially, with higher Aß burden, suggesting that complaints might signal subtle decline. Future studies should untangle how cognitive complaints in healthy aging populations are related to longitudinal changes in objective cognition and AD biomarker correlates.

Positive Effect of Cognitive Reserve on Episodic Memory, Executive and Attentional Functions Taking Into Account Amyloid-Beta, Tau, and Apolipoprotein E Status.

Studies exploring the simultaneous influence of several physiological and environmental factors on domain-specific cognition in late middle-age remain scarce. Therefore, our objective was to determine the respective contribution of modifiable risk/protective factors (cognitive reserve and allostatic load) on specific cognitive domains (episodic memory, executive functions, and attention), taking into account non-modifiable factors [sex, age, and genetic risk for Alzheimer's disease (AD)] and AD-related biomarker amount (amyloid-beta and tau/neuroinflammation) in a healthy late-middle-aged population. One hundred and one healthy participants (59.4 ± 5 years; 68 women) were evaluated for episodic memory, executive and attentional functioning via neuropsychological test battery. Cognitive reserve was determined by the National Adult Reading Test. The allostatic load consisted of measures of lipid metabolism and sympathetic nervous system functioning. The amyloid-beta level was assessed using positron emission tomography in all participants, whereas tau/neuroinflammation positron emission tomography scans and apolipoprotein E genotype were available for 58 participants. Higher cognitive reserve was the main correlate of better cognitive performance across all domains. Moreover, age was negatively associated with attentional functioning, whereas sex was a significant predictor for episodic memory, with women having better performance than men. Finally, our results did not show clear significant associations between performance over any cognitive domain and apolipoprotein E genotype and AD biomarkers. This suggests that domain-specific cognition in late healthy midlife is mainly determined by a combination of modifiable (cognitive reserve) and non-modifiable factors (sex and age) rather than by AD biomarkers and genetic risk for AD.

The pharmacokinetics of [18F]UCB-H revisited in the healthy non-human primate brain.

BACKGROUND: Positron Emission Tomography (PET) imaging of the Synaptic Vesicle glycoprotein (SV) 2A is a new tool to quantify synaptic density. [18F]UCB-H was one of the first promising SV2A-ligands to be labelled and used in vivo in rodent and human, while limited information on its pharmacokinetic properties is available in the non-human primate. Here, we evaluate the reliability of the three most commonly used modelling approaches for [18F]UCB-H in the non-human cynomolgus primate, adding the coupled fit of the non-displaceable distribution volume (VND) as an alternative approach to improve unstable fit. The results are discussed in the light of the current state of SV2A PET ligands. RESULTS: [18F]UCB-H pharmacokinetic data was optimally fitted with a two-compartment model (2TCM), although the model did not always converge (large total volume of distribution (VT) or large uncertainty of the estimate). 2TCM with coupled fit K1/k2 across brain regions stabilized the quantification, and confirmed a lower specific signal of [18F]UCB-H compared to the newest SV2A-ligands. However, the measures of VND and the influx parameter (K1) are similar to what has been reported for other SV2A ligands. These data were reinforced by displacement studies using [19F]UCB-H, demonstrating only 50% displacement of the total [18F]UCB-H signal at maximal occupancy of SV2A. As previously demonstrated in clinical studies, the graphical method of Logan provided a more robust estimate of VT with only a small bias compared to 2TCM. CONCLUSIONS: Modeling issues with a 2TCM due to a slow component have previously been reported for other SV2A ligands with low specific binding, or after blocking of specific binding. As all SV2A ligands share chemical structural similarities, we hypothesize that this slow binding component is common for all SV2A ligands, but only hampers quantification when specific binding is low.

Early brainstem [18F]THK5351 uptake is linked to cortical hyperexcitability in healthy aging.

BACKGROUNDNeuronal hyperexcitability characterizes the early stages of Alzheimer's disease (AD). In animals, early misfolded tau and amyloid-ß (Aß) protein accumulation - both central to AD neuropathology - promote cortical excitability and neuronal network dysfunction. In healthy humans, misfolded tau and Aß aggregates are first detected, respectively, in the brainstem and frontomedial and temporobasal cortices, decades prior to the onset of AD cognitive symptoms. Whether cortical excitability is related to early brainstem tau - and its associated neuroinflammation - and cortical Aß aggregations remains unknown.METHODSWe probed frontal cortex excitability, using transcranial magnetic stimulation combined with electroencephalography, in a sample of 64 healthy late-middle-aged individuals (50-69 years; 45 women and 19 men). We assessed whole-brain [18F]THK5351 PET uptake as a proxy measure of tau/neuroinflammation, and we assessed whole-brain Aß burden with [18F]Flutemetamol or [18F]Florbetapir radiotracers.RESULTSWe found that higher [18F]THK5351 uptake in a brainstem monoaminergic compartment was associated with increased cortical excitability (r = 0.29, P = 0.02). By contrast, [18F]THK5351 PET signal in the hippocampal formation, although strongly correlated with brainstem signal in whole-brain voxel-based quantification analyses (P value corrected for family-wise error [PFWE-corrected] < 0.001), was not significantly associated with cortical excitability (r = 0.14, P = 0.25). Importantly, no significant association was found between early Aß cortical deposits and cortical excitability (r = -0.20, P = 0.11).CONCLUSIONThese findings reveal potential brain substrates for increased cortical excitability in preclinical AD and may constitute functional in vivo correlates of early brainstem tau accumulation and neuroinflammation in humans.TRIAL REGISTRATIONEudraCT 2016-001436-35.FUNDINGF.R.S.-FNRS Belgium, Wallonie-Bruxelles International, ULiège, Fondation Simone et Pierre Clerdent, European Regional Development Fund.

Alzheimer's disease genetic risk and sleep phenotypes in healthy young men: association with more slow waves and daytime sleepiness.

STUDY OBJECTIVES: Sleep disturbances and genetic variants have been identified as risk factors for Alzheimer's disease (AD). Our goal was to assess whether genome-wide polygenic risk scores (PRS) for AD associate with sleep phenotypes in young adults, decades before typical AD symptom onset. METHODS: We computed whole-genome PRS for AD and extensively phenotyped sleep under different sleep conditions, including baseline sleep, recovery sleep following sleep deprivation, and extended sleep opportunity, in a carefully selected homogenous sample of 363 healthy young men (22.1 years ± 2.7) devoid of sleep and cognitive disorders. RESULTS: AD PRS was associated with more slow-wave energy, that is, the cumulated power in the 0.5-4 Hz EEG band, a marker of sleep need, during habitual sleep and following sleep loss, and potentially with larger slow-wave sleep rebound following sleep deprivation. Furthermore, higher AD PRS was correlated with higher habitual daytime sleepiness. CONCLUSIONS: These results imply that sleep features may be associated with AD liability in young adults, when current AD biomarkers are typically negative, and support the notion that quantifying sleep alterations may be useful in assessing the risk for developing AD.

Exploring with [18F]UCB-H the in vivo Variations in SV2A Expression through the Kainic Acid Rat Model of Temporal Lobe Epilepsy.

PURPOSE: The main purpose of this study was to understand how the positron emission tomography (PET) measure of the synaptic vesicle 2A (SV2A) protein varies in vivo during the development of temporal lobe epilepsy (TLE) in the kainic acid rat model. PROCEDURES: Twenty Sprague Dawley male rats were administered with multiple systemic doses of saline (control group, n = 5) or kainic acid (5 mg/kg/injection, epileptic group, n = 15). Both groups were scanned at the four phases of TLE (early, latent, transition, and chronic phase) with the [18F]UCB-H PET radiotracer and T2-structural magnetic resonance imaging. At the end of the scans (3 months post-status epilepticus), rats were monitored for 7 days with electroencephalography for the detection of spontaneous electrographic seizures. Finally, the immunofluorescence staining for SV2A expression was performed. RESULTS: Control rats presented a significant increase in [18F]UCB-H binding at the last two scans, compared with the first ones (p < 0.001). This increase existed but was lower in epileptic animals, producing significant group differences in all the phases of the disease (p < 0.028). Furthermore, the quantification of the SV2A expression in vivo with the [18F]UCB-H radiotracer or ex vivo with immunofluorescence led to equivalent results, with a positive correlation between both. CONCLUSIONS: Even if further studies in humans are required, the ability to detect a progressive decrease in SV2A expression during the development of temporal lobe epilepsy supports the use of [18F]UCB-H as a useful tool to differentiate, in vivo, between healthy and epileptic animals along with the development of the epileptic disease.

Radiolabelling of lipid-based nanocarriers with fluorine-18 for in vivo tracking by PET.

Organic nanoparticles made out of biodegradable and biocompatible materials have attracted increased attention in the therapeutic and diagnostic fields. In this study, we attempted to explore a new radiolabelling chelating free strategy for biodegradable sphingomyelin nanometric emulsions with fluorine-18 (18F), a radioisotope regularly used in clinic. [18F]fluoride was produced by the cyclotron and was incorporated into 4-[18F]fluorobenzamido-N-ethylmaleimide ([18F]FBEM), which was coupled next to the emulsions previously functionalized with a thiol group, via inclusion of either a thiol-PEG-lipid (SH-PEG12-C18), or a peptide-PEG-lipid (Cys-Pro-Ile-Glu-Asp-Arg-Pro-Met-Cys-PEG8-C18) derivative. Radiolabelled emulsions were obtained in a rapid and efficient fashion through facile-conjugated chemistry without the use of organic solvents, and characterized in terms of size, polydispersity, surface charge, pH, and osmolarity. PET imaging and biodistribution studies in BALB/c mice allowed obtaining the pharmacokinetics of the radiolabelled emulsions and determining the clearance pathways. Altogether, we confirmed the potential of this new technique for the radiolabelling of lipid-based drug nanosystems for application in PET imaging diagnosis.

In vivo imaging of synaptic loss in Alzheimer's disease with [18F]UCB-H positron emission tomography.

PURPOSE: Loss of brain synapses is an early pathological feature of Alzheimer's disease. The current study assessed synaptic loss in vivo with positron emission tomography and an 18F-labelled radiotracer of the synaptic vesicle protein 2A, [18F]UCB-H. METHODS: Twenty-four patients with mild cognitive impairment or Alzheimer's disease and positive [18F]Flutemetamol amyloid-PET were compared to 19 healthy controls. [18F]UCB-H brain uptake was quantified with Logan graphical analysis using an image-derived blood input function. SPM12 and regions-of-interest (ROI) analyses were used for group comparisons of regional brain distribution volumes and for correlation with cognitive measures. RESULTS: A significant decrease of [18F]UCB-H uptake was observed in several cortical areas (11 to 18% difference) and in the thalamus (16% difference), with the largest effect size in the hippocampus (31% difference). Reduced hippocampal uptake was related to patients' cognitive decline (ROI analysis) and unawareness of memory problems (SPM and ROI analyses). CONCLUSIONS: The findings thus highlight predominant synaptic loss in the hippocampus, confirming previous autopsy-based studies and a recent PET study with an 11C-labelled SV2A radiotracer. [18F]UCB-H PET allows to image in vivo synaptic changes in Alzheimer's disease and to relate them to patients' cognitive impairment.

Preserved wake-dependent cortical excitability dynamics predict cognitive fitness beyond age-related brain alterations.

Age-related cognitive decline arises from alterations in brain structure as well as in sleep-wake regulation. Here, we investigated whether preserved wake-dependent regulation of cortical function could represent a positive factor for cognitive fitness in aging. We quantified cortical excitability dynamics during prolonged wakefulness as a sensitive marker of age-related alteration in sleep-wake regulation in 60 healthy older individuals (50-69 y; 42 women). Brain structural integrity was assessed with amyloid-beta- and tau-PET, and with MRI. Participants' cognition was investigated using an extensive neuropsychological task battery. We show that individuals with preserved wake-dependent cortical excitability dynamics exhibit better cognitive performance, particularly in the executive domain which is essential to successful cognitive aging. Critically, this association remained significant after accounting for brain structural integrity measures. Preserved dynamics of basic brain function during wakefulness could therefore be essential to cognitive fitness in aging, independently from age-related brain structural modifications that can ultimately lead to dementia.

Progress in Difluoroalkylation of Organic Substrates by Visible Light Photoredox Catalysis.

The selective incorporation of fluorinated motifs, in particular CF2FG (FG=a functional group) and CF2H groups, into organic compounds has attrracted increasing attention since organofluorine molecules are of the utmost importance in the areas of nuclear imaging, pharmaceutical, agrochemical, and material sciences. A variety of synthetic approaches has been employed in late-stage difluoroalkylation reactions. Visible light photoredox catalysis for the production of CF2FG and CF2H radicals has provided a more sustainable alternative to other conventional radical-triggered reactions from the viewpoint of safety, cost, availability, and "green" chemistry. A wide range of difluoroalkylating reagents has been successfully implemented in these organic transformations in the presence of transition metal complexes or organic photocatalysts. In most cases, upon excitation via visible light irradiation with fluorescent light bulbs or blue light-emitting diode (LED) lamps, these photocatalysts can act as both reductive and oxidative quenchers, thus enabling the application of electron-donor or electron-acceptor difluoroalkylating reagents for the generation of CF2FG and CF2H radicals. Subsequent radical addition to substrates and additional organic transformations afford the corresponding difluoroalkylated derivatives. The present review describes the distinct strategies for the transition metal- and organic-photocatalyzed difluoroalkylation of a broad range of organic substrates by visible light irradiation reported in the literature since 2014.

Cognitive efficiency in late midlife is linked to lifestyle characteristics and allostatic load.

We investigated whether cognitive fitness in late midlife is associated with physiological and psychological factors linked to increased risk of age-related cognitive decline. Eighty-one healthy late middle-aged participants (mean age: 59.4 y; range: 50-69 y) were included. Cognitive fitness consisted of a composite score known to be sensitive to early subtle cognitive change. Lifestyle factors (referenced below as cognitive reserve factors; CRF) and affective state were determined through questionnaires, and sleep-wake quality was also assessed through actimetry. Allostatic load (AL) was determined through a large range of objective health measures. Generalized linear mixed models, controlling for sex and age, revealed that higher cognitive reserve and lower allostatic load are related to better cognitive efficiency. Crystallized intelligence, sympathetic nervous system functioning and lipid metabolism were the only sub-fields of CRF and AL to be significantly associated with cognition. These results show that previous lifestyle characteristics and current physiological status are simultaneously explaining variability in cognitive abilities in late midlife. Results further encourage early multimodal prevention programs acting on both of these modifiable factors to preserve cognition during the aging process.