A Comparative Study of Functional Connectivity Measures for Brain Network Analysis in the Context of AD Detection with EEG.

This work addresses brain network analysis considering different clinical severity stages of cognitive dysfunction, based on resting-state electroencephalography (EEG). We use a cohort acquired in real-life clinical conditions, which contains EEG data of subjective cognitive impairment (SCI) patients, mild cognitive impairment (MCI) patients, and Alzheimer's disease (AD) patients. We propose to exploit an epoch-based entropy measure to quantify the connectivity links in the networks. This entropy measure relies on a refined statistical modeling of EEG signals with Hidden Markov Models, which allow a better estimation of the spatiotemporal characteristics of EEG signals. We also propose to conduct a comparative study by considering three other measures largely used in the literature: phase lag index, coherence, and mutual information. We calculated such measures at different frequency bands and computed different local graph parameters considering different proportional threshold values for a binary network analysis. After applying a feature selection procedure to determine the most relevant features for classification performance with a linear Support Vector Machine algorithm, our study demonstrates the effectiveness of the statistical entropy measure for analyzing the brain network in patients with different stages of cognitive dysfunction.

Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities.

The N-acyl chain length of ceramides is determined by the specificity of different ceramide synthases (CerS). The CerS family in mammals consists of six members with different substrate specificities and expression patterns. We have generated and characterized a mouse line harboring an enzymatically inactive ceramide synthase 6 (CerS6KO) gene and lacz reporter cDNA coding for ß-galactosidase directed by the CerS6 promoter. These mice display a decrease in C16:0 containing sphingolipids. Relative to wild type tissues the amount of C16:0 containing sphingomyelin in kidney is ∼35%, whereas we find a reduction of C16:0 ceramide content in the small intestine to about 25%. The CerS6KO mice show behavioral abnormalities including a clasping abnormality of their hind limbs and a habituation deficit. LacZ reporter expression in the brain reveals CerS6 expression in hippocampus, cortex, and the Purkinje cell layer of the cerebellum. Using newly developed antibodies that specifically recognize the CerS6 protein we show that the endogenous CerS6 protein is N-glycosylated and expressed in several tissues of mice, mainly kidney, small and large intestine, and brain.

Microglial glucocorticoid receptors play a pivotal role in regulating dopaminergic neurodegeneration in parkinsonism.

Among the pathogenic processes contributing to dopaminergic neuron (DN) death in Parkinson disease (PD), evidence points to non-cell-autonomous mechanisms, particularly chronic inflammation mounted by activated microglia. Yet little is known about endogenous regulatory processes that determine microglial actions in pathological states. We examined the role of glucocorticoid receptors (GRs), activated by glucocorticoids released in response to stress and known to regulate inflammation, in DN survival. Overall GR level was decreased in substantia nigra of PD patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice. GR changes, specifically in the microglia after MPTP treatment, revealed a rapid augmentation in the number of microglia displaying nuclear localization of GR. Mice with selective inactivation of the GR gene in macrophages/microglia (GR(LysMCre)) but not in DNs (GR(DATCre)) showed increased loss of DNs after MPTP intoxication. This DN loss in GR(LysMCre) mice was not prevented by corticosterone treatment, in contrast to the protection observed in control littermates. Moreover, absence of microglial GRs augmented microglial reactivity and led to their persistent activation. Analysis of inflammatory genes revealed an up-regulation of Toll-like receptors (TLRs) by MPTP treatment, particularly TLR9, the level of which was high in postmortem parkinsonian brains. The regulatory control of GR was reflected by higher expression of proinflammatory genes (e.g., TNF-α) with a concomitant decrease in anti-inflammatory genes (e.g., IL-1R2) in GR(LysMCre) mice. Indeed, in GR(LysMCre) mice, alterations in phosphorylated NF-κB levels indicated its protracted activation. Together, our data indicate that GR is important in curtailing microglial reactivity, and its deregulation in PD could lead to sustained inflammation-mediated DN injury.

Kallikrein-related peptidase's significance in Alzheimer's disease pathogenesis: A comprehensive survey.

Alzheimer's disease (AD) and related dementias constitute an important global health challenge. Detailed understanding of the multiple molecular mechanisms underlying their pathogenesis constitutes a clue for the management of the disease. Kallikrein-related peptidases (KLKs), a lead family of serine proteases, have emerged as potential biomarkers and therapeutic targets in the context of AD and associated cognitive decline. Hence, KLKs were proposed to display multifaceted impacts influencing various aspects of neurodegeneration, including amyloid-beta aggregation, tau pathology, neuroinflammation, and synaptic dysfunction. We propose here a comprehensive survey to summarize recent findings, providing an overview of the main kallikreins implicated in AD pathophysiology namely KLK8, KLK6 and KLK7. We explore the interplay between KLKs and key AD molecular pathways, shedding light on their significance as potential biomarkers for early disease detection. We also discuss their pertinence as therapeutic targets for disease-modifying interventions to develop innovative therapeutic strategies aimed at halting or ameliorating the progression of AD and associated dementias.

MFGE8 does not orchestrate clearance of apoptotic neurons in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by a loss of dopaminergic neurons (DN) in the substantia nigra (SN). Several lines of evidence suggest that apoptotic cell death of DN is driven in part by non-cell autonomous mechanisms implicating microglial cells and inflammatory processes. Yet, how apoptotic DNs get removed by professional phagocytes and how this process modulates inflammatory processes are still unresolved issues. In this study, we investigated the role of MFGE8, a soluble factor involved in phagocytic recognition, in apoptotic DN clearance and neuroinflammation in PD. We report that glial expression of MFGE8 is enhanced in post-mortem PD brains compared to control individuals. Then, in vivo functional analysis of Mfge8 was assessed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD using wild-type (WT) and Mfge8-deficient mice. Neuropathological analysis consisted in evaluating (i) the loss of nigral DN and striatal DN terminals, (ii) the extent of glial cell activation and (iii) the number of apoptotic profiles. In vivo microglial phagocytic activity was further assessed by measuring the engulfment of apoptotic DN preloaded with fluorescent latex beads. Here we show that Mfge8 deficiency neither impact the phagocytic clearance of apoptotic bodies nor change the overall neuropathological parameters (DN cell loss and glial cell activation). In summary, our data argue that MFGE8 is not likely involved in the phagocytic clearance of neuronal debris associated with nigrostriatal pathway injury.

DAP12 and CD11b contribute to the microglial-induced death of dopaminergic neurons in vitro but not in vivo in the MPTP mouse model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons (DN) in the substantia nigra (SN). Several lines of evidence suggest that apoptotic cell death of DN is driven in part by non-cell autonomous mechanisms orchestrated by microglial cell-mediated inflammatory processes. Although the mechanisms and molecular network underlying this deleterious cross-talk between DN and microglial cells remain largely unknown, previous work indicates that, upon DN injury, activation of the ß2 integrin subunit CD11b is required for microglia-mediated DN cell death. Interestingly, during brain development, the CD11b integrin is also involved in microglial induction of neuronal apoptosis and has been shown to act in concert with the DAP12 immunoreceptor. Whether such a developmental CD11b/DAP12 pathway could be reactivated in a pathological context such as PD and play a role in microglia-induced DN cell death is a tantalizing hypothesis that we wished to test in this study. METHODS: To test the possibility that DAP12 could be involved in microglia-associated DN injury, we used both in vitro and in vivo toxin-based experimental models of PD recapitulating microglial-mediated non-cell autonomous mechanisms of DN cell death. In vitro, enriched mesencephalic neuronal/microglial co-cultures were exposed to the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) whereas in vivo, mice were administrated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) according to acute or subchronic mode. Mice deficient for DAP12 or CD11b were used to determine the pathological function of the CD11b/DAP12 pathway in our disease models. RESULTS: Our results show that DAP12 and CD11b partially contribute to microglia-induced DN cell death in vitro. Yet, in vivo, mice deficient for either of these factors develop similar neuropathological alterations as their wild-type counterparts in two different MPTP mouse models of PD. CONCLUSION: Overall, our data suggest that DAP12 and CD11b contribute to microglial-induced DN cell death in vitro but not in vivo in the MPTP mouse model of PD. Therefore, the CD11b/DAP12 pathway may not be considered as a promising therapeutic target for PD.

High-density Surface Electromyography as Biomarker of Muscle Aging.

Sarcopenia is a muscle disease with adverse changes that increase throughout the lifetime but with different chronological scales between individuals. Addressing "early muscle aging" is becoming a critical issue for prevention. Through the CHRONOS study, we demonstrated the ability of the high-density surface electromyography (HD-sEMG), a noninvasive, wireless, portable technology, to detect both healthy muscle aging and accelerated muscle aging related to a sedentary lifestyle, one of the risk factors of sarcopenia. The HD-sEMG signals were analyzed in 91 healthy young, middle-aged, and old subjects (25-75 years) distributed according to their physical activity status (82 active and 9 sedentary; International Physical Activity Questionnaire) and compared with current methods for muscle evaluation, including muscle mass (dual-energy X-ray absorptiometry [DXA], ultrasonography), handgrip strength, and physical performance. The HD-sEMG signals were recorded from the rectus femoris during sit-to-stand trials, and 2 indexes were analyzed: muscular contraction intensity and muscle contraction dynamics. The clinical parameters did not differ significantly across the aging and physical activity levels. Inversely, the HD-sEMG indexes were correlated to age and were different significantly through the age categories of the 82 active subjects. They were significantly different between sedentary subjects aged 45-54 years and active ones at the same age. The HD-sEMG indexes of sedentary subjects were not significantly different from those of older active subjects (≥55 years). The muscle thicknesses evaluated using ultrasonography were significantly different between the 5 age decades but did not show a significant difference with physical activity. The HD-sEMG technique can assess muscle aging and physical inactivity-related "early aging," outperforming clinical and DXA parameters.

Weighted Brain Network Analysis on Different Stages of Clinical Cognitive Decline.

This study addresses brain network analysis over different clinical severity stages of cognitive dysfunction using electroencephalography (EEG). We exploit EEG data of subjective cognitive impairment (SCI) patients, mild cognitive impairment (MCI) patients and Alzheimer's disease (AD) patients. We propose a new framework to study the topological networks with a spatiotemporal entropy measure for estimating the connectivity. Our results show that functional connectivity and graph analysis are frequency-band dependent, and alterations start at the MCI stage. In delta, the SCI group exhibited a decrease of clustering coefficient and an increase of path length compared to MCI and AD. In alpha, the opposite behavior appeared, suggesting a rapid and high efficiency in information transmission across the SCI network. Modularity analysis showed that electrodes of the same brain region were distributed over several modules, and some obtained modules in SCI were extended from anterior to posterior regions. These results demonstrate that the SCI network was more resilient to neuronal damage compared to that of MCI and even more compared to that of AD. Finally, we confirm that MCI is a transitional stage between SCI and AD, with a predominance of high-strength intrinsic connectivity, which may reflect the compensatory response to the neuronal damage occurring early in the disease process.

Older patients with COVID-19 and neuropsychiatric conditions: A study of risk factors for mortality.

BACKGROUND: Little is known about risk factors for mortality in older patients with COVID-19 and neuropsychiatric conditions. METHODS: We conducted a multicentric retrospective observational study at Assistance Publique-Hôpitaux de Paris. We selected inpatients aged 70 years or older, with COVID-19 and preexisting neuropsychiatric comorbidities and/or new neuropsychiatric manifestations. We examined demographics, comorbidities, functional status, and presentation including neuropsychiatric symptoms and disorders, as well as paraclinical data. Cox survival analysis was conducted to determine risk factors for mortality at 40 days after the first symptoms of COVID-19. RESULTS: Out of 191 patients included (median age 80 [interquartile range 74-87]), 135 (71%) had neuropsychiatric comorbidities including cognitive impairment (39%), cerebrovascular disease (22%), Parkinsonism (6%), and brain tumors (6%). A total of 152 (79%) patients presented new-onset neuropsychiatric manifestations including sensory symptoms (6%), motor deficit (11%), behavioral (18%) and cognitive (23%) disturbances, gait impairment (11%), and impaired consciousness (18%). The mortality rate at 40 days was 19.4%. A history of brain tumor or Parkinsonism or the occurrence of impaired consciousness were neurological factors associated with a higher risk of mortality. A lower Activities of Daily Living score (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.58-0.82), a neutrophil-to-lymphocyte ratio ≥ 9.9 (HR 5.69, 95% CI 2.69-12.0), and thrombocytopenia (HR 5.70, 95% CI 2.75-11.8) independently increased the risk of mortality (all p < .001). CONCLUSION: Understanding mortality risk factors in older inpatients with COVID-19 and neuropsychiatric conditions may be helpful to neurologists and geriatricians who manage these patients in clinical practice.

[Sleep apnea and cognitive impairment: Myth or reality?] / Apnées du sommeil et troubles cognitifs : Mythe ou réalité ?

A growing number of studies in animal models have highlighted the link between sleep disorders and Alzheimer's disease (AD). In the absence of curative treatment, it is therefore important to consider any comorbidities that may influence the course of AD such as Obstructive sleep apnea-hyponea (OSAH) and its syndrome (OSAHS), which appear to be potentially interesting because it is frequent, treatable and often associated with cognitive impairment. The association between OSAH/OSAHS and cognition is variable across studies, but OSAH/OSAHS is more common in older patients with AD than in cognitively normal individuals. OSAH/OSAHS is often associated with the subsequent development of mild cognitive impairment and AD. Although there is no evidence that treatment of OSAH/OSAHS in AD would have a major impact on the course of the disease, treatment would appear to improve cognition in AD patients with OSAH/OSAHS. Finally, the literature suggests a link between OSAH/OSAHS and AD biomarkers. Together, these data highlight the importance of detecting and treating OSAHS in this population.

Sleep apnoea and cognitive impairment: myth or reality?

A growing number of studies in animal models have highlighted the link between sleep disorders and Alzheimer's disease (AD). In the absence of curative treatment, it is therefore important to consider any comorbidities that may influence the course of AD such as obstructive sleep apnoea-hypnoea (OSAH) and its syndrome (OSAHS), which appear to be potentially interesting because it occurs frequently, it is treatable and it is often associated with cognitive impairment. The association between OSAH/OSAHS and cognition is variable across studies, but OSAH/OSAHS is more common in older patients with AD than in cognitively normal individuals. OSAH/OSAHS is often associated with the subsequent development of mild cognitive impairment and AD. Although there is no evidence that treatment of OSAH/OSAHS in AD would have a major impact on the course of the disease, treatment would appear to improve cognition in AD patients with OSAH/OSAHS. Finally, the literature suggests a link between OSAH/OSAHS and AD biomarkers. Taken together, these data highlight the importance of detecting and treating OSAHS in this population.

Clinical characteristics of sleep apnea in middle-old and oldest-old inpatients: symptoms and comorbidities.

BACKGROUND: Obstructive sleep apnea (OSA) is prevalent in older adults but still underdiagnosed for many reasons, such as underreported symptoms, non-specific ones because of the comorbidities and polypharmacy, or the social belief of sleep problems as normal with aging. OBJECTIVES: To identify salient symptoms and comorbidities associated with OSA, diagnosed by nocturnal respiratory polygraphy in geriatric inpatients. METHOD: We conducted a retrospective, cross-sectional study in a sample of 102 geriatric inpatients from a French Geriatric University Hospital. We reviewed medical records to collect demographic, medical information including comorbidities, the geriatric cumulative illness rating scale (CIRS-G), subjective sleep-related symptoms and data of overnight level three portable sleep polygraphy recording. RESULTS: Among classic OSA symptoms, only excessive daytime sleepiness (p = 0.02) and nocturnal choking (p = 0.03) were more prevalent in older inpatients with OSA (n = 64) than in those without (n = 38). The prevalence of comorbidities and mean CIRS-G scores were not different between groups except for the lower prevalence of chronic obstructive pulmonary disease and the higher level of creatinine clearance in OSA patients. Multivariate analysis showed OSA was associated with excessive daytime sleepiness (OR = 2.83, p = 0.02) in symptoms-related model and with composite CIRS-G score (OR 1.26, p = 0.04) in comorbidities-related model. CONCLUSIONS: Only excessive daytime sleepiness and comorbidity severity (composite CIRS-G score) were associated with the objective diagnosis of OSA, while other usual clinical OSA symptoms and comorbidities in geriatric inpatients were not. These findings emphasize the importance of excessive daytime sleepiness symptom, when reported in comorbid older patients, strongly suggesting OSA and requiring adequate nocturnal exploration.

Standardization of the psychometric hepatic encephalopathy score in a French population.

The Psychometric Hepatic Encephalopathy Score (PHES) has previously been standardized in thirteen countries on three continents, confirming its status of gold standard test to detect minimal hepatic encephalopathy (MHE). In the meantime, performance has also been shown to vary with variables such as age, education, and barely sex. The present study aimed at standardizing the PHES in a French population. One hundred and ninety-six French healthy participants completed a French version of the paper-and-pencil PHES, involving five tests and six measures. Importantly, the balance was perfect between all levels of the three controlled factors, which were sex, age (seven decade-levels from 20-29 to 80-89 years), and education (two levels below or above 12 years of education). Raw measures were transformed to fit the normal distribution. ANOVAs on transformed variables showed no effect of sex, but an effect of age on all measures, and of education on five measures. Multiple or simple regressions were completed to build up normograms. Thorough analysis of variability within each test failed to find outliers that may bias the results. Comparison between French and seminal German data showed that they highly fitted though cultural and cognitive style specificities could be observed. This is the first study to standardize the PHES in a French population and to extensively explore the effects of sex, age and education using perfectly balanced samples. Subtle differences between countries of the same continent emphasize the need to build up normative data in each country to get accurate PHES in patients.

Myoclonus-dystonia: an update.

Our knowledge of the clinical, neurophysiological, and genetic aspects of myoclonus-dystonia (M-D) has improved markedly in the recent years. Basic research has provided new insights into the complex dysfunctions involved in the pathogenesis of M-D. On the basis of a comprehensive literature search, this review summarizes current knowledge on M-D, with a focus on recent findings. We also propose modified diagnostic criteria and recommendations for clinical management.

Defective mer receptor tyrosine kinase signaling in bone marrow cells promotes apoptotic cell accumulation and accelerates atherosclerosis.

OBJECTIVE: To study the role of Mer receptor tyrosine kinase (mertk) in atherosclerosis. METHODS AND RESULTS: We irradiated and reconstituted atherosclerosis-susceptible C57Bl/6 low-density lipoprotein receptor-deficient female mice (ldlr(-/-)) with either a mertk(+/+) or mertk(-/-) (tyrosine kinase-defective mertk) bone marrow. The mice were put on high-fat diet for either 8 or 15 weeks. Mertk deficiency led to increased accumulation of apoptotic cells within the lesions, promoted a proinflammatory immune response, and accelerated lesion development. CONCLUSIONS: Mertk expression by bone marrow-derived cells is required for the disposal of apoptotic cells and controls lesion development and inflammation.

Optimized scoring tool to quantify the functional performance during the sit-to-stand transition with a magneto-inertial measurement unit.

BACKGROUND: Sit-to-stand is used as a qualitative test to evaluate functional performance, especially to detect fall risks and frail individuals. The use of various quantitative criteria would enable a better understanding of musculoskeletal deficits and movement strategy modifications. This quantification was proven possible with a magneto-inertial unit which provides a compatible wearable device for clinical routine motion analysis. METHODS: Sit-to-stand movements were recorded using a single magneto-inertial measurement unit fixed on the chest for 74 subjects in three groups healthy young, healthy senior and frail. MIMU data was used to compute 15 spatiotemporal, kinematic and energetic parameters. Nonparametric statistical test showed a significant influence of age and frailness. After reducing the number of parameters by a principal component analysis, an AgingScore and a FrailtyScore were computed. FINDINGS: The fraction of variance explained by the first principal component was 77.48 ±â€¯2.80% for principal component analysis with healthy young and healthy senior groups, and 74.94 ±â€¯2.24% with healthy and frail senior groups. By receiver operating characteristic curve analysis of this score, we were able to refine the analysis to differentiate between healthy young and healthy senior subjects as well as healthy senior and frail subjects. By radar plot of the most discriminate parameters, the motion's strategy could be characterized and be used to detect premature functional deficit or frail subjects. INTERPRETATION: Sit-to-stand measured by a single magneto-inertial unit and dedicated post processing is able to quantify subject's musculoskeletal performance and will allow longitudinal investigation of aging population.

Lactadherin deficiency leads to apoptotic cell accumulation and accelerated atherosclerosis in mice.

BACKGROUND: Atherosclerosis is an immunoinflammatory disease; however, the key factors responsible for the maintenance of immune regulation in a proinflammatory milieu are poorly understood. METHODS AND RESULTS: Here, we show that milk fat globule-EGF factor 8 (Mfge8, also known as lactadherin) is expressed in normal and atherosclerotic human arteries and is involved in phagocytic clearance of apoptotic cells by peritoneal macrophages. Disruption of bone marrow-derived Mfge8 in a murine model of atherosclerosis leads to substantial accumulation of apoptotic debris both systemically and within the developing lipid lesions. The accumulation of apoptotic material is associated with a reduction in interleukin-10 in the spleen but an increase in interferon-gamma production in both the spleen and the atherosclerotic arteries. In addition, we report a dendritic cell-dependent alteration of natural regulatory T-cell function in the absence of Mfge8. These events are associated with a marked acceleration of atherosclerosis. CONCLUSIONS: Lack of Mfge8 in bone marrow-derived cells enhances the accumulation of apoptotic cell corpses in atherosclerosis and alters the protective immune response, which leads to an acceleration of plaque development.

Spectrum of movement disorders associated with glutaric aciduria type 1: a study of 16 patients.

Glutaric aciduria type 1 (GA1) is an autosomal recessive neurometabolic disorder due to glutaryl CoA dehydrogenase deficiency. Comprehensive descriptions of GA1-associated movement disorders are rare. In order to refine the description of the motor phenotype, we prospectively studied 16 consecutive pediatric and adult GA1 patients, focusing on the movement disorders and their time course. In most patients, generalized dystonia, superimposed on baseline axial hypotonia, remained the predominant feature throughout the disease course. With aging, it tended to evolve from mobile to fixed dystonia and to be associated with akinetic-rigid parkinsonism. Prominent orofacial involvement was a consistent feature in GA1 patients with movement disorders, resulting in speech disorders with features of combined hyperkinetic dysarthria and speech apraxia. The types and outcome of movement disorders in this setting should be taken into consideration during rehabilitation and for patient selection and evaluation in therapeutic trials.

Diagnosis of Alzheimer's disease with Electroencephalography in a differential framework.

This study addresses the problem of Alzheimer's disease (AD) diagnosis with Electroencephalography (EEG). The use of EEG as a tool for AD diagnosis has been widely studied by comparing EEG signals of AD patients only to those of healthy subjects. By contrast, we perform automated EEG diagnosis in a differential diagnosis context using a new database, acquired in clinical conditions, which contains EEG data of 169 patients: subjective cognitive impairment (SCI) patients, mild cognitive impairment (MCI) patients, possible Alzheimer's disease (AD) patients, and patients with other pathologies. We show that two EEG features, namely epoch-based entropy (a measure of signal complexity) and bump modeling (a measure of synchrony) are sufficient for efficient discrimination between these groups. We studied the performance of our methodology for the automatic discrimination of possible AD patients from SCI patients and from patients with MCI or other pathologies. A classification accuracy of 91.6% (specificity = 100%, sensitivity = 87.8%) was obtained when discriminating SCI patients from possible AD patients and 81.8% to 88.8% accuracy was obtained for the 3-class classification of SCI, possible AD and other patients.