Early rise of glutamate-glutamine levels in mild cognitive impairment: Evidence for emerging excitotoxicity.

BACKGROUND: Use proton magnetic resonance spectroscopy (1H-MRS) non invasive technique to assess the modifications of glutamate-glutamine (Glx) and gammaaminobutyric acid (GABA) brain levels in patients reporting a cognitive complain METHODS: Posterior cingular cortex 1H-MRS spectra of 46 patients (19 male, 27 female) aged 57 to 87 years (mean : 73.32 ± 7.33 years) with a cognitive complaint were examined with a MEGA PRESS sequence at 3T, and compounds Glutamateglutamine (Glx), GABA, Creatine (Cr) and NAA were measured. From this data the metabolite ratios Glx/Cr, GABA/Cr and NAA/Cr were calculated. In addition, all patient performed the Mini Mental State Evaluation (MMSE) and 2 groups were realized with the clinical threshold of 24. RESULTS: 16 patients with MMSE 〈 24 and 30 patients with MMSE 〉 24. Significant increase of Glx/Cr in PCC of patients with MMSE 〈 24 compared to patients with MMSE 〉 24. Moreover, GABA/Cr ratio exhibited a trend for a decrease in PCC between the two groups, while they showed a significant decrease NAA/Cr ratio. CONCLUSION: Our results concerning Glx are in agreement with a physiopathological hypothesis involving a biphasic variation of glutamate levels associated with excitotoxicity, correlated with the clinical evolution of the disease. These observations suggest that MRS assessment of glutamate levels could be helpful for both diagnosis and classification of cognitive impairment in stage.

Physical activity, biomarkers of brain pathologies and dementia risk: Results from the Memento clinical cohort.

INTRODUCTION: This study aims to examine whether physical activity moderates the association between biomarkers of brain pathologies and dementia risk. METHODS: From the Memento cohort, we analyzed 1044 patients with mild cognitive impairment, aged 60 and older. Self-reported physical activity was assessed using the International Physical Activity Questionnaire. Biomarkers of brain pathologies comprised medial temporal lobe atrophy (MTA), white matter lesions, and plasma amyloid beta (Aß)42/40 and phosphorylated tau181. Association between physical activity and risk of developing dementia over 5 years of follow-up, and interactions with biomarkers of brain pathologies were tested. RESULTS: Physical activity moderated the association between MTA and plasma Aß42/40 level and increased dementia risk. Compared to participants with low physical activity, associations of both MTA and plasma Aß42/40 on dementia risk were attenuated in participants with high physical activity. DISCUSSION: Although reverse causality cannot be excluded, this work suggests that physical activity may contribute to cognitive reserve. HIGHLIGHTS: Physical activity is an interesting modifiable target for dementia prevention. Physical activity may moderate the impact of brain pathology on dementia risk. Medial temporal lobe atrophy and plasma amyloid beta 42/40 ratio were associated with increased dementia risk especially in those with low level of physical activity.

Attention-guided neural network for early dementia detection using MRS data.

Imaging bio-markers have been widely used for Computer-Aided Diagnosis (CAD) of Alzheimer's Disease (AD) with Deep Learning (DL). However, the structural brain atrophy is not detectable at an early stage of the disease (namely for Mild Cognitive Impairment (MCI) and Mild Alzheimer's Disease (MAD)). Indeed, potential biological bio-markers have been proved their ability to early detect brain abnormalities related to AD before brain structural damage and clinical manifestation. Proton Magnetic Resonance Spectroscopy (1H-MRS) provides a promising solution for biological brain changes detection in a no invasive manner. In this paper, we propose an attention-guided supervised DL framework for early AD detection using 1H-MRS data. In the early stages of AD, features may be closely related and often complex to delineate between subjects. Hence, we develop a 1D attention mechanism that explicitly guides the classifier to focus on diagnostically relevant metabolites for classes discrimination. Synthetic data are used to tackle the lack of data problem and to help in learning the feature space. Data used in this paper are collected in the University Hospital of Poitiers, which contained 111 1H-MRS samples extracted from the Posterior Cingulate Cortex (PCC) brain region. The data contain 33 Normal Control (NC), 49 MCI due to AD, and 29 MAD subjects. The proposed model achieves an average classification accuracy of 95.23%. Our framework outperforms state of the art imaging-based approaches, proving the robustness of learning metabolites features against traditional imaging bio-markers for early AD detection.

Explaining the association between social and lifestyle factors and cognitive functions: a pathway analysis in the Memento cohort.

BACKGROUND: This work aimed to investigate the potential pathways involved in the association between social and lifestyle factors, biomarkers of Alzheimer's disease and related dementia (ADRD), and cognition. METHODS: The authors studied 2323 participants from the Memento study, a French nationwide clinical cohort. Social and lifestyle factors were education level, current household incomes, physical activity, leisure activities, and social network from which two continuous latent variables were computed: an early to midlife (EML) and a latelife (LL) indicator. Brain magnetic resonance imaging (MRI), lumbar puncture, and amyloid-positron emission tomography (PET) were used to define three latent variables: neurodegeneration, small vessel disease (SVD), and AD pathology. Cognitive function was defined as the underlying factor of a latent variable with four cognitive tests. Structural equation models were used to evaluate cross-sectional pathways between social and lifestyle factors and cognition. RESULTS: Participants' mean age was 70.9 years old, 62% were women, 28% were apolipoprotein-ε4 carriers, and 59% had a Clinical Dementia Rating (CDR) score of 0.5. Higher early to midlife social indicator was only directly associated with better cognitive function (direct ß = 0.364 (0.322; 0.405), with no indirect pathway through ADRD biomarkers (total ß = 0.392 (0.351; 0.429)). In addition to a direct effect on cognition (direct ß = 0.076 (0.033; 0.118)), the association between latelife lifestyle indicator and cognition was also mostly mediated by an indirect effect through lower neurodegeneration (indirect ß = 0.066 (0.042; 0.090) and direct ß = - 0.116 (- 0.153; - 0.079)), but not through AD pathology nor SVD. CONCLUSIONS: Early to midlife social factors are directly associated with higher cognitive functions. Latelife lifestyle factors may help preserve cognitive functions through lower neurodegeneration.

Semantic loss marks early Alzheimer's disease-related neurodegeneration in older adults without dementia.

OBJECTIVE: To assess progression of semantic loss in early stages of cognitive decline using semantic and letter fluency performance, and its relation with Alzheimer's disease (AD)-specific neurodegeneration using longitudinal multimodal neuroimaging measures. METHODS: Change in verbal fluency was analyzed among 2261 non-demented individuals with a follow-up diagnosis of no mild cognitive impairment (MCI), amnestic MCI (aMCI), non-amnestic MCI (naMCI), or incident dementia, using linear mixed models across 4 years of follow-up, and relations with magnetic resonance imaging (MRI; n = 1536) and 18F-fluorodeoxyglucose brain positron emission tomography (18F-FDG-PET) imaging (n = 756) using linear regression models across 2 years of follow-up. RESULTS: Semantic fluency declined-fastest in those at higher risk for AD (apolipoprotein E [APOE] e4 carriers, Clinical Dementia Rating score of .5, aMCI, or incident dementia)-while letter fluency did not except for those with incident dementia. Lower baseline semantic fluency was associated with an increase in white matter hyperintensities and total mean cortical thinning over time, and regionally with less hippocampal volume as well as more cortical thinning and reduced 18F-FDG-PET uptake in the inferior parietal lobule, entorhinal cortex, isthmus cingulate, and precuneus-posterior cingulate area. In contrast, baseline letter fluency was not associated with change in total nor regional neurodegeneration. Whole-brain neurodegeneration over time was associated with faster decline in both fluencies, while AD-specific regions were associated with a faster rate of decline in semantic but not letter fluency. INTERPRETATION: This study provides strong evidence of distinctive degeneration of semantic abilities early on in relation to both cognitive decline and AD-specific neurodegeneration.

How many patients are eligible for disease-modifying treatment in Alzheimer's disease? A French national observational study over 5 years.

OBJECTIVE: We aimed to study the epidemiology of the prodromal and mild stages of Alzheimer's disease (AD) patients who are eligible for clinical trials with disease-modifying therapies. SETTINGS: We analysed two large complementary databases to study the incidence and characteristics of this population on a nationwide scope in France from 2014 to 2018. The National Alzheimer Database contains data from 357 memory centres and 90 private neurologists. Data from 2014 to 2018 have been analysed. PARTICIPANTS: Patients, 50-85 years old, diagnosed with AD who had an Mini-Mental State Exam (MMSE) score of ≥20 were included. We excluded patients with mixed and non-AD neurocognitive disorders. PRIMARY OUTCOME MEASURE: Descriptive statistics of the population of interest was the primary measure. RESULTS: In the National Alzheimer Database, 550 198 patients were assessed. Among them, 72 174 (13.1%) were diagnosed with AD and had an MMSE ≥20. Using corrections for specificity of clinical diagnosis of AD, we estimated that about 50 000 (9.1%) had a prodromal or mild AD. In the combined electronic clinical records database of 11 French expert memory centres, a diagnosis of prodromal or mild AD, certified by the use of cerebrospinal fluid AD biomarkers, could be established in 195 (1.3%) out of 14 596 patients. CONCLUSIONS: AD was not frequently diagnosed at a prodromal or mild dementia stage in France in 2014 to 2018. Diagnosis rarely relied on a pathophysiological marker even in expert memory centres. National databases will be valuable to monitor early stage AD diagnosis efficacy in memory centres when a disease-modifying treatment becomes available.

Differential chemokine expression under the control of peripheral blood mononuclear cells issued from Alzheimer's patients in a human blood brain barrier model.

Growing evidence highlights the peripheral blood mononuclear cells (PBMCs) role and the chemokine involvement in the Alzheimer's disease (AD) physiopathology. However, few data are available about the impact of AD PBMCs in the chemokine signature in a brain with AD phenotype. Therefore, this study analyzed the chemokine levels in a human blood brain barrier model. A human endothelial cell line from the immortalized cerebral microvascular endothelial cell line (hCMEC/D3) and a human glioblastoma U-87 MG cell line, both with no AD phenotype were used while PBMCs came from AD at mild or moderate stage and control patients. PBMCs from moderate AD patients decreased CCL2 and CCL5 levels in endothelial, and also CXCL10 in abluminal compartments and in PBMCs compared to PBMCs from mild AD patients. The CX3CL1 expression increased in endothelial and abluminal compartments with PBMCs from mild AD patients compared to controls. AD PBMCs can convert the chemokine signature towards that found in AD brain, targeting some chemokines as new biomarkers in AD.

Blood Inflammatory Mediators and Cognitive Decline in Alzheimer's Disease: A Two Years Longitudinal Study.

Peripheral inflammatory processes are involved in Alzheimer's disease (AD). We aimed to determine whether plasma inflammatory mediator levels at diagnosis are associated with cognitive decline through a 2-year follow-up in AD patients. Patients (n = 109, mean age 79.44 (6.82) years) were included at diagnosis with MMSE scores between 16 and 25, with C-reactive protein <10 mg/L, and without any acute or chronic inflammation status. Plasma IL-1ß, IL-6, TNF-α, and CCL5 were measured using Luminex X-MAP technology at baseline, and after one year and two years of follow-up. The mean values of IL-1ß, IL-6, TNF-α, and CCL5 at diagnosis were 0.3, 1.94, 6.57, and 69,615.81 pg/mL, respectively. Mean cognitive decline in MMSE was 3.35 points. No correlation between plasmatic value of IL-1ß, IL-6, TNF-α, or CCL5 at diagnosis and cognitive decline during the two years of follow-up was found. Cognitive decline in AD does not appear to be predictable by the tested inflammatory mediators.

Current view and perspectives in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS), identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole (the only disease-modifying drug approved for this disease). Nowadays, there is still no curative treatment for ALS: palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent advances and promising therapeutics and biomarkers in the field of ALS.

Peripheral Blood Mononuclear Cells of Alzheimer's Disease Patients Control CCL4 and CXCL10 Levels in a Human Blood Brain Barrier Model.

BACKGROUND: Alzheimer's disease (AD) is accompanied by a neuroinflammation triggering chemoattractant signals towards peripheral blood mononuclear cells (PBMCs), which in turn could reduce amyloid plaques after transmigration through the blood brain barrier (BBB). But the chemotactic environment remains unclear. OBJECTIVE: To analyze five chemokines known to be involved in AD in three different cellular models to better understand the cellular and molecular interactions in the BBB. METHOD: Chemokines (CCL-2, 4 and 5, CXCL10 and CX3CL1) were measured in isolated cells, a BBB model without PBMCs (H4 and hCMEC/D3 cells, a neuroglioma and human endothelial cells, respectively) and in a complete BBB model with PBMCs from AD patients at a moderate stage. In one set of experiments, H4 cells were treated with Aß42. RESULTS: CCL2 and CCL5 significantly increased in hCMEC/D3 and H4 cells in the complete BBB model. In turn, the rate of CCL2 increased in PBMCs whereas for CCL5, it decreased. CXCL10 increased in all cellular actors in the complete BBB model, compared to isolated cells. For CCL4, PBMCs induced a robust increase in H4 and hCMEC/D3. In turn, the level of CCL4 decreased in PBMCs. Furthermore, PBMCs triggered a significant increase in CX3CL1 in hCMEC/D3. Surprisingly, no effect of Aß42 was observed in the complete BBB model. CONCLUSION: These findings highlight the interest of a BBB model in order to explore chemokine production. For the first time, results showed that PBMCs from patients with AD can control the production of CCL4 and CXCL10 in a human BBB model.

Management and therapeutic perspectives in amyotrophic lateral sclerosis.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder affecting both upper and lower motor neurons. Despite much research and effort, no clear insights into a unifying hypothesis for the pathogenesis has so far emerged for this disease. Areas covered: We review the main pathophysiological hypotheses and the potential therapeutic targets in ALS, as well as the management of these patients (in order to improve their survival and quality of life). Expert commentary: ALS is a complex neurodegenerative disease, these days considered as a multisystem disorder with predominant motor symptoms (and various clinical forms). Further comprehension of the pathophysiology of this disease is required, although pathophysiological mechanisms (such as TDP-43) show promise in the search for new therapies. There is still no curative treatment for ALS, but the emergence of multidisciplinary specialized ALS clinics has increased both the quality of life and the survival of these patients.

Long-term outcome of basilar stenosis in Erdheim-Chester disease: A case report.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis. This inflammatory myeloid neoplasm is frequently complicated by neurological symptoms, but stroke is an exceptional manifestation of this disease. METHODS: We report the case of a 59-year-old woman who presented a vertebrobasilar stroke secondary to infiltration and severe stenosis of the basilar artery, improved after interferon-alpha therapy. We performed a review of the relevant literature and reported the few other cases described. RESULTS: With our patient, we have found only 7 observations of cerebrovascular disorder in ECD. Most of them had supravascular arteries involvement. CONCLUSION: Stroke is a rare treatable and potentially reversible complication of ECD. The pathophysiological processes explaining stroke in this disease are uncertain, but periarterial stenosis of cerebral arteries may be a mechanism.

Inflammatory Stress on Autophagy in Peripheral Blood Mononuclear Cells from Patients with Alzheimer's Disease during 24 Months of Follow-Up.

Recent findings indicate that microglia in Alzheimer's disease (AD) is senescent whereas peripheral blood mononuclear cells (PBMCs) could infiltrate the brain to phagocyte amyloid deposits. However, the molecular mechanisms involved in the amyloid peptide clearance remain unknown. Autophagy is a physiological degradation of proteins and organelles and can be controlled by pro-inflammatory cytokines. The purpose of this study was to evaluate the impact of inflammation on autophagy in PBMCs from AD patients at baseline, 12 and 24 months of follow-up. Furthermore, PBMCs from healthy patients were also included and treated with 20 µM amyloid peptide 1-42 to mimic AD environment. For each patient, PBMCs were stimulated with the mitogenic factor, phytohaemagglutin (PHA), and treated with either 1 µM C16 as an anti-inflammatory drug or its vehicle. Autophagic markers (Beclin-1, p62/sequestosome 1 and microtubule-associated protein-light chain 3: LC3) were quantified by western blot and cytokines (Interleukin (IL)-1ß, Tumor necrosis Factor (TNF)-α and IL-6) by Luminex X-MAP® technology. Beclin-1 and TNF-α levels were inversely correlated in AD PBMCs at 12 months post-inclusion. In addition, Beclin-1 and p62 increased in the low inflammatory environment induced by C16. Only LC3-I levels were inversely correlated with cognitive decline at baseline. For the first time, this study describes longitudinal changes in autophagic markers in PBMCs of AD patients under an inflammatory environment. Inflammation would induce autophagy in the PBMCs of AD patients while an anti-inflammatory environment could inhibit their autophagic response. However, this positive response could be altered in a highly aggressive environment.

There is no correlation between peripheral inflammation and cognitive status at diagnosis in Alzheimer's disease.

BACKGROUND: Besides the neurofibrillary tangles and amyloid plaques, an inflammatory process is involved at central and peripheral levels in Alzheimer's disease (AD). We aimed to determine whether peripheral inflammatory parameter levels, in plasma and in peripheral blood mononuclear cells (PBMCs), could be correlated with the cognitive status at the time of AD diagnosis. METHODS: Patients were included at diagnosis with MMSE score between 16 and 25 and were naive of symptomatic treatment for AD. C-reactive protein >10 mg/L and any acute or chronic inflammation were considered as exclusion criteria. Cognitive assessment also included the ADAScog scale. Plasma interleukins (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and the chemokine ligand 5 (CCL5) were measured using Luminex(®) X-MAP(®) technology. A subgroup of patients also underwent measures of these parameters in extracellular and intracellular compartments of PBMCs (ancillary study). RESULTS: One hundred and nine patients were included; mean age 79.4 ± 6.8 years with 37 patients in the ancillary study. The mean values of IL-1ß, TNF-α, IL-6 and CCL5 values were 1.49, 7.18, 3.09 and 69,615.81 pg/mL, respectively. No correlation between plasma cytokines or chemokine levels and cognitive scores was found. In PBMCs, the levels of cytokines were detectable but did not either show any correlation with cognitive scores. CONCLUSION: Our data indicate that at diagnosis, peripheral levels of cytokines and CCL5 display low values without any correlation with the cognitive status. Further results of our study will show if these circulating markers are related to the progression of AD.

Restless legs syndrome and pregnancy: follow-up of pregnant women before and after delivery.

AIMS: To describe the frequency of restless legs syndrome (RLS) in a French population of randomly selected women during their third trimester of pregnancy and its evolution up to 3 months after delivery and to identify potential factors associated with the improvement of RLS after delivery. METHODS: A cross-sectional questionnaire survey. RESULTS: 186 pregnant women living in a French town were included. 32% of women were affected by RLS during the third trimester of their pregnancy. Multiple pregnancies and iron intake during pregnancy were significantly associated with RLS during the third trimester. RLS disappeared after delivery among 64.8% of the women, and by less than 2 weeks after delivery in half of them. This improvement after delivery was not associated with the number of previous pregnancies, the RLS severity and iron intake during pregnancy, peridural anaesthesia, caesarean section, delivery complications, newborn weight, breastfeeding, dopaminergic agent intake after delivery, and with the absence of RLS before pregnancy. CONCLUSIONS: RLS affects one third of pregnant women during their third trimester and usually improves after delivery. Although there is no allowed treatment, most of the time only counselling and iron status assessment should be provided.

Restless legs syndrome and pregnancy: a questionnaire study in the Poitiers District, France.

AIMS: To perform a large and detailed epidemiologic study on restless legs syndrome (RLS) during pregnancy in a European country. METHODS: A cross-sectional questionnaire survey. The questionnaire was distributed by the medical staff in different outpatient waiting rooms (obstetrics and gynecology department of the university hospital, obstetrics and gynecology department of a private clinic, private midwives, private obstetrician-gynecologists, radiological centers before fetal ultrasound examination and general practitioners) in a French town and its surrounding area (200,000 inhabitants): A woman was considered affected if she met the International RLS Study Group criteria for RLS diagnosis. RESULTS: 1,022 pregnant women living in a French town were included. 24% of women were affected by RLS during their pregnancy. The disease was strongly related to the third trimester of pregnancy and had a significant impact on sleep leading to severe nocturnal and diurnal consequences with a high consumption of sleep medication. CONCLUSIONS: RLS affects one quarter of pregnant women, essentially during the third trimester and represents an important public health issue with sleep medication intake.