Isolated REM Sleep without Atonia Is Not Equivalent to REM Sleep Behavior Disorder in Early-Stage Parkinson's Disease.

BACKGROUND: In early-stage Parkinson's disease (PD), rapid eye movement (REM) sleep behavior disorder (RBD) predicts poor cognitive and motor outcome. However, the baseline significance and disease evolution associated with isolated REM sleep without atonia (iRWA, ie, enhanced muscle tone during 8.7% of REM sleep, but no violent behavior) are not well understood. OBJECTIVES: The objective is to determine whether iRWA was a mild form of RBD and progressed similarly over time. METHODS: Participants with early PD (<4 years from medical diagnosis) were included from 2014 to 2021 in a longitudinal study. They underwent interviews and examinations in the motor, cognitive, autonomous, psychiatric, sensory, and sleep domains every year for 4 years along with a video polysomnography and magnetic resonance imaging examination of the locus coeruleus/subcoeruleus complex (LC/LsC) at baseline. The clinical characteristics were compared between groups with normal REM sleep, with iRWA and with RBD, at baseline and for 4 years. RESULTS: Among 159 PD participants, 25% had RBD, 25% had iRWA, and 50% had normal REM sleep. At baseline, the non-motor symptoms were less prevalent and the LC/LsC signal intensity was more intense in participants with iRWA than with RBD. Over 4 years, participants with normal REM sleep and with iRWA had a similar cognitive and motor trajectory, whereas participants with RBD had greater cognitive and motor decline. CONCLUSIONS: We demonstrated that iRWA is frequent in early PD, but is not a milder form of RBD. Both groups have distinct baseline characteristics and clinical trajectories. They should be distinguished in clinical routine and research protocols. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Clinical correlates of respiratory disorders in patients with severe multiple sclerosis: A cross-sectional cohort.

BACKGROUND: Respiratory disorders remain incompletely described in multiple sclerosis (MS), even though they are a frequent cause of death. METHODS: The objective was to describe respiratory disorders in MS patients with Expanded Disability Status Score (EDSS) ⩾ 6.5. Diaphragm dysfunction was defined by at least two of the seven criteria: clinical signs, inspiratory recruitment of neck muscles during wakefulness, reduced upright vital capacity (VC) < 80%, upright-to-supine VC ⩾ 15% of upright VC, decrease in Maximal Inspiratory Pressure < 60%, phasic activation of inspiratory neck muscles during sleep, and opposition of thoracic and abdominal movements during sleep. Cough weakness was defined by a peak cough flow < 270 L/min and/or need for cough assist. Sleep apnea syndrome was defined by an apnea-hypopnea index ⩾ 15. RESULTS: Notably, 71 MS patients were included: median age 54 [48, 61] years; median disease duration 21.4 [16.0, 31.4] years. Of these, 52 patients had one or more respiratory disorders; diaphragm dysfunction was the most frequent (n = 34). Patients with diaphragm dysfunction and cough weakness were more disabled. The fatigue score and the cognitive evaluations did not differ between the groups. Five patients required non-invasive ventilation. CONCLUSION: Respiratory disorders are frequent in severe MS, mostly diaphragm dysfunction. Of interest, instrumental interventions are available to address these disorders.

Plasma lysosphingolipids in GRN-related diseases: Monitoring lysosomal dysfunction to track disease progression.

GRN mutations are among the main genetic causes of frontotemporal dementia (FTD). Considering the progranulin involvement in lysosomal homeostasis, we aimed to evaluate if plasma lysosphingolipids (lysoSPL) are increased in GRN mutation carriers, and whether they might represent relevant fluid-based biomarkers in GRN-related diseases. We analyzed four lysoSPL levels in plasmas of 131 GRN carriers and 142 non-carriers, including healthy controls and patients with frontotemporal dementias (FTD) carrying a C9orf72 expansion or without any mutation. GRN carriers consisted of 102 heterozygous FTD patients (FTD-GRN), three homozygous patients with neuronal ceroid lipofuscinosis-11 (CLN-11) and 26 presymptomatic carriers (PS-GRN), the latter with longitudinal assessments. Glucosylsphingosin d18:1 (LGL1), lysosphingomyelins d18:1 and isoform 509 (LSM18:1, LSM509) and lysoglobotriaosylceramide (LGB3) were measured by electrospray ionization-tandem mass spectrometry coupled to ultraperformance liquid chromatography. Levels of LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers (p < 0.0001). No lysoSPL increases were detected in FTD patients without GRN mutations. LGL1 and LSM18:1 progressively increased with age at sampling, and LGL1 with disease duration, in FTD-GRN. Among PS-GRN carriers, LSM18:1 and LGL1 significantly increased over 3.4-year follow-up. LGL1 levels were associated with increasing neurofilaments in presymptomatic carriers. This study evidences an age-dependent increase of ß-glucocerebrosidase and acid sphingomyelinase substrates in GRN patients, with progressive changes as early as the presymptomatic phase. Among FTD patients, plasma lysoSPL appear to be uniquely elevated in GRN carriers, and thus might serve as suitable non-invasive disease-tracking biomarkers of progression, specific to the pathophysiological process. Finally, this study might add lysoSPL to the portfolio of fluid-based biomarkers, and pave the way to disease-modifying approaches based on lysosomal function rescue in GRN diseases.

Cognitive effect of antiseizure medications in medial temporal lobe epilepsy.

BACKGROUND AND PURPOSE: The specific effects of antiseizure medications (ASMs) on cognition are a rich field of study, with many ongoing questions. The aim of this study was to evaluate these effects in a homogeneous group of patients with epilepsy to guide clinicians to choose the most appropriate medications. METHODS: We retrospectively identified 287 refractory patients with medial temporal lobe epilepsy associated with hippocampal sclerosis. Scores measuring general cognition (global, verbal and performance IQ), working memory, episodic memory, executive functions, and language abilities were correlated with ASM type, number, dosage and generation (old vs. new). We also assessed non-modifiable factors affecting cognition, such as demographics and epilepsy-related factors. RESULTS: Key parameters were total number of ASMs and specific medications, especially topiramate (TPM) and sodium valproate (VPA). Four cognitive profiles of the ASMs were identified: (i) drugs with an overall detrimental effect on cognition (TPM, VPA); (ii) drugs with negative effects on specific areas: verbal memory and language skills (carbamazepine), and language functions (zonisamide); (iii) drugs affecting a single function in a specific and limited area: visual denomination (oxcarbazepine, lacosamide); and (iv) drugs without documented cognitive side effects. Non-modifiable factors such as age at testing, age at seizure onset, and history of febrile seizures also influenced cognition and were notably influenced by total number of ASMs. CONCLUSION: We conclude that ASMs significantly impact cognition. Key parameters were total number of ASMs and specific medications, especially TPM and VPA. These results should lead to a reduction in the number of drugs received and the avoidance of medications with unfavorable cognitive profiles.

Long-term deep intracerebral microelectrode recordings in patients with drug-resistant epilepsy: Proposed guidelines based on 10-year experience.

PURPOSE: Human neuronal activity, recorded in vivo from microelectrodes, may offer valuable insights into physiological mechanisms underlying human cognition and pathophysiological mechanisms of brain diseases, in particular epilepsy. Continuous and long-term recordings are necessary to monitor non predictable pathological and physiological activities like seizures or sleep. Because of their high impedance, microelectrodes are more sensitive to noise than macroelectrodes. Low noise levels are crucial to detect action potentials from background noise, and to further isolate single neuron activities. Therefore, long-term recordings of multi-unit activity remains a challenge. We shared here our experience with microelectrode recordings and our efforts to reduce noise levels in order to improve signal quality. We also provided detailed technical guidelines for the connection, recording, imaging and signal analysis of microelectrode recordings. RESULTS: During the last 10 years, we implanted 122 bundles of Behnke-Fried hybrid macro-microelectrodes, in 56 patients with pharmacoresistant focal epilepsy. Microbundles were implanted in the temporal lobe (74%), as well as frontal (15%), parietal (6%) and occipital (5%) lobes. Low noise levels depended on our technical setup. The noise reduction was mainly obtained after electrical insulation of the patient's recording room and the use of a reinforced microelectrode model, reaching median root mean square values of 5.8 µV. Seventy percent of the bundles could record multi-units activities (MUA), on around 3 out of 8 wires per bundle and for an average of 12 days. Seizures were recorded by microelectrodes in 91% of patients, when recorded continuously, and MUA were recorded during seizures for 75 % of the patients after the insulation of the room. Technical guidelines are proposed for (i) electrode tails manipulation and protection during surgical bandage and connection to both clinical and research amplifiers, (ii) electrical insulation of the patient's recording room and shielding, (iii) data acquisition and storage, and (iv) single-units activities analysis. CONCLUSIONS: We progressively improved our recording setup and are now able to record (i) microelectrode signals with low noise level up to 3 weeks duration, and (ii) MUA from an increased number of wires . We built a step by step procedure from electrode trajectory planning to recordings. All these delicate steps are essential for continuous long-term recording of units in order to advance in our understanding of both the pathophysiology of ictogenesis and the neuronal coding of cognitive and physiological functions.

SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration.

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

Characterization of Recessive Parkinson Disease in a Large Multicenter Study.

Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene-targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ-1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab-Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa-induced motor complications, dysautonomia, and dementia than those without mutations. ANN NEUROL 2020;88:843-850.

Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications.

OBJECTIVE: Neurofilament light chain (NfL) is a promising biomarker in genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We evaluated plasma neurofilament light chain (pNfL) levels in controls, and their longitudinal trajectories in C9orf72 and GRN cohorts from presymptomatic to clinical stages. METHODS: We analysed pNfL using Single Molecule Array (SiMoA) in 668 samples (352 baseline and 316 follow-up) of C9orf72 and GRN patients, presymptomatic carriers (PS) and controls aged between 21 and 83. They were longitudinally evaluated over a period of >2 years, during which four PS became prodromal/symptomatic. Associations between pNfL and clinical-genetic variables, and longitudinal NfL changes, were investigated using generalised and linear mixed-effects models. Optimal cut-offs were determined using the Youden Index. RESULTS: pNfL levels increased with age in controls, from ~5 to~18 pg/mL (p<0.0001), progressing over time (mean annualised rate of change (ARC): +3.9%/year, p<0.0001). Patients displayed higher levels and greater longitudinal progression (ARC: +26.7%, p<0.0001), with gene-specific trajectories. GRN patients had higher levels than C9orf72 (86.21 vs 39.49 pg/mL, p=0.014), and greater progression rates (ARC:+29.3% vs +24.7%; p=0.016). In C9orf72 patients, levels were associated with the phenotype (ALS: 71.76 pg/mL, FTD: 37.16, psychiatric: 15.3; p=0.003) and remarkably lower in slowly progressive patients (24.11, ARC: +2.5%; p=0.05). Mean ARC was +3.2% in PS and +7.3% in prodromal carriers. We proposed gene-specific cut-offs differentiating patients from controls by decades. CONCLUSIONS: This study highlights the importance of gene-specific and age-specific references for clinical and therapeutic trials in genetic FTD/ALS. It supports the usefulness of repeating pNfL measurements and considering ARC as a prognostic marker of disease progression. TRIAL REGISTRATION NUMBERS: NCT02590276 and NCT04014673.

Distinctive neuropsychological profiles of lateral temporal lobe epilepsy.

OBJECTIVE: Lateral temporal lobe epilepsies (LTLE) are poorly characterized heterogeneous epilepsies. As the lateral temporal lobe supports distinct functions, we hypothesized that neuropsychological profiles could differ according to the localization of the seizure focus within the lateral temporal lobe. METHODS: We retrospectively examined the neuropsychological characteristics of 74 consecutive patients with refractory LTLE assessed in the context of a presurgical investigation at the Pitié-Salpêtrière Hospital in Paris between 1998 and 2018. Precise localization of the epileptic focus was correlated with scores on tests of intelligence (Global, Verbal and Performance IQ), working memory, episodic memory (verbal and visual learning and forgetting), executive functions, and language abilities. RESULTS: We demonstrated an impact of the localization of the epileptic focus within the lateral temporal lobe with worse learning and/or executive performances depicted in the infero-basal and pure pole LTLE groups and greater language difficulties in the posterior LTLE group, Antiepileptic drugs had a greater effect than parameters related to the epilepsy itself as the lesion or the disease duration, and finally as in medial TLE, the age, education, and sex influenced some cognitive performances. CONCLUSION: Our findings show that the lateral temporal neocortex is also part of the neural substrate for memory processing and executive functions and suggest that this involvement could be related to functions devoted to specific subregions of the temporal lobe (i.e., temporal pole, inferior and basal regions) that support language and semantic processing.

Radiological classification of dementia from anatomical MRI assisted by machine learning-derived maps.

BACKGROUND AND PURPOSE: Many artificial intelligence tools are currently being developed to assist diagnosis of dementia from magnetic resonance imaging (MRI). However, these tools have so far been difficult to integrate in the clinical routine workflow. In this work, we propose a new simple way to use them and assess their utility for improving diagnostic accuracy. MATERIALS AND METHODS: We studied 34 patients with early-onset Alzheimer's disease (EOAD), 49 with late-onset AD (LOAD), 39 with frontotemporal dementia (FTD) and 24 with depression from the pre-existing cohort CLIN-AD. Support vector machine (SVM) automatic classifiers using 3D T1 MRI were trained to distinguish: LOAD vs. Depression, FTD vs. LOAD, EOAD vs. Depression, EOAD vs. FTD. We extracted SVM weight maps, which are tridimensional representations of discriminant atrophy patterns used by the classifier to take its decisions and we printed posters of these maps. Four radiologists (2 senior neuroradiologists and 2 unspecialized junior radiologists) performed a visual classification of the 4 diagnostic pairs using 3D T1 MRI. Classifications were performed twice: first with standard radiological reading and then using SVM weight maps as a guide. RESULTS: Diagnostic performance was significantly improved by the use of the weight maps for the two junior radiologists in the case of FTD vs. EOAD. Improvement was over 10 points of diagnostic accuracy. CONCLUSION: This tool can improve the diagnostic accuracy of junior radiologists and could be integrated in the clinical routine workflow.

EEG evidence of compensatory mechanisms in preclinical Alzheimer's disease.

Early biomarkers are needed to identify individuals at high risk of preclinical Alzheimer's disease and to better understand the pathophysiological processes of disease progression. Preclinical Alzheimer's disease EEG changes would be non-invasive and cheap screening tools and could also help to predict future progression to clinical Alzheimer's disease. However, the impact of amyloid-ß deposition and neurodegeneration on EEG biomarkers needs to be elucidated. We included participants from the INSIGHT-preAD cohort, which is an ongoing single-centre multimodal observational study that was designed to identify risk factors and markers of progression to clinical Alzheimer's disease in 318 cognitively normal individuals aged 70-85 years with a subjective memory complaint. We divided the subjects into four groups, according to their amyloid status (based on 18F-florbetapir PET) and neurodegeneration status (evidenced by 18F-fluorodeoxyglucose PET brain metabolism in Alzheimer's disease signature regions). The first group was amyloid-positive and neurodegeneration-positive, which corresponds to stage 2 of preclinical Alzheimer's disease. The second group was amyloid-positive and neurodegeneration-negative, which corresponds to stage 1 of preclinical Alzheimer's disease. The third group was amyloid-negative and neurodegeneration-positive, which corresponds to 'suspected non-Alzheimer's pathophysiology'. The last group was the control group, defined by amyloid-negative and neurodegeneration-negative subjects. We analysed 314 baseline 256-channel high-density eyes closed 1-min resting state EEG recordings. EEG biomarkers included spectral measures, algorithmic complexity and functional connectivity assessed with a novel information-theoretic measure, weighted symbolic mutual information. The most prominent effects of neurodegeneration on EEG metrics were localized in frontocentral regions with an increase in high frequency oscillations (higher beta and gamma power) and a decrease in low frequency oscillations (lower delta power), higher spectral entropy, higher complexity and increased functional connectivity measured by weighted symbolic mutual information in theta band. Neurodegeneration was associated with a widespread increase of median spectral frequency. We found a non-linear relationship between amyloid burden and EEG metrics in neurodegeneration-positive subjects, either following a U-shape curve for delta power or an inverted U-shape curve for the other metrics, meaning that EEG patterns are modulated differently depending on the degree of amyloid burden. This finding suggests initial compensatory mechanisms that are overwhelmed for the highest amyloid load. Together, these results indicate that EEG metrics are useful biomarkers for the preclinical stage of Alzheimer's disease.

Elucidating the Structural and Functional Correlates of Upper-Limb Poststroke Motor Impairment.

Background and Purpose- Many studies have attempted to bring to light the neural correlates of poststroke motor impairment, but few have used multimodal approach to explain it. The aim of this study was to elucidate neural structural and functional correlates of upper limb motor impairment by combining electrophysiological, anatomic, and functional neuroimaging data. Methods- Forty ischemic stroke patients (median [min-max] age: 63 [33-82] years, time poststroke: 3.5 [1.1-58] months) with unilateral upper limb weakness were included. The upper limb motor impairment was defined by a motor composite score. Simple linear analysis followed by multiple linear regression analysis were performed to identify which variables (corticospinal excitability, laterality indices within the primary motor cortex or corticospinal [CST], and corpus callosum tracts integrity) were the best explaining factors of upper limb motor impairment. Results- There was a significant correlation between the resting motor threshold ratio and CST damage (r= -0.50 [95% CI, -0.70 to -0.22]; P<0.001) as well as the motor-evoked potentials amplitude (r= -0.73 [95% CI, -0.85 to -0.54]; P<0.001). Only the resting motor threshold ratio was retained by the multiple regression model and explained half of the variance (49%; P<0.001) of the upper limb motor impairment after stroke. Conclusions- The implementation of quantitative neurophysiological measurements such as the resting motor threshold as a surrogate marker of impairment could be considered in neurorehabilitation trials.

Relationship between Basal Forebrain Resting-State Functional Connectivity and Brain Amyloid-ß Deposition in Cognitively Intact Older Adults with Subjective Memory Complaints.

Purpose To evaluate the association between the global fibrillary amyloid-ß pathology and the basal forebrain connectivity at rest in cognitively intact older adults at risk for Alzheimer disease. Materials and Methods This retrospective study was approved by the local ethics committee and written informed consent was obtained from all participants. Resting-state functional connectivity (RSFC) of anterior and posterior basal forebrain seeds was investigated, as well as PET-measured global amyloid-ß load by using standardized uptake value ratio (SUVR) in 267 older cognitively intact individuals with subjective memory complaints (age range, 70-85 years; overall mean age, 75.8 years; 167 women [mean age, 75.9 years] and 100 men [mean age, 75.8 years]). The participants were from the Investigation of Alzheimer's Predictors in Subjective Memory Complainers (INSIGHT-preAD) cohort (date range, 2013-present). The relationship between SUVR and the basal forebrain RSFC was assessed, followed by the effects of apolipoprotein E (APOE) genotype and sex on the basal forebrain RSFC. Results Higher SUVR values correlated with lower posterior basal forebrain RSFC in the hippocampus and the thalamus (Pearson r =-0.23; P <.001 corrected for familywise error [FWE]). Both sex and APOE genotype impacted the associations between basal forebrain RSFC and the global amyloid deposition (t values >3.59; P <.05 corrected for FWE). Conclusion Data indicate a distinct in vivo association between posterior basal forebrain dynamics and global fibrillary amyloid-ß pathology in cognitively intact older adults with subjective memory complaints; both apolipoprotein E and sex moderate such association. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Caspers in this issue.

Neurite density is reduced in the presymptomatic phase of C9orf72 disease.

OBJECTIVE: To assess the added value of neurite orientation dispersion and density imaging (NODDI) compared with conventional diffusion tensor imaging (DTI) and anatomical MRI to detect changes in presymptomatic carriers of chromosome 9 open reading frame 72 (C9orf72) mutation. METHODS: The PREV-DEMALS (Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis) study is a prospective, multicentre, observational study of first-degree relatives of individuals carrying the C9orf72 mutation. Sixty-seven participants (38 presymptomatic C9orf72 mutation carriers (C9+) and 29 non-carriers (C9-)) were included in the present cross-sectional study. Each participant underwent one single-shell, multishell diffusion MRI and three-dimensional T1-weighted MRI. Volumetric measures, DTI and NODDI metrics were calculated within regions of interest. Differences in white matter integrity, grey matter volume and free water fraction between C9+ and C9- individuals were assessed using linear mixed-effects models. RESULTS: Compared with C9-, C9+ demonstrated white matter abnormalities in 10 tracts with neurite density index and only 5 tracts with DTI metrics. Effect size was significantly higher for the neurite density index than for DTI metrics in two tracts. No tract had a significantly higher effect size for DTI than for NODDI. For grey matter cortical analysis, free water fraction was increased in 13 regions in C9+, whereas 11 regions displayed volumetric atrophy. CONCLUSIONS: NODDI provides higher sensitivity and greater tissue specificity compared with conventional DTI for identifying white matter abnormalities in the presymptomatic C9orf72 carriers. Our results encourage the use of neurite density as a biomarker of the preclinical phase. TRIAL REGISTRATION NUMBER: NCT02590276.

Brain Aß load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD.

INTRODUCTION: Successful development of effective ß-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies. METHODS: We investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-ß (Aß) deposition, using positron emission tomography global standard uptake value ratios. RESULTS: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline Aß-positron emission tomography global standard uptake value ratios. DISCUSSION: Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain Aß production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials.

Sex differences in functional and molecular neuroimaging biomarkers of Alzheimer's disease in cognitively normal older adults with subjective memory complaints.

INTRODUCTION: Observational multimodal neuroimaging studies indicate sex differences in Alzheimer's disease pathophysiological markers. METHODS: Positron emission tomography brain amyloid load, neurodegeneration (hippocampus and basal forebrain volumes adjusted to total intracranial volume, cortical thickness, and 2-deoxy-2-[fluorine-18]fluoro-D-glucose-positron emission tomography metabolism), and brain resting-state functional connectivity were analyzed in 318 cognitively intact older adults from the INSIGHT-preAD cohort (female n = 201, male n = 117). A linear mixed-effects model was performed to investigate sex effects and sex∗apolipoprotein E genotype interaction on each marker as well as sex∗amyloid group interaction for non-amyloid markers. RESULTS: Men compared with women showed higher anterior cingulate cortex amyloid load (P = .009), glucose hypometabolism in the precuneus (P = .027), posterior cingulate (P < .001) and inferior parietal (P = .043) cortices, and lower resting-state functional connectivity in the default mode network (P = .024). No brain volumetric markers showed differences between men and women. Sex∗apolipoprotein E genotype and sex∗amyloid status interactions were not significant. DISCUSSION: Our findings suggest that cognitively intact older men compared with women have higher resilience to pathophysiological processes of Alzheimer's disease.

Sleep disorders in Parkinson's disease, an early and multiple problem.

In Parkinson's disease (PD), it remains unclear whether sleep disorders including insomnia, REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS), restless legs syndrome (RLS) and sleep-disordered breathing (SDB), are isolated or combined, interact with each other and are associated with clinical factors. We sought to determine the prevalence and combinations of the main sleep disorders, and their clinical and polysomnographic associations in early stage PD. Sleep disorders were systematically diagnosed after medical interview and video-polysomnography in 162 participants with early stage PD and 58 healthy controls from the baseline of the longitudinal ICEBERG cohort. Demographic, clinical (motor, cognitive, autonomic, psychological and sensory tests), therapeutic and polysomnographic associations of sleep disorders were investigated. Sleep disorders were frequent (71%) and combined in half of the patients. The number of sleep disorders increased with disease duration and dysautonomia. Insomnia was the most common (41%), followed by definite RBD (25%), EDS (25%), and RLS (16%). These disorders were more frequent than in controls whereas SDB was rare, moderate and similar in both groups. In patients, insomnia (mainly difficulties maintaining sleep) was associated with female gender, shorter sleep time and RLS, but not with motor or psychological symptoms. RBD was associated with dysautonomia and advanced age, but not with motor and cognitive measures. EDS was associated with psychiatric and motor symptoms as well as the sedative effects of dopamine agonists but not with other sleep disturbances. Sleep disturbances are frequent and combined in early patients with PD. Their determinants and markers are more organic than psychological.

Genotype-phenotype correlation in PRKN-associated Parkinson's disease.

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson's disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.

Late but not early seizures impact negatively early post stroke recovery: A case-control study.

BACKGROUND: Seizures are a frequent complication of strokes. The initial severity of the stroke is a risk factor for both seizure occurrence and poor functional recovery. AIM: To determine whether epilepsy has a negative impact on functional recovery or is just a proxy for the initial severity of the stroke. PATIENTS AND METHODS: We conducted a monocentric retrospective case-control study in 408 consecutive patients hospitalized in the neurological rehabilitation department of the Pitié-Salpêtrière Hospital for rehabilitation of a recent stroke between 1999 and 2019. We matched 1:1 stroke patients with and without seizures according to numerous variables that may influence the outcome: type of stroke (ischemic vs hemorrhagic (ICH)), type of endovascular treatment performed (thrombolysis, thrombectomy), exact location of the stroke (arterial territory for ischemic strokes, lobar territory for ICH), extent of the stroke, side of the stroke, and age at the time of stroke. Two criteria were used to judge the impact on neurological recovery: the change in modified Rankin score between entry and the discharge from the rehabilitation department, and the length of stay. Seizures were divided into early (within 7 days of stroke) and late (after 7 days) seizures. RESULTS: We accurately matched 110 stroke patients with and without seizures. Compared to seizure-free matched stroke patients, stroke patients with late seizures had a poorer neurological functional recovery in terms of Rankin score evolution (p = 0.011*) and length of stay (p = 0.004*). The occurrence of early seizures had no significant impact on functional recovery criteria. CONCLUSION: Late seizures, that is, stroke-related epilepsy, have a negative impact on early rehabilitation, whereas early symptomatic seizures do not negatively impact functional recovery. These results reinforce the recommendation not to treat early seizures.

Validation of the French version of the Multiple Sclerosis Intimacy and Sexuality Questionnaire 15 Tools which help nurse for assessing the effect of perceived multiple sclerosis symptoms on sexual activity and satisfaction.

AIM: To validate a French version of the Multiple Sclerosis Intimacy and Sexuality Questionnaire 15 which examines patients' perception of the effect of multiple sclerosis symptoms on their sexual activity. METHODS: After completing a translation/re-translation process to ensure linguistic and content validity, the Multiple Sclerosis Intimacy and Sexuality Questionnaire 15 French (MSISQ-15Fr) was completed by patients with multiple sclerosis. The validity of the construction, reliability, stability and reproducibility of the translation was evaluated. EXPLANATORY MIXED OBSERVATIONAL STUDY: Validation of a French assessment tool for sexual disorders (borrowed theoretical framework): the Multiple Sclerosis Intimacy and Sexuality Questionnaire 15 (MSISQ 15) RESULTS: The normed χ2 was 1.21, the root mean square error of approximation was 0.046 [0.00; 0.07], the comparative fit index was 0.974, and the standardized root mean square was 0.065. The calculated Cronbach's coefficients indicated strong internal coherence, and the intraclass correlation coefficient was satisfactory at 0.9. Translations of the Multiple Sclerosis Intimacy and Sexuality Questionnaire 15 (MSISQ-15) have already been validated in five languages. This French version is valid, stable and reproducible. It provides French-speaking nurses an accessible and appropriate tool that will enable them to play an active role in the sexual health strategy recommended by the World Health Organization.