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Expanded CAG repeats in coding regions of different genes are the most common cause of dominantly inherited spinocerebellar ataxias (SCAs). These repeats are unstable through the germline, and larger repeats lead to earlier onset. We measured somatic expansion in blood samples collected from 30 SCA1, 50 SCA2, 74 SCA3, and 30 SCA7 individuals over a mean interval of 8.5 years, along with postmortem tissues and fetal tissues from SCA1, SCA3, and SCA7 individuals to examine somatic expansion at different stages of life. We showed that somatic mosaicism in the blood increases over time. Expansion levels are significantly different among SCAs and correlate with CAG repeat lengths. The level of expansion is greater in individuals with SCA7 who manifest disease compared to that of those who do not yet display symptoms. Brain tissues from SCA individuals have larger expansions compared to the blood. The cerebellum has the lowest mosaicism among the studied brain regions, along with a high expression of ATXNs and DNA repair genes. This was the opposite in cortices, with the highest mosaicism and lower expression of ATXNs and DNA repair genes. Fetal cortices did not show repeat instability. This study shows that CAG repeats are increasingly unstable during life in the blood and the brain of SCA individuals, with gene- and tissue-specific patterns.
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Mosaicismo , Ataxias Espinocerebelares , Expansão das Repetições de Trinucleotídeos , Humanos , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos/genética , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Cerebelo/metabolismo , Cerebelo/patologia , Idoso , Encéfalo/metabolismo , Encéfalo/patologia , Ataxina-1/genéticaRESUMO
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.
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BACKGROUND: International clinical criteria are the reference for the diagnosis of degenerative parkinsonism in clinical research, but they may lack sensitivity and specificity in the early stages. OBJECTIVES: To determine whether magnetic resonance imaging (MRI) analysis, through visual reading or machine-learning approaches, improves diagnostic accuracy compared with clinical diagnosis at an early stage in patients referred for suspected degenerative parkinsonism. MATERIALS: Patients with initial diagnostic uncertainty between Parkinson's disease (PD), progressive supranuclear palsy (PSP), and multisystem atrophy (MSA), with brain MRI performed at the initial visit (V1) and available 2-year follow-up (V2), were included. We evaluated the accuracy of the diagnosis established based on: (1) the international clinical diagnostic criteria for PD, PSP, and MSA at V1 ("Clin1"); (2) MRI visual reading blinded to the clinical diagnosis ("MRI"); (3) both MRI visual reading and clinical criteria at V1 ("MRI and Clin1"), and (4) a machine-learning algorithm ("Algorithm"). The gold standard diagnosis was established by expert consensus after a 2-year follow-up. RESULTS: We recruited 113 patients (53 with PD, 31 with PSP, and 29 with MSA). Considering the whole population, compared with clinical criteria at the initial visit ("Clin1": balanced accuracy, 66.2%), MRI visual reading showed a diagnostic gain of 14.3% ("MRI": 80.5%; P = 0.01), increasing to 19.2% when combined with the clinical diagnosis at the initial visit ("MRI and Clin1": 85.4%; P < 0.0001). The algorithm achieved a diagnostic gain of 9.9% ("Algorithm": 76.1%; P = 0.08). CONCLUSION: Our study shows the use of MRI analysis, whether by visual reading or machine-learning methods, for early differentiation of parkinsonism. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Diagnóstico Precoce , Imageamento por Ressonância Magnética , Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Humanos , Feminino , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/normas , Masculino , Idoso , Pessoa de Meia-Idade , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/diagnóstico , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/diagnóstico , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/diagnóstico , Aprendizado de Máquina , Incerteza , Diagnóstico Diferencial , Sensibilidade e EspecificidadeRESUMO
Reissner's fiber (RF) is an extracellular polymer comprising the large monomeric protein SCO-spondin (SSPO) secreted by the subcommissural organ (SCO) that extends through cerebrospinal fluid (CSF)-filled ventricles into the central canal of the spinal cord. In zebrafish, RF and CSF-contacting neurons (CSF-cNs) form an axial sensory system that detects spinal curvature, instructs morphogenesis of the body axis, and enables proper alignment of the spine. In mammalian models, RF has been implicated in CSF circulation. However, challenges in manipulating Sspo, an exceptionally large gene of 15,719 nucleotides, with traditional approaches has limited progress. Here, we generated a Sspo knockout mouse model using CRISPR/Cas9-mediated genome-editing. Sspo knockout mice lacked RF-positive material in the SCO and fibrillar condensates in the brain ventricles. Remarkably, Sspo knockout brain ventricle sizes were reduced compared to littermate controls. Minor defects in thoracic spine curvature were detected in Sspo knockouts, which did not alter basic motor behaviors tested. Altogether, our work in mouse demonstrates that SSPO and RF regulate ventricle size during development but only moderately impact spine geometry.
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Moléculas de Adesão Celular Neuronais , Ventrículos Cerebrais , Peixe-Zebra , Animais , Camundongos , Moléculas de Adesão Celular Neuronais/metabolismo , Ventrículos Cerebrais/metabolismo , Medula Espinal/metabolismo , Peixe-Zebra/metabolismoRESUMO
BACKGROUND: Though not originally developed for this purpose, the Healthy Aging Brain Care Monitor (HABC-M) seems a valuable instrument for assessing anosognosia in Alzheimer's disease (AD). OBJECTIVES: Our study aimed at 1) investigating the validity of the HABC-M (31 items), and its cognitive, psychological, and functional subscales, in discriminating AD patients from controls; 2) exploring whether the HABC-M discrepancy scores between the self-reports of patients/controls in these different domains and the respective ratings provided by their caregivers/informants correlate with an online measure of self-awareness; 3) determining whether the caregiver burden level, also derived from the HABC-M, could add additional support for detecting anosognosia. METHODS: The HABC-M was administered to 30 AD patients and 30 healthy controls, and to their caregivers/informants. A measure of online awareness was established from subjects' estimation of their performances in a computerized experiment. RESULTS: The HABC-M discrepancy scores distinguished AD patients from controls. The cognitive subscale discriminated the two groups from the prodromal AD stage, with an AUC of 0.88 [95% CI: 0.78;0.97]. Adding the caregiver burden level raised it to 0.94 [0.86;0.99]. Significant correlations between the HABC-M and online discrepancy scores were observed in the patients group, providing convergent validity of these methods. CONCLUSIONS: The cognitive HABC-M (six items) can detect anosognosia across the AD spectrum. The caregiver burden (four items) may corroborate the suspicion of anosognosia. The short-hybrid scale, built from these 10 items instead of the usual 31, showed the highest sensitivity for detecting anosognosia from the prodromal AD stage, which may further help with timely diagnosis.
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Agnosia , Doença de Alzheimer , Humanos , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Sintomas Prodrômicos , Cuidadores/psicologia , Encéfalo , Agnosia/diagnóstico , Agnosia/etiologia , Agnosia/psicologia , Testes NeuropsicológicosRESUMO
Reissner's fiber (RF) is an extracellular polymer comprising the large monomeric protein SCO-spondin (SSPO) secreted by the subcommissural organ (SCO) that extends through cerebrospinal fluid (CSF)-filled ventricles into the central canal of the spinal cord. In zebrafish, RF and CSF-contacting neurons (CSF-cNs) form an axial sensory system that detects spinal curvature, instructs morphogenesis of the body axis, and enables proper alignment of the spine. In mammalian models, RF has been implicated in CSF circulation. However, challenges in manipulating Sspo , an exceptionally large gene of 15,719 nucleotides, with traditional approaches has limited progress. Here, we generated a Sspo knockout mouse model using CRISPR/Cas9-mediated genome-editing. Sspo knockout mice lacked RF-positive material in the SCO and fibrillar condensates in the brain ventricles. Remarkably, Sspo knockout brain ventricle sizes were reduced compared to littermate controls. Minor defects in thoracic spine curvature were detected in Sspo knockouts, which did not alter basic motor behaviors tested. Altogether, our work in mouse demonstrates that SSPO and RF regulate ventricle size during development but only moderately impact spine geometry.
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Unawareness of memory deficits is an early manifestation in patients with Alzheimer's disease (AD), which often delays diagnosis. This intriguing behavior constitutes a form of anosognosia, whose neural mechanisms remain largely unknown. We hypothesized that anosognosia may depend on a critical synaptic failure in the error-monitoring system, which would prevent AD patients from being aware of their own memory impairment. To investigate, we measured event-related potentials (ERPs) evoked by erroneous responses during a word memory recognition task in two groups of amyloid positive individuals with only subjective memory complaints at study entry: those who progressed to AD within the five-year study period (PROG group), and those who remained cognitively normal (CTRL group). A significant reduction in the amplitude of the positivity error (Pe), an ERP related to error awareness, was observed in the PROG group at the time of AD diagnosis (vs study entry) in intra-group analysis, as well as when compared with the CTRL group in inter-group analysis, based on the last EEG acquisition for all subjects. Importantly, at the time of AD diagnosis, the PROG group exhibited clinical signs of anosognosia, overestimating their cognitive abilities, as evidenced by the discrepancy scores obtained from caregiver/informant vs participant reports on the cognitive subscale of the Healthy Aging Brain Care Monitor. To our knowledge, this is the first study to reveal the emergence of a failure in the error-monitoring system during a word memory recognition task at the early stages of AD. This finding, along with the decline of awareness for cognitive impairment observed in the PROG group, strongly suggests that a synaptic dysfunction in the error-monitoring system may be the critical neural mechanism at the origin of unawareness of deficits in AD.
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Agnosia , Doença de Alzheimer , Transtornos da Memória , Reconhecimento Psicológico , Humanos , Masculino , Feminino , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Transtornos da Memória/diagnóstico , Transtornos da Memória/fisiopatologia , Transtornos da Memória/psicologia , Eletroencefalografia , Potenciais Evocados , Agnosia/diagnóstico , Agnosia/fisiopatologia , Agnosia/psicologia , Sinapses , Testes NeuropsicológicosRESUMO
BACKGROUND: Carriers of small cytosine-adenine-guanine (CAG) repeats below 39 in the HTT gene are traditionally associated with milder Huntington's disease, but their clinical profile has not been extensively studied. OBJECTIVE: To study the phenotype of CAG36-38 repeat carriers. METHODS: We included 35 patients and premanifest carriers of CAG36-38 repeats. We compared clinical and neuropsychological profiles of 11 CAG36-38 patients with 11 matched CAG40-42 patients. In addition, we analyzed 243 CAG36-38 individuals from the ENROLL study to complete the phenotype description. RESULTS: Global cognitive efficiency and performance in different cognitive subdomains were similar in small CAG36-38 and typically CAG40-42 expanded individuals. Chorea as the first symptom was significantly less frequent for CAG36-38 patients (P = 0.04) despite similar total motor scores at first visit. Total motor score at last visit was significantly lower in CAG36-38 carriers (P = 0.003). The similar cognitive and different motor profile of CAG36-38 (n = 243) and CAG40-42 (n = 4675) carriers was confirmed in the ENROLL database. Additionally, clinicians were significantly less confident in diagnosing Huntington's disease (P = 2.4e-8) and diagnosis happened significantly later in CAG36-38 (P = 2.2e-6) despite a similar age at symptom onset (P = 0.29). CONCLUSIONS: We showed that small CAG36-38 expansion carriers had a similar cognitive profile to those with the more common CAG40-42 expansions. These individuals may evade molecular diagnosis because of the absence of chorea rather than because of a low penetrance of symptoms. This finding should encourage neurologists to consider Huntington's disease in cognitively impaired elderly patients without typical chorea and anticipate consequences for genetic counseling in their offspring. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Coreia , Doença de Huntington , Humanos , Doença de Huntington/diagnóstico , Coreia/complicações , Fenótipo , HeterozigotoRESUMO
Healthcare professionals' statistical illiteracy can impair medical decision quality and compromise patient safety. Previous studies have documented clinicians' insufficient proficiency in statistics and a tendency in overconfidence. However, an underexplored aspect is clinicians' awareness of their lack of statistical knowledge that precludes any corrective intervention attempt. Here, we investigated physicians', residents' and medical students' alignment between subjective confidence judgments and objective accuracy in basic medical statistics. We also examined how gender, profile of experience and practice of research activity affect this alignment, and the influence of problem framing (conditional probabilities, CP vs. natural frequencies, NF). Eight hundred ninety-eight clinicians completed an online survey assessing skill and confidence on three topics: vaccine efficacy, p value and diagnostic test results interpretation. Results evidenced an overall consistent poor proficiency in statistics often combined with high confidence, even in incorrect answers. We also demonstrate that despite overconfidence bias, clinicians show a degree of metacognitive sensitivity, as their confidence judgments discriminate between their correct and incorrect answers. Finally, we confirm the positive impact of the more intuitive NF framing on accuracy. Together, our results pave the way for the development of teaching recommendations and pedagogical interventions such as promoting metacognition on basic knowledge and statistical reasoning as well as the use of NF to tackle statistical illiteracy in the medical context.
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Ilusões , Metacognição , Médicos , Humanos , Julgamento , Pessoal de Saúde , Médicos/psicologiaRESUMO
The pathogenic bacterium Streptococcus pneumoniae (S. pneumoniae) can invade the cerebrospinal fluid (CSF) and cause meningitis with devastating consequences. Whether and how sensory cells in the central nervous system (CNS) become activated during bacterial infection, as recently reported for the peripheral nervous system, is not known. We find that CSF infection by S. pneumoniae in larval zebrafish leads to changes in posture and behavior that are reminiscent of pneumococcal meningitis, including dorsal arching and epileptic-like seizures. We show that during infection, invasion of the CSF by S. pneumoniae massively activates in vivo sensory neurons contacting the CSF, referred to as "CSF-cNs" and previously shown to detect spinal curvature and to control posture, locomotion, and spine morphogenesis. We find that CSF-cNs express orphan bitter taste receptors and respond in vitro to bacterial supernatant and metabolites via massive calcium transients, similar to the ones observed in vivo during infection. Upon infection, CSF-cNs also upregulate the expression of numerous cytokines and complement components involved in innate immunity. Accordingly, we demonstrate, using cell-specific ablation and blockade of neurotransmission, that CSF-cN neurosecretion enhances survival of the host during S. pneumoniae infection. Finally, we show that CSF-cNs respond to various pathogenic bacteria causing meningitis in humans, as well as to the supernatant of cells infected by a neurotropic virus. Altogether, our work uncovers that central sensory neurons in the spinal cord, previously involved in postural control and morphogenesis, contribute as well to host survival by responding to the invasion of the CSF by pathogenic bacteria during meningitis.
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Infecções do Sistema Nervoso Central , Streptococcus pneumoniae , Animais , Humanos , Streptococcus pneumoniae/fisiologia , Peixe-Zebra/fisiologia , Sistema Nervoso Central , Células Receptoras Sensoriais/fisiologiaRESUMO
INTRODUCTION: Quantitative biomarkers for clinical differentiation of parkinsonian syndromes are still lacking. Our aim was to evaluate the value of combining clinically feasible manual measurements of R2* relaxation rates and mean diffusivity (MD) in subcortical regions and brainstem morphometric measurements to improve the discrimination of parkinsonian syndromes. METHODS: Twenty-two healthy controls (HC), 25 patients with Parkinson's disease (PD), 19 with progressive supranuclear palsy (PSP) and 27 with multiple system atrophy (MSA, 21 with the parkinsonian variant -MSAp, 6 with the cerebellar variant -MSAc) were recruited. R2*, MD measurements and morphometric biomarkers including the midbrain to pons area ratio and the Magnetic Resonance Parkinsonism Index (MRPI) were compared between groups and their diagnostic performances were assessed. RESULTS: Morphometric biomarkers discriminated better patients with PSP (ratio: AUC 0.89, MRPI: AUC 0.89) and MSAc (ratio: AUC 0.82, MRPI: AUC 0.75) from other groups. R2* and MD measurements in the posterior putamen performed better in separating patients with MSAp from PD (R2*: AUC 0.89; MD: AUC 0.89). For the three-class classification "MSA vs PD vs PSP", the combination of MD and R2* measurements in the posterior putamen with morphometric biomarkers (AUC: 0.841) outperformed each marker separately. At the individual-level, there were seven discordances between imaging-based prediction and clinical diagnosis involving MSA. Using the new Movement Disorder Society criteria for the diagnosis of MSA, three of these seven patients were clinically reclassified as predicted by quantitative imaging. CONCLUSION: Combining R2* and MD measurements in the posterior putamen with morphometric biomarkers improves the discrimination of parkinsonism.
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Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Humanos , Transtornos Parkinsonianos/patologia , Paralisia Supranuclear Progressiva/patologia , Imagem de Difusão por Ressonância Magnética , Tronco Encefálico/patologia , Atrofia de Múltiplos Sistemas/patologia , Imageamento por Ressonância Magnética/métodos , Diagnóstico DiferencialRESUMO
BACKGROUND: The locus coeruleus/subcoeruleus complex (LC/LsC) is a structure comprising melanized noradrenergic neurons. OBJECTIVE: To study the LC/LsC damage across Parkinson's disease (PD) and atypical parkinsonism in a large group of subjects. METHODS: We studied 98 healthy control subjects, 47 patients with isolated rapid eye movement sleep behavior disorder (RBD), 75 patients with PD plus RBD, 142 patients with PD without RBD, 19 patients with progressive supranuclear palsy (PSP), and 19 patients with multiple system atrophy (MSA). Twelve patients with MSA had proven RBD. LC/LsC signal intensity was derived from neuromelanin magnetic resonance imaging using automated software. RESULTS: The signal intensity was reduced in all parkinsonian syndromes compared with healthy control subjects, except in PD without RBD. The signal intensity decreased as age increased. Moreover, the signal intensity was lower in MSA than in isolated RBD and PD without RBD groups. In PD, the signal intensity correlated negatively with the percentage of REM sleep without atonia. There were no differences in signal intensity between PD plus RBD, PSP, and MSA. CONCLUSIONS: Neuromelanin signal intensity was reduced in all parkinsonian disorders, except in PD without RBD. The presence of RBD in parkinsonian disorders appears to be associated with lower neuromelanin signal intensity. Furthermore, lower LC/LsC signal changes in PSP could be partly caused by the effect of age. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Humanos , Locus Cerúleo/diagnóstico por imagem , Locus Cerúleo/patologia , Transtornos Parkinsonianos/complicações , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Paralisia Supranuclear Progressiva/patologia , Atrofia de Múltiplos Sistemas/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
Background The time course of cellular damage after acute ischemic stroke (IS) is currently not well known, and specific noninvasive markers of microstructural alterations linked to inflammation are lacking, which hinders the monitoring of anti-inflammatory treatment. Purpose To evaluate the temporal pattern of neuronal and glial microstructural changes after stroke using in vivo single-voxel diffusion-weighted MR spectroscopy. Materials and Methods In this prospective longitudinal study, participants with IS and healthy volunteers (HVs) underwent MRI at 3.0 T. In participants with IS, apparent diffusion coefficients (ADCs) and concentrations of total N-acetyl-aspartate (tNAA), total creatine (tCr), and total choline (tCho) were measured in volumes of interest (VOIs), including the lesion VOI (VOIles) and the contralateral VOI (VOIcl) at 2 weeks, 1 month, and 3 months after IS. HVs were examined once, with VOIs located in the same brain regions as participants with IS. Within- and between-group differences and longitudinal changes were examined using linear mixed-effects models. Results Twenty participants with IS (mean age, 61 years ± 13 [SD]; 12 women) and 20 HVs (mean age, 59 years ± 13; 12 women) were evaluated. No differences in ADCs or concentrations were observed in VOIcl between HVs and participants with IS. In participants with IS, the ADC of tCr was higher in VOIles than in VOIcl at 1 month (+14.4%, P = .004) and 3 months after IS (+19.0%, P < .001), while the ADC of tCho was higher only at 1 month (+16.7%, P = .001). No difference in the ADC of tNAA was observed between the two VOIs at any time point. tNAA and tCr concentrations were lower in VOIles than in VOIcl and were stable over time (approximately -50% and -30%, respectively; P < .001). Conclusion High diffusivity of choline-containing compounds and total creatine (tCr) in the ischemic lesion 1 month after ischemic stroke (IS) indicates glial morphologic changes, suggesting that active inflammation is still ongoing at this time point. High tCr diffusivity up to 3 months after IS likely reflects the presence of astrogliosis at the chronic stage of cerebral ischemia. Clinical trial registration no. NCT02833961 © RSNA, 2022 Online supplemental material is available for this article.
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Isquemia Encefálica , AVC Isquêmico , Humanos , Feminino , Pessoa de Meia-Idade , Creatina , AVC Isquêmico/diagnóstico por imagem , Estudos Longitudinais , Estudos Prospectivos , Espectroscopia de Ressonância Magnética/métodos , Isquemia Encefálica/diagnóstico por imagem , Colina , Receptores de Antígenos de Linfócitos TRESUMO
Presurgical evaluation of mesial temporal and neocortical focal pharmacoresistant epilepsy patients using intracranial EEG recordings has led to the generation of extensive data on interictal epileptiform discharges, located within or remotely from seizure onset zones. In this study, we used this data to investigate how interictal epileptiform discharges are modulated and how their spatial distribution changes during wake and sleep and analysed the relationship between these discharge events and seizure onset zones. Preoperative evaluation data from 11 adult patients with focal pharmacoresistant epilepsy were extracted from the Epilepsiae database. Interictal epileptiform discharges were automatically detected during wakefulness and over several hours of continuous seizure-free sleep (total duration of EEG recordings:106.7â h; mean per patient: 9.7â h), and analysed across four brain areas (mesial temporal, lateral neocortical, basal cortical and the temporal pole). Sleep stages were classified manually from scalp EEG. Discharge events were characterized according to their rate and morphology (amplitude, sharpness and duration). Eight patients had a seizure onset zone over mesial areas and three patients over lateral neocortical areas. Overall, discharge rates varied across brain areas during wakefulness and sleep [wake/sleep stages × brain areas interaction; Wald χ 2(df = 6) = 31.1, P < 0.0001]. N2-N3 non-rapid eye movement sleep increased interictal epileptiform discharges in mesial areas compared with wakefulness and rapid eye movement sleep (P < 0.0001), and to other areas (P < 0.0001 for all comparisons). This mesial pattern was observed both within and outside of seizure onset zones. During wakefulness, the rate of interictal epileptiform discharges was significantly higher than during N2-N3 non-rapid eye movement sleep (P = 0.04), and rapid eye movement sleep (P = 0.01) in lateral neocortical areas (referred to as lateral neocortical pattern), a finding that was more pronounced in seizures onset zones (P = 0.004). The morphological characteristics of the discharge events were modulated during wakefulness and sleep stages across brain areas. The effect of seizure onset zones on discharge morphology was conditioned by brain area and was particularly marked in temporal pole areas. Our analysis of discharge patterns in relation to cerebral localization, vigilance state and the anatomical affiliation of seizure onset zones revealed the global and local aspects of the complex relationship between interictal discharges, sleep and seizure onset zones. This novel approach may lead to a better understanding of cognitive decline and responses to therapy, as well as to adaptation of surgical interventions for epileptic patients.
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PURPOSE: Hereditary spastic paraplegia type 4 is extremely variable in age at onset; the same variant can cause onset at birth or in the eighth decade. We recently discovered that missense variants in SPAST, which influences microtubule dynamics, are associated with earlier onset and more severe disease than truncating variants, but even within the early and late-onset groups there remained significant differences in onset. Given the rarity of the condition, we adapted an extreme phenotype approach to identify genetic modifiers of onset. METHODS: We performed a genome-wide association study on 134 patients bearing truncating pathogenic variants in SPAST, divided into early- and late-onset groups (aged ≤15 and ≥45 years, respectively). A replication cohort of 419 included patients carrying either truncating or missense variants. Finally, age at onset was analyzed in the merged cohort (N = 553). RESULTS: We found 1 signal associated with earlier age at onset (rs10775533, P = 8.73E-6) in 2 independent cohorts and in the merged cohort (N = 553, Mantel-Cox test, P < .0001). Western blotting in lymphocytes of 20 patients showed that this locus tends to upregulate SARS2 expression in earlier-onset patients. CONCLUSION: SARS2 overexpression lowers the age of onset in hereditary spastic paraplegia type 4. Lowering SARS2 or improving mitochondrial function could thus present viable approaches to therapy.
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Serina-tRNA Ligase , Paraplegia Espástica Hereditária , Humanos , Estudo de Associação Genômica Ampla , Mutação , Serina-tRNA Ligase/genética , Serina-tRNA Ligase/metabolismo , Paraplegia Espástica Hereditária/genética , Espastina/genética , Espastina/metabolismoRESUMO
Background Apathy is a common behavioral syndrome that occurs across neurological and psychiatric disorders. An influential theoretical framework defined apathy as the quantitative reduction of self-generated voluntary and purposeful behaviors. There is evidence in the literature of the multidimensional nature of apathy with cognitive, behavioral, and emotional dimensions. To date, apathy has been assessed using various scales and questionnaires. Alternative objective and ecological measurements of apathy are needed. New method We used the ECOCAPTURE protocol and an ethological approach to investigate behavior in bvFTD patients under ecological conditions (a waiting room) while they freely explored a novel environment. Data were collected by behavioral coding from 7-minute video using an ethogram and transformed into behavior time series data. We present an approach considering behavioral kinetics to assess behavior. We aimed to construct a new behavior analysis method, called ECOCAPTURE kinetics, using temporal classification for behavior time series data analysis. To develop our classifier, we retained a nonelastic Euclidian metric, combined with a convolutional approach. Results We applied the ECOCAPTURE kinetics method to a cohort of 20 bvFTD patients and 18 healthy controls. We showed that bvFTD patients can be classified according to their behavioral kinetics into three groups. Each subgroup was characterized by specific behavior disorders and neuropsychological profile. Comparison with Existing Method(s) The ECOCAPTURE kinetics method is different from those of the classical approach of measuring behavior, producing time budgets, frequency of behavior occurrences, or kinematic diagrams. Conclusions This approach can be extended to any behavioral study encoding time.
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Apatia , Demência Frontotemporal , Humanos , Testes Neuropsicológicos , Fatores de TempoRESUMO
BACKGROUND: Neurodegeneration in the substantia nigra pars compacta (SNc) in parkinsonian syndromes may affect the nigral territories differently. OBJECTIVE: The objective of this study was to investigate the regional selectivity of neurodegenerative changes in the SNc in patients with Parkinson's disease (PD) and atypical parkinsonism using neuromelanin-sensitive magnetic resonance imaging (MRI). METHODS: A total of 22 healthy controls (HC), 38 patients with PD, 22 patients with progressive supranuclear palsy (PSP), 20 patients with multiple system atrophy (MSA, 13 with the parkinsonian variant, 7 with the cerebellar variant), 7 patients with dementia with Lewy body (DLB), and 4 patients with corticobasal syndrome were analyzed. volume and signal-to-noise ratio (SNR) values of the SNc were derived from neuromelanin-sensitive MRI in the whole SNc. Analysis of signal changes was performed in the sensorimotor, associative, and limbic territories of the SNc. RESULTS: SNc volume and corrected volume were significantly reduced in PD, PSP, and MSA versus HC. Patients with PSP had lower volume, corrected volume, SNR, and contrast-to-noise ratio than HC and patients with PD and MSA. Patients with PSP had greater SNR reduction in the associative region than HC and patients with PD and MSA. Patients with PD had reduced SNR in the sensorimotor territory, unlike patients with PSP. Patients with MSA did not differ from patients with PD. CONCLUSIONS: This study provides the first MRI comparison of the topography of neuromelanin changes in parkinsonism. The spatial pattern of changes differed between PSP and synucleinopathies. These nigral topographical differences are consistent with the topography of the extranigral involvement in parkinsonian syndromes. © 2022 International Parkinson and Movement Disorder Society.
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Atrofia de Múltiplos Sistemas , Doença de Parkinson , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Humanos , Imageamento por Ressonância Magnética/métodos , Melaninas , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/patologia , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Substância Negra/diagnóstico por imagem , Substância Negra/patologia , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Paralisia Supranuclear Progressiva/patologiaRESUMO
Although calcium waves have been widely observed in glial cells, their occurrence in vivo during behavior remains less understood. Here, we investigated the recruitment of glial cells in the hindbrain and spinal cord after acousto-vestibular (AV) stimuli triggering escape responses using in vivo population calcium imaging in larval zebrafish. We observed that gap-junction-coupled spinal glial network exhibits large and homogenous calcium increases that rose in the rostral spinal cord and propagated bi-directionally toward the spinal cord and toward the hindbrain. Spinal glial calcium waves were driven by the recruitment of neurons and in particular, of noradrenergic signaling acting through α-adrenergic receptors. Noradrenergic neurons of the medulla-oblongata (NE-MO) were revealed in the vicinity of where the calcium wave started. NE-MO were recruited upon AV stimulation and sent dense axonal projections in the rostro-lateral spinal cord, suggesting these cells could trigger the glial wave to propagate down the spinal cord. Altogether, our results revealed that a simple AV stimulation is sufficient to recruit noradrenergic neurons in the brainstem that trigger in the rostral spinal cord two massive glial calcium waves, one traveling caudally in the spinal cord and another rostrally into the hindbrain.
Assuntos
Sinalização do Cálcio , Norepinefrina , Animais , Proteína Glial Fibrilar Ácida/metabolismo , Neuroglia/metabolismo , Medula Espinal/metabolismo , Peixe-Zebra/metabolismoRESUMO
Molecular and brain regional/network-wise pathophysiological changes at preclinical stages of Alzheimer's disease (AD) have primarily been found through knowledge-based studies conducted in late-stage mild cognitive impairment/dementia populations. However, such an approach may compromise the objective of identifying the earliest spatial-temporal pathophysiological processes. We investigated 261 individuals with subjective memory complaints, a condition at increased risk of AD, to test a whole-brain, non-a-priori method based on partial least squares in unraveling the association between plasma Aß42/Aß40 ratio and an extensive set of brain regions characterized through molecular imaging of Aß accumulation and cortical metabolism. Significant associations were mapped onto large-scale networks, identified through an atlas and by knowledge, to elaborate on the reliability of the results. Plasma Aß42/40 ratio was associated with Aß-PET uptake (but not FDG-PET) in regions generally investigated in preclinical AD such as those belonging to the default mode network, but also in regions/networks normally not accounted - including the central executive and salience networks - which likely have a selective vulnerability to incipient Aß accumulation. The present whole-brain approach is promising to investigate early pathophysiological changes of AD to fully capture the complexity of the disease, which is essential to develop timely screening, detection, diagnostic, and therapeutic interventions.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Fragmentos de Peptídeos/sangue , Idoso , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons , RiscoRESUMO
INTRODUCTION: Serum phenotyping of elite cyclists regarding cortisol, IGF1 and testosterone is a way to detect endocrine disruptions possibly explained by exercise overload, non-balanced diet or by doping. This latter disruption-driven approach is supported by fundamental physiology although without any evidence of any metabolic markers. OBJECTIVES: Serum samples were distributed through Low, High or Normal endocrine classes according to hormone concentration. A 1H NMR metabolomic study of 655 serum obtained in the context of the longitudinal medical follow-up of 253 subjects was performed to discriminate the three classes for every endocrine phenotype. METHODS: An original processing algorithm was built which combined a partial-least squares-based orthogonal correction of metabolomic signals and a shrinkage discriminant analysis (SDA) to get satisfying classifications. An extended validation procedure was used to plan in larger size cohorts a minimal size to get a global prediction rate (GPR), i.e. the product of the three class prediction rates, higher than 99.9%. RESULTS: Considering the 200 most SDA-informative variables, a sigmoidal fitting of the GPR gave estimates of a minimal sample size to 929, 2346 and 1408 for cortisol, IGF1 and testosterone, respectively. Analysis of outliers from cortisol and testosterone Normal classes outside the 97.5%-confidence limit of score prediction revealed possibly (i) an inadequate protein intake for outliers or (ii) an intake of dietary ergogenics, glycine or glutamine, which might explain the significant presence of heterogeneous metabolic profiles in a supposedly normal cyclists subgroup. CONCLUSION: In a next validation metabolomics study of a so-sized cohort, anthropological, clinical and dietary metadata should be recorded in priority at the blood collection time to confirm these functional hypotheses.