La matrice extracellulaire est composée d’environ 300 protéines et protéoglycanes qui constituent le matrisome et de 800 protéines associées (Naba et al., 2012a) et glycosaminoglycanes. C’est un protéome sous-exploré qui est modifié dans de nombreuses pathologies. Les fragments bioactifs issus de la matrice extracellulaire (matricryptines) sont capables de réguler des processus physiopathologiques et notamment l’angiogenèse et les pathologies cérébrales (Ricard-Blum and Salza, 2014). Environ 90 % des patients atteints de la maladie d’Alzheimer (MA) ont une angiopathie amyloïde cérébrale. L’angiogenèse contribue au déroulement de la MA. Nous nous sommes intéressés à l’endostatine (ES), une matricryptine du collagène XVIII qui possède des activités anti-angiogéniques, anti-tumorales et est également présente dans les plaques amyloïdes chez les patients atteints de la MA. Elle est libérée par les neurones et est capable de former des fibrilles amyloïdes in vitro (Kranenburg et al., 2003). Elle pourrait donc avoir une implication dans la MA. Nous avons montré que l'ES est présente dans le liquide céphalorachidien et que le rapport de sa concentration à celle des marqueurs classiques de la MA permet d’améliorer le diagnostic des patients atteint de démence fronto-temporale (DFT) et de discriminer les patients atteints de MA de ceux atteint de DFT et de pathologie nonMA/nonDFT. Nous avons établi les répertoires d’interactions extracellulaire du peptide -amyloïde (1-42) sous formes monomérique, oligomérique, fibrillaire ou agrégée et montré que l’oligomérisation et la fibrillogenèse augmentent la capacité d’interaction du peptide -amyloïde. Nous avons établi le réseau d’interaction global de l’endostatine par résonance plasmonique de surface en mode imagerie et identifiés 21 nouveaux partenaires de cette matricryptine. Nous avons plus particulièrement caractérisé son interaction avec la Procollagen C-Proteinase Enhancer-1, une protéine dont nous avons montré qu’elle donne naissance à une matricryptine anti-angiogénique. Nous avons enfin construit les réseaux d’interactions extracellulaires spécifiques de l’angiogenèse et de la maladie d’Alzheimer et des processus amyloïdes pour identifier les protéines connectant ces deux processus qui sont des cibles thérapeutiques potentielles. Ces réseaux d’interactions ont été créés à l’aide de 239 interactions que nous avons identifiées expérimentalement et des interactions décrites dans la littérature. Ces données seront à terme disponibles dans la base de données spécifique des interactions extracellulaires créée au laboratoire, MatrixDB, dans la nouvelle version à laquelle nous avons contribué. / The extracellular matrix include approximately 300 proteins and proteoglycans which constitute the matrisome and 800 associated proteins (Naba et al., 2012a) and glycosaminoglycans. It is an under-explored proteome which is modified in many diseases. Extracellular matrix bioactives fragments (matricryptins) are able to regulate physiopathological process like angiogenesis and cerebral disorders (Ricard-Blum and Salza, 2014). About 90 % of patients with Alzheimer's disease (AD) have cerebral amyloid angiopathy. Angiogenesis contributes to the development of AD. We are studying endostatin (ES), a matricryptin of collagen XVIII which has anti-angiogenic and anti-tumoral activities and is also present in amyloid plaques in AD patients. ES is released by neurons and is able to form amyloid fibrils in vitro (Kranenburg et al., 2003). This anti-angiogenic matricryptin could therefore be involved in AD. We have shown that ES is present in the cerebrospinal fluid of AD patients and the ratio of its concentrations to conventional markers of AD improves the diagnosis of patients with frontotemporal dementia (FTD) and discriminate AD patients from those suffering from FTD and pathology noAD/noDFT. We have established the extracellular interactions repertoires of the -amyloid peptide (1-42) in monomeric, oligomeric, fibrillar or aggregated forms and showed that the oligomerization and fibrillogenesis increase the interaction capacity of the -amyloid peptide. We have established the global interaction network of endostatin by surface plasmon resonance imaging and identified 21 new partners of this matricryptin. Specifically, we characterized its interaction with the Procollagen C-Proteinase Enhancer-1, a protein which gives rise to an anti-angiogenic matricryptin. We finally built networks of specific extracellular interactions of angiogenesis and of Alzheimer's disease and amyloid process to identify proteins connecting these two processes that are potential therapeutic targets. These interaction networks have been built using 239 interactions including those we have identified experimentally and those described in the literature. This data will be available in the database specific of extracellular interactions created in the laboratory, MatrixDB, in the new version of which we contributed.

No description available.

No description available.

Alzheimers sjukdom (AD, eng. Alzheimer’s disease) upptäcktes för 111 år sedan av Alois Alz-heimer. Idag är det den ledande orsaken till demens hos äldre, och incidencen förväntas öka med befolkningens ökande livslängd. År 2050 förutspås antalet patienter med AD nå 10 miljoner personer [1]. Det har gjorts många försök att angripa AD via dess främsta kännetäcken, såsom plack av beta-amyloid (Aβ), Aβ-oligomerer, och ansamlingar av tau-protein, kallat tau-trassel. Trots att forskning om AD bedrivits i flera årtionden är dess orsak alltjämt okänd.På sistone har det funnits ett fokus på de inflammatoriska komponenterna inom AD. Det finns en utbredd aktivering av immunförsvaret i det centrala nervsystemet hos patienter med AD, men varken dess orsak eller dess roll inom AD är känd. Däremot finns det tydliga tecken på att inflammationen är av autoimmun art. Med detta i åtanke är det tydligt att det finns ett stort behov att utröna auto-immunitetens roll inom AD. I denna forskningsstudie användes proteomik-metoder för att bestämma autoantikroppsprofilerna inom plasma och cerebrospinalvätska (CSF, eng. cerebrospinal fluid) hos AD-patienter och en frisk kontrollgrupp.I denna studie användes par av plasma- och CSF-prover från 23 friska individer och 49 patien-ter. Dessutom inkluderades 2 plasmaprover och 18 CSF-prover från patienter. En 380-faldig och en 314-faldig riktad analys gjordes med hjälp utav suspension bead array-teknologi (SBA). Varje SBA bestod av färgkodade, magnetiska mikrosfärer i suspension, med antigen immobiliserade på kulornas yta. Denna analysmetod användes för att undersöka autoantikropssprofilerna i alla prover. Resul-taten visade en ökad respons från autoantikroppar mot antigenen SLC17A6 (Solute Carrier Family 17 Member 6), MAP1A (Microtubule Associated Protein 1A), och MAP2 (Microtubule Associated Protein 2) i patiener gentemot friska individer. Dock har dessa antigen uppvisat en bred reaktivitet i tidigare, opublicerade studier. Därför behövs ytterligare forskning för att fastställa deras roll inom AD.Dessutom användes paren av plasma- och CSF-prover för att undersöka autoantikroppsprofilernas överrensstämmelse inom varje patient. Det visade sig att korrelationen följde en normalfördelning, med starkare korrelation inom antigen med starkare reaktivitet mot den motsvarande autoantikroppen. Denna studie utgör en av de första storskaliga forskningsstudierna av överrensstämmelsen mellan autoantikroppsprofilerna inom plasma och CSF. / Alzheimer’s disease (AD) was discovered 111 years ago by Alois Alzheimer. Today, it is the leading cause of dementia in elderly, and incidence is expected to increase with life expectancy. By 2050, the number of a˙ected individuals is predicted to reach 10 million [1]. There have been numerous attempts to describe AD by its primary hallmarks, including amyloid plaques, amyloid beta (Aβ) oligomers, and tau tangles. However, despite several decades of intense research, the cause of AD remains unknown.Recently, there has been a focus on the inflammatory components of AD. There is an extensive activation of the immune system within the CNS of AD patients, but neither its cause nor its role in AD is known. However, there are strong indications that the inflammation has an autoimmune character. Considering this, there is an imperative need to examine autoimmunity within AD. In the present study, a proteomic approach was used to determine the autoantibody profiles within plasma and cerebrospinal fluid (CSF) within AD patients and healthy controls.Paired plasma and CSF samples from 23 healthy controls and 49 patients were included in the present study. In addition, 2 plasma samples and 18 CSF samples from patients were included (not paired). One 380-plex and one 314-plex targeted suspension bead array (SBA), each consisting of color-coded magnetic microspheres with immobilized antigens, were used to analyze autoantibody profiles in all samples. The resulting data revealed an increased autoantibody response towards anti-gens SLC17A6 (Solute Carrier Family 17 Member 6), MAP1A (Microtubule Associated Protein 1A), and MAP2 (Microtubule Associated Protein 2) in patients compared to healthy controls. However, as these antigens have displayed wide reactivities in previous, unpublished studies, they require further investigation to determine their role in AD.Furthermore, the paired CSF and plasma samples were used to investigate the correlation of autoantibody profiles within patients. The correlation was found to follow a normal distribution, with correlation being higher in antigens displaying stronger autoantibody reactivity. This work represents one of the first large-scale studies on the correlation of autoantibody profiles in plasma and CSF.

<p dir="ltr">The brain is a dynamic tissue that is passively driven by a combination of the cardiac cycle, respiration, and slow wave oscillations. The function of the brain relies on its ability to maintain a normal homeostatic balance between its mechanical environment and metabolic demands, which can be greatly altered in the cases of neurodegeneration or traumatic brain injury. It has been a challenge in the field to quantify the dynamics of the tissue and cerebrospinal fluid flow in human subjects on a patient-specific basis over the many spatial and temporal scales that it relies upon. Non-invasive imaging tools like structural, functional, and dynamic MRI sequences provide modern researchers with an unprecedented view into the human brain. Our work leverages these sequences by developing novel, open-source pipelines to 1) quantify the biomechanical environment of the brain tissue over 133 functional brain regions, and 2) estimate real-time cerebrospinal fluid velocity from flow artifacts on functional MRI by employing breathing regimens to enhance fluid motion. These pipelines provide a comprehensive view of the macroscale tissue and fluid motion in a given patient. Additionally, we sought to understand how the transmission of macroscale forces, in the context of traumatic brain injury, contribute to neuronal damage by 3) developing a digital twin to simulate 30-200 g-force loading of 2D neuronal cultures and observing the morphological and electrophysiological consequences of these impacts in vitro by our collaborators. Taken together, we believe these works are a steppingstone that will enable future researchers to deeply understand the mechanical contributions that underly clinical neurological outcomes and perhaps lead to the development of earlier diagnostics, which is of dire need in the case of neurodegenerative diseases.</p>

No description available.

PURPOSE: To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius in multiple sclerosis (MS) patients and healthy controls (HC) using cine phase contrast imaging. MATERIALS AND METHODS: In all, 67 MS patients (48 relapsing-remitting [RR] and 19 secondary-progressive [SP]), nine patients with clinically isolated syndrome (CIS), and 35 age- and sex-matched HC were examined. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and magnetic resonance imaging (MRI) disease outcomes. RESULTS: Significantly decreased CSF net flow was detected in MS patients compared to HC (-3.7 vs. -7.1 muL/beat, P = 0.005). There was a trend for increased net positive flow between SP, RR, and CIS patients. Altered CSF flow and velocity measures were associated with more severe T1 and T2 lesion volumes, lateral and fourth ventricular volumes, and third ventricular width in MS and CIS patients (P < 0.01 for all). In CIS patients, conversion to clinically definite MS in the following year was related to decreased CSF net flow (P = 0.007). There was a trend between increased annual relapse rate and altered CSF flow/velocity measures in RRMS patients (P < 0.05). CONCLUSION: CSF flow dynamics are altered in MS patients. More severe clinical and MRI outcomes in RRMS and CIS patients relate to altered CSF flow and velocity measures.

Die Liquordiagnostik im Rahmen von Demenzerkrankungen ist trotz neuer diagnostischer Möglichkeiten im Bereich der PET(Positronen-Emissions-Tomographie)-Bildgebung weiterhin von hoher klinischer Relevanz. Insbesondere für die Alzheimer-Erkrankung existieren validierte Biomarker, die die Diagnose untermauern und bei der diagnostischen Abgrenzung anderer Demenzätiologien hilfreich sein können.Während unauffällige Liquorbefunde mit negativen Demenz- und Destruktionsmarkern die überwiegende Mehrzahl neurodegenerativer Demenzursachen mit hoher diagnostischer Sicherheit ausschließen, stellen in der klinischen Praxis vor allem überlappende Biomarkerprofile bei primär neurodegenerativen Demenzursachen ein substanzielles Problem bei der Befundinterpretation dar. Deshalb bedarf die Liquorbefundinterpretation stets einer kontextualisierten Betrachtung unter Würdigung der klinischen Symptomatik und Verlaufscharakteristika des entsprechenden demenziellen Syndroms. Außerdem stellen auchMischbefunde eine häufige diagnostische Herausforderung dar, ür deren Interpretation es profunder Kenntnisse im Bereich von Präanalytik, möglicher Liquorbefundkonstellationen und natürlich der verschiedenen in Betracht kommenden Demenzätiologien bedarf. Auch Liquorbiomarker für Synukleinopathien, Tauopathien sowie TDP43(Transactive response DNA binding protein 43 kDa)-Proteinopathien sind Gegenstand aktueller Untersuchungen, wenngleich diese noch nicht den Weg in die klinische Routinediagnostik gefunden haben.

No / The purpose of this article is to investigate characteristics of cine phase contrast-calculated cerebrospinal fluid (CSF) flow and velocity measures in patients with relapsing-remitting (RR) multiple sclerosis (MS) receiving standard medical treatment who had been diagnosed with chronic cerebrospinal venous insufficiency (CCSVI) and underwent percutaneous transluminal angioplasty (PTA). This case-controlled, magnetic resonance (MR) imaging-blinded study included 15 patients with RR MS who presented with significant stenoses (>/=50% lumen reduction on catheter venography) in the azygous or internal jugular veins. Eight patients underwent PTA in addition to medical therapy immediately following baseline assessments (case group) and seven had delayed PTA after 6 months of medical therapy alone (control group). CSF flow and velocity measures were quantified over 32 phases of the cardiac cycle by a semiautomated method. Outcomes were compared between groups at baseline and at 6 and 12 months of the study by mixed-effect model analysis. At baseline, no significant differences in CSF flow or velocity measures were detected between groups. At month 6, significant improvement in flow (P<.001) and velocity (P = .013) outcomes were detected in the immediate versus the delayed group, and persisted to month 12 (P = .001 and P = .021, respectively). Within-group flow comparisons from baseline to follow-up showed a significant increase in the immediate group (P = .033) but a decrease in the delayed group (P = .024). Altered CSF flow and velocity measures were associated with worsening of clinical and MR outcomes in the delayed group. PTA in patients with MS with CCSVI increased CSF flow and decreased CSF velocity, which are indicative of improved venous parenchyma drainage.

Objetivos: Malformação de Chiari do tipo I (MC-I) é a principal doença malformativa congênita da junção craniovertebral, manifestando-se com ampla variedade de sinais e sintomas neurológicos. A melhor técnica cirúrgica a ser empregada no tratamento dos pacientes com malformação de Chiari do tipo I é ainda controversa. A descompressão das estruturas da fossa craniana posterior com plástica de ampliação dural é considerada procedimento padrão. Embora efetiva e de baixa morbidade, a craniectomia occipital isolada, sem abertura e ampliação dural, implica maior taxa de recidiva dos sintomas. Métodos que selecionam os pacientes quanto a necessidade da duroplastia não foram estabelecidos. O presente trabalho avalia a eficácia da mensuração intraoperatória da velocidade do fluxo do líquido cefalorraquidiano através da ultrassonografia (USG) na seleção da técnica cirúrgica a ser utilizada. Métodos: Foram analisados de forma prospectiva 49 pacientes submetidos à cirurgia para MC-I. A indicação de craniectomia da fossa posterior associada ou não à plástica de ampliação da dura-máter baseou-se na velocidade do fluxo do líquido cefalorraquidiano, mensurada pela ultrassonografia intraoperatória. Dor cervical, cefaleia e qualidade de vida foram avaliadas antes e após o tratamento cirúrgico. Resultados: Dos 49 pacientes incluídos, 36 pacientes (73%) apresentavam fluxo do líquido cefalorraquidiano superior a 3 cm/s e não foram submetidos a duroplastia ampliadora. Nos 13 (27%) pacientes com fluxo inicial inferior a 3 cm/s, indicou-se craniectomia occipital com duroplastia de ampliação. Não houve diferença significativa entre os dois grupos com relação aos parâmetros estudados. Conclusão: A ultrassonografia intraoperatória com avaliação da dinâmica e velocidade do fluxo do líquido cefalorraquidiano da junção craniovertebral auxilia a indicação de duroplastia durante descompressão da fossa craniana posterior em pacientes adultos com MC-I / Objectives: Chiari malformation Type I (CM-I) is the main congenital malformation disease of the craniovertebral junction, and may be responsible for a variety of neurological symptoms. The ideal surgical technique used to treat patients with CM-I is still controversial. Invasive procedures that enters CSF space and are associated with dural repair, are considered the gold standard. Although effective and less morbidity, isolated bone decompression without dural opening, implies greater recurrence of symptoms. Objective parameters to select patients, who need or not to have a duroplasty performed, have not been established. Our study evaluates the efficacy of intra-operative CSF flow measurement through the use of ultrasonography (USG) as a determining parameter in the selection of these patients. Methods: We analyzed prospectively 49 posterior fossa surgeries for patients with CM-I. Patients underwent decompressive surgery with or without opening of the dura mater after conducting USG intra-operatively with measured flow rate, being adopted 3cm/s flow rate as a determining value. The quality of life before and after surgery and the improvement of neck pain and headache were the parameters evaluated. Results: Of the 49 patients enrolled, 36 patients (73%) had adequate CSF flow above 3 cm / s and have not undergone duroplasty. In 13 (27%) patients with initial flow < 3 cm / s an opening in dura mater was performed together with duroplasty. There was no significant difference between the two groups regarding the parameters studied. Conclusion: Intraoperative ultrasound with measurement of CSF flow, having a flow of 3 cm / s as cut-off, allows the proper selection of patients with CM-I that can have a less invasive surgery with bone decompression without duroplasty