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We performed a retrospective analysis of the patients assessed at our memory unit for whom Alzheimer disease (AD) cerebrospinal fluid biomarker results were available. We selected patients diagnosed with mild cognitive impairment due to AD (National Institute on Aging-Alzheimer's Association clinical criteria), confirmed neuropsychological deficit, a Global Deterioration Scale score of 3, and an abnormal profile of cerebrospinal fluid biomarkers. Of the 588 cases reviewed, 110 met the inclusion criteria. During follow-up, 50 cases (45.45%) progressed to dementia due to AD. Baseline levels of total and phosphorylated tau were higher in the group of patients that progressed to dementia than in those remaining with mild cognitive impairment. After adjusting for age, sex, history of hypertension, diabetes, and educational level, a 10% increase in total tau protein values was associated with a 7.60% increase in the risk of progression to dementia (hazard ratio: 2.22; 95% confidence interval, 1.28-3.84]; P = .004). Among patients with mild cognitive impairment due to AD and abnormal cerebrospinal fluid biomarker profiles, progressively higher concentrations of total or phosphorylated tau were associated with increased risk of progression to dementia.

The glymphatic-lymphatic fluid transport system (GLFTS) consists of glymphatic pathway and cerebrospinal fluid (CSF) lymphatic outflow routes, allowing biological liquids from the brain parenchyma to access the CSF along with perivascular space and to be cleaned out of the skull through lymphatic vessels. It is known that increased local pressure due to physical compression of tissue improves lymphatic transport in peripheral organs, but little is known about the exact relationship between increased intracranial pressure (IICP) and GLFTS. In this study, we verify our hypothesis that IICP significantly impacts GLFTS, and this effect depends on severity of the IICP. Using a previously developed inflating balloon model to induce IICP and inject fluorescent tracers into the cisterna magna, we found significant impairment of the glymphatic circulation after IICP. We further found that cerebrovascular occlusion occurred, and cerebrovascular pulsation decreased after IICP. IICP also interrupted the drainage of deep cervical lymph nodes and dorsal meningeal lymphatic function, enhancing spinal lymphatic outflow to the sacral lymph nodes. Notably, these effects were associated with the severity of IICP. Thus, our findings proved that the intensity of IICP significantly impacts GLFTS. This may have translational applications for preventing and treating related neurological disorders.

Rationale and Objectives Accurate cerebrospinal fluid (CSF) pressure measurements are critical for diagnosis and treatment of pathologic processes involving the central nervous system. Measuring opening CSF pressure using an analog device takes several minutes, which can be burdensome in a busy practice. The purpose of this study was to compare accuracy of a digital pressure measurement device with analog manometry, the reference gold standard. Secondary purpose included an assessment of possible time savings. Materials and Methods This study was a retrospective, cross-sectional investigation of 71 patients who underwent image-guided lumbar puncture (LP) with opening CSF pressure measurement at a single institution from June 2019 to September 2019. Exclusion criteria were examinations without complete data for both the digital and analog measurements or without recorded needle gauge. All included LPs and CSF pressures were measured with the patient in the left lateral decubitus position, legs extended. Acquired data included (1) digital and analog CSF pressures and (2) time required to measure CSF pressure. Results A total of 56 procedures were analyzed in 55 patients. There was no significant difference in mean CSF pressures between devices: 22.5 cm H2O digitally vs 23.1 analog ( p = .7). Use of the digital manometer resulted in a time savings of 6 min (438 s analog vs 78 s digital, p < .001). Conclusion Cerebrospinal fluid pressure measurements obtained with digital manometry demonstrate comparable accuracy to the reference standard of analog manometry, with an average time savings of approximately 6 min per case.

External ventricular drainage (EVD)-related infection (ERI) represents an important condition with potential high morbidity with significant impact on patient outcomes. Prophylactic systemic antibiotics are routinely administered to patients with EVD, but they do not significantly lower the incidence of ERIs. Intraventricular treatment with vancomycin appeared to be safe and effective, but most reports are case-reports/-series and retrospective studies.A prospective non-randomized case-control study was conducted in a consecutive series of 116 patients treated with EVD insertion. The study includes the group of patients treated with intrathecal vancomycin (Group A, 62 patients) compared with the control group treated with daily intravenous cefazolin (Group B, 54 patients).No statistically significant differences were found between the 2 groups with regard to the duration of catheterization and occurrence of ERI during hospitalization. EVD was replaced in 16 cases (25.8%) in group A and in 12 cases (22.2%) in the control group B (P 0.67). Three cases (4.8%) of ERI have been found in group A and 5 (9.3%) in the control group (P = 0.34). All reported cases of infection in group A were caused by gram-negative agents; on the opposite, cases of infections in the control group B were caused above all by gram-positive bacteria with a statistical difference (P = 0.03).In this first prospective study on this topic, we found that intrathecal Vancomycin administration in EVDs does not reduce the occurrence of ERI compared with intravenous cefazolin prophylaxis, but induces selection of gram-negative bacteria.

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/initiatives/parelsnoer).Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria 'La Caixa', Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formacion en Investigacion en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenom ics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme-Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delco de. The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl).ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-0417). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALFagreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 20050762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 20132496), Swedish Brain Power, Hjarnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (2018092016862), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG06839801), and the Alzheimer's Association 2021 Zenith Award (ZEN-21848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

Laboratory studies identified changes in the metabolism of halogens in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease, which indicates the presence of «accelerated self-halogenation» of CSF and/or an increase in haloperoxidases, specifically serum thyroperoxidase and CSF lactoperoxidase. Furthermore, an excess of some halogenated derivatives, such as advanced oxygenation protein products (AOPP), has been detected in the CSF and serum. «Accelerated self-halogenation» and increased levels of haloperoxidases and AOPP proteins indicate that halogenative stress is present in Parkinson's disease. In addition, 3-iodo-L-tyrosine, a halogenated derivative, shows «parkinsonian» toxicity in experimental models, since it has been observed to induce α-synuclein aggregation and damage to dopaminergic neurons in the mouse brain and intestine. The hypothesis is that patients with Parkinson's disease display halogenative stress related to a haloenzymatic alteration of the synthesis or degradation of oxyacid of halogens and their halogenated derivatives. This halogenative stress would be related to nervous system damage.

Hypothermia is a promising therapeutic strategy for severe vasospasm and other types of non-thrombotic cerebral ischemia, but its clinical application is limited by significant systemic side effects. We aimed to develop an intraventricular device for the controlled cooling of the cerebrospinal fluid, to produce a targeted hypothermia in the affected cerebral hemisphere with a minimal effect on systemic temperature. An intraventricular cooling device (acronym: V-COOL) was developed by in silico modelling, in vitro testing, and in vivo proof-of-concept application in healthy Wistar rats (n = 42). Cerebral cortical temperature, rectal temperature, and intracranial pressure were monitored at increasing flow rate (0.2 to 0.8 mL/min) and duration of application (10 to 60 min). Survival, neurological outcome, and MRI volumetric analysis of the ventricular system were assessed during the first 24 h. The V-COOL prototyping was designed to minimize extra-cranial heat transfer and intra-cranial pressure load. In vivo application of the V-COOL device produced a flow rate-dependent decrease in cerebral cortical temperature, without affecting systemic temperature. The target degree of cerebral cooling (− 3.0 °C) was obtained in 4.48 min at the flow rate of 0.4 mL/min, without significant changes in intracranial pressure. Survival and neurological outcome at 24 h showed no significant difference compared to sham-treated rats. MRI study showed a transient dilation of the ventricular system (+ 38%) in a subset of animals. The V-COOL technology provides an effective, rapid, selective, and safe cerebral cooling to a clinically relevant degree of − 3.0 °C.

Prodromal constipation (PC) at Parkinson's disease (PD) onset may mark a distinct neurodegenerative trajectory; accordingly, presenting phenotype, biochemical signature, and progression of PD patients with PC (PD + PC) might differ from those without (PDwoPC). We compared the clinical-biochemical profile of de novo PD patients with and without PC, and the respective mid-term progression, to establish the grouping effect of PC.Motor and non-motor scores were collected at diagnosis in n = 57 PD + PC patients and n = 73 PDwoPC. Paired CSF biomarkers (α-synuclein, amyloid and tau peptides, lactate, CSF/serum albumin ratio or AR) were assessed into a smaller sample and n = 46 controls. Clinical progression was estimated as Hoehn and Yahr stage (HY) and levodopa equivalent daily dose (LEDD) change 2.06 ± 1.35 years after diagnosis.At onset, PD + PC patients had higher HY and MDS-UPDRS-part III scores, and higher CSF AR. PDwoPC had higher Non-Motor Symptoms Scale domain-2 score, and lower CSF α-synuclein level. At follow-up, PD + PC had greater LEDD.PC identifies a group of de novo patients with more severe motor impairment, possible blood brain barrier disruption, and greater dopaminergic requirement at mid-term; conversely, de novo PDwoPC patients had prominent fatigue, and pronounced central synucleinopathy.

Background: This study aimed at comparing, within the 2018 NIA-AA amyloidosis/tauopathy/neurodegeneration (ATN) framework, the distribution of T ± profiles across A + patients with MCI and dementia in a retrospective, single-center, clinic-based cohort. Methods: We retrospectively collected data on N = 168 A + patients with either MCI due to AD (N = 50) or probable AD dementia (ADD; N = 118). ATN status was assigned, according to the 2018 NIA-AA framework, based on cerebrospinal fluid (CSF) biomarker concentrations. A χ2-test for independent samples was run to compare the distribution of A + T + vs. A + T- profiles, regardless of N status, across MCI and dementia patients. Results: The most represented ATN profile in both groups was A + T + N + (MCI: 54%; dementia: 70.3%); 3.4% of dementia patients and none within the MCI cohort presented with an A + T-N + profile. When grouping ATN profiles solely based on A and T dimensions, the prevalence of A + T + was of 76.3% and 66% in dementia and MCI patients, respectively. No association between clinical diagnoses (i.e., MCI vs. dementia status) and AT profiles (i.e., A + T + vs. A + T-) was detected. Discussion: The distribution of A + T + vs. A + T- does not differ between MCI and ADD, with A + T + profiles being predominant in both clinical categories. This does not support the common notion of A + T- profiles being relatively more prevalent in MCI patients, as indexing an earlier and/or less severe disease. Hence, caution should be exerted in attributing a case of MCI to prodromal AD solely based on A-positivity in the presence of a T-negative profile.

CSF hypotension arises in the context of a leak of CSF which causes negative intracranial pressure. Sacral fractures result from high-energy trauma which are frequently underdiagnosed. A ten-year-old boy presented with hip pain, after a fall. He mobilized both lower limbs, reported no leg pain, irradiation nor lack of sphincter control. The neurological examination was normal. When asked to stand, he began biparietal headache, nausea and vomiting, which improved laying down. CT scan showed an occult intrasacral meningocele; the MRI revealed collections of CSF along the spine, a S3 fracture with potential laceration of the meningocele and opening of a CSF fistula. Our diagnosis was the CSF hypotension, secondary to the fistula opening. The diagnosis was challenging. The child first presented with symptoms of CSF hypotension without evident cause. The discovery of the meningocele led us to hypothesize the opening of a fistula, a rare diagnosis, later confirmed by MRI. info:eu-repo/semantics/publishedVersion

PurposeBiochemical biomarkers to determine the injury severity and the potential for functional recovery of traumatic spinal cord injury (TSCI) are highly warranted; however, it remains to be clarified whether cerebrospinal fluid (CSF) or peripheral blood (PB) is the ideal sample media. This study aims to measure and compare biomarker concentrations in CSF and PB and to explore associations between biomarker concentrations and injury severity, i.e., American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, and biomarker concentrations and clinical outcome, i.e., AIS grade improvement and Spinal Cord Independent Measure version III (SCIM-III) score.MethodsFrom 2018 to 2020, we conducted a single-center prospective pilot study of TSCI patients (n=15) and healthy controls (n=15). Sample collection and clinical outcome assessment were performed at median 13 h [IQR: 19], 9 days [IQR: 2], and 148 days [IQR: 49] after TSCI. Concentrations of neuron-specific enolase (NSE); glial fibrillary acid protein (GFAP); neurofilament light chain (NfL); interferon-γ (IFN-γ); interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, and IL-13; and tumor necrosis factor α (TNF-α) were measured and associated to clinical outcomes.ResultsThe biomarker concentrations were higher in CSF than PB. CSF concentrations of GFAP, NSE, IFN-y, TNF-a, IL-2, IL-12p70, IL-4, IL-10, and IL-13 and PB concentrations of GFAP and IFN-y were significantly associated with AIS grade, but not with AIS grade improvement or SCIM-III score.ConclusionsOur results support GFAP as a potential diagnostic biomarker that may be measured in CSF as well as PB. PURPOSE: Biochemical biomarkers to determine the injury severity and the potential for functional recovery of traumatic spinal cord injury (TSCI) are highly warranted; however, it remains to be clarified whether cerebrospinal fluid (CSF) or peripheral blood (PB) is the ideal sample media. This study aims to measure and compare biomarker concentrations in CSF and PB and to explore associations between biomarker concentrations and injury severity, i.e., American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, and biomarker concentrations and clinical outcome, i.e., AIS grade improvement and Spinal Cord Independent Measure version III (SCIM-III) score.METHODS: From 2018 to 2020, we conducted a single-center prospective pilot study of TSCI patients (n=15) and healthy controls (n=15). Sample collection and clinical outcome assessment were performed at median 13 h [IQR: 19], 9 days [IQR: 2], and 148 days [IQR: 49] after TSCI. Concentrations of neuron-specific enolase (NSE); glial fibrillary acid protein (GFAP); neurofilament light chain (NfL); interferon-γ (IFN-γ); interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, and IL-13; and tumor necrosis factor α (TNF-α) were measured and associated to clinical outcomes.RESULTS: The biomarker concentrations were higher in CSF than PB. CSF concentrations of GFAP, NSE, IFN-y, TNF-a, IL-2, IL-12p70, IL-4, IL-10, and IL-13 and PB concentrations of GFAP and IFN-y were significantly associated with AIS grade, but not with AIS grade improvement or SCIM-III score.CONCLUSIONS: Our results support GFAP as a potential diagnostic biomarker that may be measured in CSF as well as PB.

Brain growth in early childhood is reflected in the evolution of proportional cerebrospinal fluid volumes (pCSF), grey matter (pGM), and white matter (pWM). We study brain development as reflected in the relative fractions of these three tissues for a cohort of 388 children that were longitudinally followed between the ages of 18 and 96 months. We introduce statistical methodology (Riemannian Principal Analysis through Conditional Expectation, RPACE) that addresses major challenges that are of general interest for the analysis of longitudinal neuroimaging data, including the sparsity of the longitudinal observations over time and the compositional structure of the relative brain volumes. Applying the RPACE methodology, we find that longitudinal growth as reflected by tissue composition differs significantly for children of mothers with higher and lower maternal education levels.

IntroductionAmyotrophic Lateral Sclerosis (ALS) is characterized by progressive motoneuron degeneration through cell autonomous and non-cell autonomous mechanisms; and the involvement of the innate and adaptive immune system has been hypothesized based on human and murine model data. We have explored if B-cell activation and IgG responses, as detected by IgG Oligoclonal bands (OCB) in serum and cerebrospinal fluid, were associated with ALS or with a subgroup of patients with distinct clinical features.MethodsIgG OCB were determined in patients affected by ALS (n=457), Alzheimer Disease (n=516), Mild Cognitive Impairment (n=91), Tension-type Headache (n=152) and idiopathic Facial Palsy (n=94). For ALS patients, clinico-demographic and survival data were prospectively collected in the Register Schabia.ResultsThe prevalence of IgG OCB is comparable in ALS and the four neurological cohorts. When the OCB pattern was considered (highlighting either intrathecal or systemic B-cells activation), no effect of OCB pattern on clinic-demographic parameters and overall. ALS patients with intrathecal IgG synthesis (type 2 and 3) were more likely to display infectious, inflammatory or systemic autoimmune conditions.DiscussionThese data suggest that OCB are not related to ALS pathophysiology but rather are a finding possibly indicative a coincidental infectious or inflammatory comorbidity that merits further investigation.

Cerebrospinal fluid (CSF) metabolites are increasingly recognized as prognostic factors in aneurysmal subarachnoid hemorrhage (SAH). The CSF arginine/ornithine ratio (Arg/Orn) was shown to predict cerebral vasospasms and clinical outcome in SAH. The additive prognostic value of Arg/Orn over established prognostic scores has not been investigated. CSF Arg/Orn and the established prognostic scores SAH, FRESH, SAH-PDS, HAIR, Rosen–McDonald, Hunt and Hess, WFNS and modified Fisher scale were determined in a prospective cohort of patients with aneurysmal SAH. Logistic regression models to predict a favorable outcome, defined as a modified Rankin Scale score of 0–3 at 3 months follow-up, were constructed for each score, both with and without the addition of Arg/Orn. The impact of Arg/Orn was assessed comparing logistic regression models containing the respective score with and without Arg/Orn with the likelihood ratio chi-squared test. CSF Arg/Orn and clinical scores were determined in 38 SAH patients. Arg/Orn was an independent predictor of clinical outcome when added to established prognostic scores (p p = 0.078). All models were significantly improved if Arg/Orn was added as a covariable (p

Background Cerebrospinal fluid (CFS) leaks are a well-known complication in spinal surgery, caused mostly by incidental durotomy (ID). Management of ID is a matter of ongoing debate. Different treatment strategies have been described ranging from no specific treatment to intraoperative suture or even complex reconstructive procedures. The role of bedrest has also been controversially discussed. The aim of this study was thus to evaluate a potential benefit of post-operative bedrest after ID. Methods ID management following lumbar spine surgery at a high-volume center between 01/2014 and 12/2017 was retrospectively assessed. Several risk factors such as type of surgery, size of dural lesion, intraoperatively chosen strategy, post-operative management (e.g. bedrest) and surgery-related complications were analyzed. Failure of the chosen strategy was defined as symptomatic CSF leakage, requiring revision surgery. Results Sufficient data was available for 135 patients with intraoperatively detected incidental durotomy. Eighty-seven patients with intraoperatively detected ID (64.4%) were additionally managed with bedrest, whereas 48 patients (35.6%) were immediately mobilized after surgery. Sixteen patients overall needed to be revised. However, patients treated with additional bedrest did not show a significant reduction of CSF fistula rate (p=0.27). The degree of laceration (>5mm) negatively affected the outcome (p=0.027). The hospital stay was significantly prolonged in patients, who were subjected to additional bedrest (p=0.001). Conclusions Postoperative CSF leakage represents a serious postoperative complication of lumbar surgery. Intraoperative dural repair plays a crucial role to avoid further neurological morbidity. Postoperative bedrest might be spared in case of watertight dural closure.

Chromosomally integrated human herpesvirus 6 (ciHHV6) is a condition where HHV6- DNA is integrated into the host germline genome. ciHHV6 can be misdiagnosed as active HHV6 infection. We report a 30-year-old woman presenting with psychological symptoms without a history of immunodeficiency. She had an ovarian teratoma and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in the cerebrospinal fluid (CSF) with HHV6-DNA in the serum and CSF. The final diagnosis was anti-NMDAR encephalitis and ciHHV6 because laparoscopic oophorectomy and immunotherapy ameliorated her symptoms and HHV6-DNA was detected in her oral mucosa cells. This case suggests the need to assess whether HHV6-DNA is related to infection or ciHHV6 when HHV6-DNA is detected in the CSF of patients with encephalitis.

BACKGROUND: Suspected non-Alzheimer's disease pathophysiology (SNAP) is a biomarker concept that encompasses individuals with neuronal injury but without amyloidosis. We aim to investigate the pathophysiology of SNAP, defined as abnormal tau without amyloidosis, in individuals with mild cognitive impairment (MCI) by cerebrospinal fluid (CSF) proteomics. METHODS: Individuals were classified based on CSF amyloid beta (Aβ)1-42 (A) and phosphorylated tau (T), as cognitively normal A-T- (CN), MCI A-T+ (MCI-SNAP), and MCI A+T+ (MCI-AD). Proteomics analyses, Gene Ontology (GO), brain cell expression, and gene expression analyses in brain regions of interest were performed. RESULTS: A total of 96 proteins were decreased in MCI-SNAP compared to CN and MCI-AD. These proteins were enriched for extracellular matrix (ECM), hemostasis, immune system, protein processing/degradation, lipids, and synapse. Fifty-one percent were enriched for expression in the choroid plexus. CONCLUSION: The pathophysiology of MCI-SNAP (A-T+) is distinct from that of MCI-AD. Our findings highlight the need for a different treatment in MCI-SNAP compared to MCI-AD. ispartof: ALZHEIMERS & DEMENTIA vol:19 issue:3 pages:807-820 ispartof: location:United States status: published

It is uncertain whether subjective cognitive decline (SCD) in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum.Cross-sectional and longitudinal data from the multicenter, memory clinic-based DELCODE study.The SCD group showed slightly worse cognition as well as more subtle functional and behavioral symptoms than the control group (CO). SCD-A+ cases (39.3% of all SCD) showed greater hippocampal atrophy, lower cognitive and functional performance, and more behavioral symptoms than CO-A+. Amyloid concentration in the CSF had a greater effect on longitudinal cognitive decline in SCD than in the CO group.Our data suggests that SCD serves the identification of stage 2 of the AD continuum and that stage 2, operationalized as SCD-A+, is associated with subtle, but extended impact of AD pathology in terms of neurodegeneration, symptoms and clinical progression.

The cerebrospinal fluid neutrophil-to-lymphocyte ratio (CSF NLR) as a diagnostic biomarker of bacterial meningitis has been reported in adult trials. The aim of this study was to evaluate the CSF NLR as a diagnostic biomarker of bacterial meningitis in children and to define an optimal CSF NLR concentration.We performed a retrospective cohort study of children with clinical findings compatible with meningitis. CSF NLR was calculated as the ratio of neutrophil count to lymphocyte count in cerebrospinal fluid (CSF). Initial data included clinical, radiological, and laboratory diagnostics.We determined CSF parameters from children with infectious meningitis (n = 348) and subdivided them into bacterial meningitis (n = 112) and viral meningitis (n = 236). CSF NLR was significantly higher in bacterial meningitis than in viral meningitis (P 0.001), and its level was higher in Gram-negative bacterial infections than in Gram-positive bacterial infections (P = 0.01). In the receiver operating characteristic curve analysis, CSF NLR was better than CSF protein/sugar/WBC in the ability to distinguish bacterial meningitis from viral meningitis (AUC 0.91 ± 0.02 versus 0.88 ± 0.03/0.87 ± 0.03/0.86 ± 0.03), and using a cutoff point of 0.68, the sensitivity was 0.90, and the specificity was 0.75. Compared with Gram-positive infection, CSF NLR with Gram-negative infection was higher (media, IQR (1.18 (0.19-2.33) versus 3.90 (1.50-8.91), P = 0.01).CSF NLR is a more useful diagnostic tool to distinguish between bacterial meningitis and viral meningitis in children. While at a cutoff value of 0.68, CSF NLR has better sensitivity and specificity for bacterial meningitis, and the higher level of CSF NLR could be related to Gram-negative bacterial infection.

Background: α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the brain and may be targeted by autoantibodies, leading to autoimmune synaptic encephalitis (AE). AE can be associated with other autoimmune diseases. However, the cooccurrence of anti-AMPA and NMDA receptor AE together with myasthenia gravis (MG) is unusual.Case presentation: A 24-year-old previously healthy male presented with seronegative ocular MG, the diagnosis of which was supported by single-fiber electrophysiology findings. Three months later, he developed AE, initially being positive for AMPA receptor antibodies and subsequently for NMDA receptor antibodies. No underlying malignancy was found. In response to aggressive immunosuppressive treatment, he recovered (modified Rankin Scale (mRS) score change from 5 to 1). Despite some cognitive problems at the 1-year follow-up, which were not revealed using the mRS, he was able to return to his studies.Conclusions: AE may coexist with other autoimmune disorders. Patients with seronegative MG, including ocular MG, may develop autoimmune encephalitis with more than one cell-surface antibody. Background: α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the brain and may be targeted by autoantibodies, leading to autoimmune synaptic encephalitis (AE). AE can be associated with other autoimmune diseases. However, the cooccurrence of anti-AMPA and NMDA receptor AE together with myasthenia gravis (MG) is unusual.Case presentation: A 24-year-old previously healthy male presented with seronegative ocular MG, the diagnosis of which was supported by single-fiber electrophysiology findings. Three months later, he developed AE, initially being positive for AMPA receptor antibodies and subsequently for NMDA receptor antibodies. No underlying malignancy was found. In response to aggressive immunosuppressive treatment, he recovered (modified Rankin Scale (mRS) score change from 5 to 1). Despite some cognitive problems at the 1-year follow-up, which were not revealed using the mRS, he was able to return to his studies.Conclusions: AE may coexist with other autoimmune disorders. Patients with seronegative MG, including ocular MG, may develop autoimmune encephalitis with more than one cell-surface antibody.

Alzheimer’s disease is a neurodegenerative disorder characterized clinically by cognitive decline and pathologically by amyloid deposition and neurofibrillary changes. These neuropathological hallmarks are accompanied by reactive events including microglial activation and astrogliosis. The inflammatory response in Alzheimer’s disease brains is distinguished by a pro-inflammatory signature involving amyloid peptides1, inflammasome signaling2 and disrupted blood brain barrier3. Inflammatory changes are observed also in the cerebrospinal fluid in Alzheimer’s disease4,5. It remains unknown, however, whether the choroid plexus which produces cerebrospinal fluid and guards the brain from peripheral inflammatory insults6,7, contributes to the inflammation and pathogenesis of Alzheimer’s disease. Here we show that the choroid plexus in Alzheimer’s disease exhibits a pro-inflammatory signature with aberrant protein accumulations, which contribute to the age-dependent inflammatory changes observed in the cerebrospinal fluid. Magnetic resonance imaging reveals that the choroid plexus in patients with Alzheimer’s disease displays pathological signal and increased volume, which inversely correlates with cognitive decline. Our findings suggest that the choroid plexus, being unable to efficiently resolve inflammatory insults over the lifetime, eventually ignites and drives the aberrant inflammatory response observed in Alzheimer’s disease. These findings advance our understanding of the pathogenesis and open new vistas in the diagnostics and therapeutics of Alzheimer’s disease.

Aim: Analysis of cerebrospinal fluid (CSF) is essential for diagnostic workup of patients with neurological diseases and includes differential cell typing. The current gold standard is based on microscopic examination by specialised technicians and neuropathologists, which is time‐consuming, labour‐intensive and subjective. Methods: We, therefore, developed an image analysis approach based on expert annotations of 123,181 digitised CSF objects from 78 patients corresponding to 15 clinically relevant categories and trained a multiclass convolutional neural network (CNN). Results: The CNN classified the 15 categories with high accuracy (mean AUC 97.3%). By using explainable artificial intelligence (XAI), we demonstrate that the CNN identified meaningful cellular substructures in CSF cells recapitulating human pattern recognition. Based on the evaluation of 511 cells selected from 12 different CSF samples, we validated the CNN by comparing it with seven board‐certified neuropathologists blinded for clinical information. Inter‐rater agreement between the CNN and the ground truth was non‐inferior (Krippendorff's alpha 0.79) compared with the agreement of seven human raters and the ground truth (mean Krippendorff's alpha 0.72, range 0.56–0.81). The CNN assigned the correct diagnostic label (inflammatory, haemorrhagic or neoplastic) in 10 out of 11 clinical samples, compared with 7–11 out of 11 by human raters. Conclusions: Our approach provides the basis to overcome current limitations in automated cell classification for routine diagnostics and demonstrates how a visual explanation framework can connect machine decision‐making with cell properties and thus provide a novel versatile and quantitative method for investigating CSF manifestations of various neurological diseases.

Contains fulltext : 292317.pdf (Publisher’s version ) (Open Access) The European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) is a consortium established with the ambition to set up the largest European longitudinal trial-ready cohort of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD), the most common autosomal dominantly inherited ataxia worldwide. A major focus of ESMI has been the identification of SCA3/MJD biomarkers to enable future interventional studies. As biosample collection and processing variables significantly impact the outcomes of biomarkers studies, biosampling procedures standardisation was done previously to study visit initiation. Here, we describe the ESMI consensus biosampling protocol, developed within the scope of ESMI, that ultimately might be translated to other neurodegenerative disorders, particularly ataxias, being the first step to protocol harmonisation in the field. 01 april 2023

Anti N-methyl-D-aspartate (NMDA) receptor encephalitis is new entity discovered over a decade. It is a type of autoimmune encephalitis characterized by a sequential onset of neuropsychiatric symptoms especially in the young population. Early diagnosis and treatment lead to better outcome and may prevent permanent neurological deficit or even death. Most patients respond well to first-line treatment and the resection of tumors associated with the disease. Here we present a case, which based on radiological findings, was diagnosed as cerebral venous sinus thrombosis (CVST), and was started on anticoagulation. Failure to respond to treatment and development of new movement abnormalities warranted for further investigations and he was found to have anti-NMDA receptor antibody positive in cerebrospinal fluid. Due to overlapping symptoms of CVST and encephalitis, high incidence of cerebral venous sinus thrombosis in this part of the world, and radiological findings, was initially thought to have CVST which was also confirmed on brain imaging. Lack of consent by the parents for a lumbar puncture delayed the definitive diagnosis. Patient developed movement disorder suggestive of autoimmune encephalitis, and this time after extensive counselling, when the cerebrospinal fluid was send for work up, it showed a positive anti-NMDA receptor antibody. He was promptly started on plasmapheresis after which patient had dramatic improvement both in movement abnormalities and neuropsychiatric symptoms.

Chronic sleep disturbance is a risk factor for dementia disease, possibly due to impaired sleep-dependent clearance of toxic metabolic by-products. We compared enrichment of a cerebrospinal fluid (CSF) tracer within brain of patients reporting good or poor sleep quality, assessed by the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Tracer enrichment in a selection of brain regions was assessed using multiphase magnetic resonance imaging up to 48 hours after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml) serving as tracer. Tracer enrichment differed between patients with good (PSQI ≤5) and poor (PSQI >5) sleep quality in a cohort of non-dementia individuals (n = 44; age 42.3 ± 14.5 years), and in patients with the dementia subtype idiopathic normal pressure hydrocephalus (n = 24; age 71.0 ± 4.9 years). Sleep impairment was associated with increased CSF tracer enrichment in several brain regions. Cortical brain volume as well as entorhinal cortex thickness was reduced in the oldest cohort and was correlated with the severity of sleep disturbance and the degree of cortical tracer enrichment. We suggest chronic sleep disturbance is accompanied by altered glymphatic function along enlarged perivascular spaces.

Background and Purpose: Left ventricular (LV) mass index is a marker of subclinical LV remodeling that relates to white matter damage in aging, but molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of microglial activation (sTREM2 [soluble triggering receptor expressed on myeloid cells 2]), axonal injury (NFL [neurofilament light]), neurodegeneration (total-tau), and amyloid-β, and whether these biomarkers partially accounted for associations between increased LV mass index and white matter damage. We hypothesized higher LV mass index would relate to greater CSF biomarker levels, and these pathologies would partially mediate associations with cerebral white matter microstructure. Methods: Vanderbilt Memory and Aging Project participants who underwent cardiac magnetic resonance, lumbar puncture, and diffusion tensor imaging (n=142, 72±6 years, 37% mild cognitive impairment [MCI], 32% APOE -ε4 positive, LV mass index 51.4±8.1 g/m 2 , NFL 1070±588 pg/mL) were included. Linear regressions and voxel-wise analyses related LV mass index to each biomarker and diffusion tensor imaging metrics, respectively. Follow-up models assessed interactions with MCI and APOE -ε 4 . In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated white matter associations. Results: Among all participants, LV mass index was unrelated to CSF biomarkers ( P >0.33). LV mass index interacted with MCI ( P =0.01), such that higher LV mass index related to increased NFL among MCI participants. Associations were also present among APOE -ε4 carriers ( P =0.02). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter damage. Conclusions: Subclinical cardiovascular remodeling, measured as an increase in LV mass index, is associated with neuroaxonal degeneration among individuals with MCI and APOE -ε4. Neuroaxonal degeneration partially reflects associations between higher LV mass index and white matter damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or microglia, may be more relevant in pathways between structural cardiovascular remodeling and white matter damage.

Background Hyperventilation resulting in hypocapnic alkalosis (HA) is frequently encountered in spontaneously breathing patients with acute cerebrovascular conditions. The underlying mechanisms of this respiratory response have not been fully elucidated. The present study describes, applying the physical–chemical approach, the acid-base characteristics of cerebrospinal fluid (CSF) and arterial plasma of spontaneously breathing patients with aneurismal subarachnoid hemorrhage (SAH) and compares these results with those of control patients. Moreover, it investigates the pathophysiologic mechanisms leading to HA in SAH. Methods Patients with SAH admitted to the neurological intensive care unit and patients (American Society of Anesthesiologists physical status of 1 and 2) undergoing elective surgery under spinal anesthesia were enrolled. CSF and arterial samples were collected simultaneously. Electrolytes, strong ion difference (SID), partial pressure of carbon dioxide (PCO2), weak noncarbonic acids (ATOT), and pH were measured in CSF and arterial blood samples. Results Twenty spontaneously breathing patients with SAH and 25 controls were enrolled. The CSF of patients with SAH, as compared with controls, was characterized by a lower SID (23.1 ± 2.3 vs. 26.5 ± 1.4 mmol/L, p 2 (40 ± 4 vs. 46 ± 3 mm Hg, p TOT (1.2 ± 0.5 vs. 1.2 ± 0.2 mmol/L, p = 0.95) and pH (7.34 ± 0.06 vs. 7.35 ± 0.02, p = 0.69) were observed. The reduced CSF SID was mainly caused by a higher lactate concentration (3.3 ± 1.3 vs. 1.4 ± 0.2 mmol/L, p r = 0.71, p 2. A higher proportion of patients with SAH were characterized by arterial HA, as compared with controls (40 vs. 4%, p = 0.003). A reduced CSF-to-plasma difference in PCO2 was observed in nonhyperventilating patients with SAH (0.4 ± 3.8 vs. 7.8 ± 3.7 mm Hg, p Conclusions Patients with SAH have a reduction of CSF SID due to an increased lactate concentration. The resulting localized acidifying effect is compensated by CSF hypocapnia, yielding normal CSF pH values and resulting in a higher incidence of arterial HA.

Background Tuberculous meningitis (TBM) is a highly lethal form of central nervous system tuberculosis (CNS TB) that causes high mortality and morbidity in children and adults. Nonspecific clinical presentation and fewer TB bacilli challenge clinicians resulting in delays in diagnosis and treatment. Aim This study aimed to evaluate the utility of GeneXpert alone and in combination with culture using 1 mL of cerebrospinal fluid (CSF) in a volume constraint situation. Methods A total of 125 clinically confirmed TBM and 110 non-TBM cases, comprised of both infectious and noninfectious diseases. were included in the study. Patient details including clinical signs and symptoms, CSF, and imaging data were collected from the case records. CSF samples were obtained from all the patients and were tested by the mycobacterial culture method and GeneXpert test. The performance of both the tests was statistically calculated and reported in the form of sensitivity and specificity. Results Out of 125 TBM cases, 40 were detected positive by culture and 26 by GeneXpert. All 110 non-TBM cases were identified negative by both methods. The sensitivity and specificity of GeneXpert in comparison with culture were 27 and 100%, respectively. The culture was found to be more sensitive (32%) than GeneXpert. But the assay was able to detect a considerable number of clinically confirmed culture-negative TBM cases. Conclusion GeneXpert is a rapid test and including this as an adjunctive test along with the culture in routine clinical practice can improve the diagnosis of TBM in volume constraint scenario.

Background The Brain Trauma Foundation (BTF) published evidence-based guidelines with a detailed approach to the management of intracranial hypertension (ICH) in traumatic brain injury (TBI) patients. However, management with cerebrospinal fluid (CSF) drainage in TBI patients remains a controversial topic and is a recent addition to the 4th Edition of the BTF guidelines. External lumbar drainage (ELD) has been proposed for the management of patients with refractory ICH despite aggressive measures. ELD has been described in the literature with possible benefits in outcomes; still, many questions remain unanswered. Methods A systematic search on MEDLINE was conducted for articles that studied lumbar CSF drainage in adult TBI patients with ICH. Results Eleven studies met the inclusion criteria, which included 5 prospective and 6 retrospective studies. Several studies showed that CSF drainage via lumbar drain resulted in significant reduction of ICP compared to before ELD placement and had a low complication rate. However, the data reporting mortality and functional outcomes are varied across studies. Conclusion The literature suggests that ELD may play a role in the management of refractory ICH in TBI patients when first and second-tier measures fail and may be a safe, effective, and minimally invasive method to significantly lower ICP. Additional research and standardized treatment protocols are necessary.

OBJECTIVE: Do MRI-based metrics of a CSF-dynamics disorder, disproportionately enlarged subarachnoid-space hydrocephalus (DESH), correlate with discordant amyloid biomarkers (low CSF β-amyloid 1–42, normal Aβ-PET scan)? METHODS: Individuals ≥50 years from the Mayo Clinic Study of Aging, with MRI, (11)C-Pittsburgh compound B (Aβ) PET scans, and CSF phosphorylated-tau protein and Aβ42, were categorized into four groups: normal/ abnormal by CSF β-amyloid 1–42 and Aβ amyloid PET. Within groups, we noted MRI patterns of CSF-dynamics disorders; categorization into low-CSF β-amyloid 1–42/normal Aβ-PET scan versus normal-CSF and PET groups; and Aβ-PET accumulation-change rate. RESULTS: 100 participants (21%) in the abnormal-CSF/normal-PET group had highest DESH-pattern scores and lowest CSF-phosphorylated-tau levels. Among normal amyloid-PET individuals, a one-unit DESH-pattern score increase correlated with 30%-greater odds of abnormal amyloid CSF after age and sex adjustment. Mean rate over time of amyloid-PET accumulation in abnormal-CSF/normal-PET individuals approximated individuals with normal amyloid values. Adjusting for phosphorylated-tau, abnormal CSF-amyloid/normal amyloid-PET individuals had higher mean amyloid-PET accumulation rates than normal individuals. CONCLUSIONS: CSF dynamics disorders confound β-amyloid and phosphorylated-tau CSF-biomarker interpretation.

Degenerative cervical myelopathy (DCM) is hallmarked by spinal canal narrowing and related cord compression and myelopathy. CSF pressure dynamics are likely disturbed due to spinal canal stenosis. The study aims to investigate the diagnostic value of continuous intraoperative CSF pressure monitoring during surgical decompression. Prospective single center study (NCT02170155) with enrolment of DCM patients that underwent surgical decompression between December 2019 and May 2021. Data from N=17 patients were analyzed, symptom severity graded with the modified Japanese Orthopedic Score (mJOA). CSF pulsations were continuously monitored with a lumbar intrathecal catheter during surgical decompression. Mean patient age was 62±9 years (range 38-73; 8F), symptoms were mild-moderate in most patients (mean mJOA 14±2, range 10-18). Measurements were well tolerated without safety concerns. In 15/16 (94%) CSF pulsations increased at the time of surgical decompression. In one case, responsiveness could not be evaluated for technical reasons. Unexpected CSF pulsation decrease was related to adverse events (i.e., CSF leakage). Median CSF pulsation amplitudes increased from pre-decompression (0.52 mmHg [IQR 0.71]) to post-decompression (0.72 mmHg [IQR 0.96]) (P=0.001). Mean baseline CSF pressure increased with lower magnitude than pulsations, from 9.5±3.5 to 10.3±3.8 mmHg (P=0.003). Systematic relations of CSF pulsations were confined to surgical decompression, independent of arterial blood pressure (P=0.927) or heart rate (P=0.102). Intraoperative CSF pulsation monitoring was sensitive, timely, and specifically related to surgical decompression while in addition adverse events could be discerned. Further investigation of the clinical value of intraoperative guidance for decompression in complex DCM surgery is promising.

Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt–Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann–Sträussler–Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt–Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt–Jakob disease-E200K, Gerstmann–Sträussler–Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.

Objectives We report the clinical, radiological, laboratory, and neuropathological findings in support of the first diagnosis of lethal, small-vessel cerebral vasculitis triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a pediatric patient. Patient description A previously healthy, 8-year-old Hispanic female presented with subacute onset left-sided weakness two weeks after a mild febrile illness. SARS-CoV-2 nasopharyngeal swab was positive. Magnetic resonance imaging (MRI) revealed an enhancing right frontal lobe lesion with significant vasogenic edema. Two brain biopsies of the lesion showed perivascular and intraluminal lymphohistiocytic inflammatory infiltrate consistent with vasculitis. Despite extensive treatment with immunomodulatory therapies targeting primary angiitis of the central nervous system, she experienced neurologic decline and died 93 days after presentation. SARS-CoV-2 testing revealed positive serum IgG and positive cerebrospinal fluid IgM. Comprehensive infectious, rheumatologic, hematologic/oncologic, and genetic evaluation did not identify an alternative etiology. Post-mortem brain autopsy remained consistent with vasculitis. Discussion This is the first pediatric presentation to suggest SARS-CoV-2 can lead to a fatal, post-infectious, inflammatory small-vessel cerebral vasculitis. Our case is unique in including supportive cerebrospinal fluid and post-mortem tissue analysis. While most children recover well from neurologic complications of SARS-CoV-2, we emphasize the potential mortality in a child with no risk factors for severe disease.

Cerebrospinal fluid (CSF) plays an important role in the clearance of metabolic waste products from the brain, yet the driving forces of CSF movement are not fully understood. It is commonly believed that CSF movement is facilitated by blood vessel wall movements (i.e., hemodynamic oscillations) in the brain. A coherent pattern of low frequency hemodynamic oscillations and CSF movement was recently found during non-rapid eye movement (NREM) sleep via functional MRI. However, questions remain regarding 1) the explanation of coupling between hemodynamic oscillations and CSF movement from fMRI signals; 2) the existence of the coupling during wakefulness; 3) the direction of CSF movement. In this resting state fMRI study, we proposed a mechanical model to explain the coupling between hemodynamics and CSF movement through the lens of fMRI. We found that the observed delays between hemodynamics and CSF movement match those predicted by the model. Moreover, by conducting separate fMRI scans of the brain and neck, we confirmed the low frequency CSF movement at the fourth ventricle is bidirectional. Our finding also demonstrates that CSF movement is facilitated by hemodynamic oscillations mainly in the low frequency range, even when the individual is awake.

Alzheimer’s disease CSF biomarkers 42 amino acid long amyloid-β peptide (Aβ1–42), total tau protein (T-tau), and tau protein phosphorylated at threonine 181 (P-tau181) are considered surrogate biomarkers of Alzheimer’s disease pathology, and significantly improve diagnostic accuracy. Their ability to reflect neuropathological changes later in the disease course is not well characterized. This study aimed to assess the potential of CSF biomarkers measured in mid to late stage Alzheimer’s disease to reflect post-mortem neuropathological changes. Individuals were selected from two autopsy cohorts of Alzheimer’s disease patients in Antwerp and Amsterdam. Neuropathological diagnosis was performed according to the updated consensus National Institute on Aging-Alzheimer’s Association guidelines, which includes quantification of amyloid-β plaque, neurofibrillary tangle, and neuritic plaque load. CSF samples were analysed for Aβ1–42, T-tau, and P-tau181 by ELISA. One hundred and fourteen cases of pure definite Alzheimer’s disease were included in the study (mean age 74 years, disease duration 6 years at CSF sampling, 50% females). Median interval between CSF sampling and death was 1 year. We found no association between Aβ1–42 and Alzheimer’s disease neuropathological change profile. In contrast, an association of P-tau181 and T-tau with Alzheimer’s disease neuropathological change profile was observed. P-tau181 was associated with all three individual Montine scores, and the associations became stronger and more significant as the interval between lumbar puncture and death increased. T-tau was also associated with all three Montine scores, but in individuals with longer intervals from lumbar puncture to death only. Stratification of the cohort according to APOE ε4 carrier status revealed that the associations applied mostly to APOE ε4 non-carriers. Our data suggest that similar to what has been reported for Aβ1–42, plateau levels of P-tau181 and T-tau are reached during the disease course, albeit at later disease stages, reducing the potential of tau biomarkers to monitor Alzheimer’s disease pathology as the disease progresses. As a consequence, CSF biomarkers, which are performant for clinical diagnosis of early Alzheimer’s disease, may not be well suited for staging or monitoring Alzheimer’s disease pathology as it progresses through later stages.

Objective To assess if SARS-CoV-2 causes a persistent central nervous system infection. Methods SARS-CoV-2 specific antibody index and SARS-CoV-2 RNA studied in cerebrospinal fluid following COVID-19. Results Cerebrospinal fluid was assessed between day 1-30 (n=12), between day 31-90 (n=8), or later than 90 days (post-COVID-19, n=20) of COVID-19 diagnosis. SARS-CoV-2 RNA was absent in all patients, and in none of the 20 patients with post-COVID-19 syndrome intrathecally produced anti-SARS-CoV-2 antibodies were detected. Interpretation The absence of evidence of SARS-CoV-2 in cerebrospinal fluid argues against a persistent central nervous system infection as a cause of neurological or neuropsychiatric post-COVID-19 syndrome. This article is protected by copyright. All rights reserved.

Movement disorders associated with glial fibrillary acidic protein (GFAP) autoantibodies have rarely been reported as ataxia or tremors. A 32-year-old man with headache and fever, initially diagnosed with viral meningoencephalitis, showed gradual improvement with empirical treatment. Two weeks after the illness, he suddenly developed orofacial, tongue, and neck dyskinesia accompanied by oculomotor abnormalities, which developed into severe generalized choreoballism. Brain magnetic resonance imaging (fluid-attenuated inversion recovery) showed signal hyperintensities in the bilateral globus pallidus interna. The clinical picture suggested an acute inflammatory trigger of secondary autoimmune encephalitis. The autoimmune antibody test was positive for GFAP, with the strongest reactivity in the cerebrospinal fluid (CSF) before treatment and decreased reactivity in serial CSF examinations during immunotherapy. Dyskinesia gradually improved to the extent that it could be controlled with only oral medications. This patient presented with parainfectious GFAP meningoencephalitis with distinctive clinical features and imaging findings.

Background and Purpose: According to the classical hypothesis, the cerebrospinal fluid (CSF) is actively secreted inside the brain’s ventricular system, predominantly by the choroid plexuses, before flowing unidirectionally in a cranio-caudal orientation toward the arachnoid granulations (AGs), where it is reabsorbed into the dural venous sinuses. This concept has been accepted as a doctrine for more than 100 years and was subjected only to minor modifications. Its inability to provide an adequate explanation to questions arising from the everyday clinical practice, in addition to the ever growing pool of experimental data contradicting it, has led to the identification of its limitations. Literature includes an increasing number of studies suggesting a more complex mechanism than that previously described. This review article summarizes the proposed mechanisms of CSF regulation, referring to the key clinical and experimental developments supporting or defying them. Methods: A non-systematical literature search of the major databases was performed for studies on the mechanisms of CSF homeostasis. Gray literature was additionally assessed employing a hand-search technique. No restrictions were imposed regarding the time, language, or type of publication. Conclusion: CSF secretion and absorption are expected to take place throughout the entire brain’s capillaries network under the regulation of hydrostatic and osmotic gradients. The unidirectional flow is defied, highlighting the possibility of its complete absence. The importance of AGs is brought into question, potentiating the significance of the lymphatic system as the primary site of reabsorption. However, the definition of hydrocephalus and its treatment strategies remain strongly associated with the classical hypothesis.

Knowledge about the dynamic metabolism and function of cerebrospinal fluid (CSF) physiology has rapidly progressed in recent decades. It has traditionally been suggested that CSF is produced by the choroid plexus and drains to the arachnoid villi. However, recent findings have revealed that the brain parenchyma produces a large portion of CSF and drains through the perivascular glymphatic system and meningeal lymphatic vessels into the blood. The primary function of CSF is not limited to maintaining physiological CNS homeostasis but also participates in clearing waste products resulting from neurodegenerative diseases and acute brain injury. Aneurysmal subarachnoid hemorrhage (SAH), a disastrous subtype of acute brain injury, is associated with high mortality and morbidity. Post-SAH complications contribute to the poor outcomes associated with SAH. Recently, abnormal CSF flow was suggested to play an essential role in the post-SAH pathophysiological changes, such as increased intracerebral pressure, brain edema formation, hydrocephalus, and delayed blood clearance. An in-depth understanding of CSF dynamics in post-SAH events would shed light on potential development of SAH treatment options. This review summarizes and updates the latest physiological characteristics of CSF dynamics and discusses potential pathophysiological changes and therapeutic targets after SAH.

Neuropsychiatric manifestations (NP) are common in systemic lupus erythematosus (SLE). However, the pathophysiological mechanisms are not completely understood. Neurofilament light protein (NfL) is part of the neuronal cytoskeleton. Increased NfL concentrations, reflecting neurodegeneration, is observed in cerebrospinal fluid (CSF) in several neurodegenerative and neuroinflammatory conditions. We aimed to explore if plasma NfL could serve as a biomarker for central nervous system (CNS) involvement in SLE. Sixty-seven patients with SLE underwent neurological examination; 52 underwent lumbar puncture, while 62 underwent cerebral magnetic resonance imaging (MRI). We measured selected auto-antibodies and other laboratory variables postulated to have roles in NP pathophysiology in the blood and/or CSF. We used SPM12 software for MRI voxel-based morphometry. Age-adjusted linear regression analyses revealed increased plasma NfL concentrations with increasing creatinine (β = 0.01, p

Background and ObjectivesTo report the clinical, biological, and imaging features and clinical course of a French cohort of patients with glial fibrillary acidic protein (GFAP) autoantibodies.MethodsWe retrospectively included all patients who tested positive for GFAP antibodies in the CSF by immunohistochemistry and confirmed by cell-based assay using cells expressing human GFAPα since 2017 from 2 French referral centers.ResultsWe identified 46 patients with GFAP antibodies. Median age at onset was 43 years, and 65% were men. Infectious prodromal symptoms were found in 82%. Other autoimmune diseases were found in 22% of patients, and coexisting neural autoantibodies in 11%. Tumors were present in 24%, and T-cell dysfunction in 23%. The most frequent presentation was subacute meningoencephalitis (85%), with cerebellar dysfunction in 57% of cases. Other clinical presentations included myelitis (30%) and visual (35%) and peripheral nervous system involvement (24%). MRI showed perivascular radial enhancement in 32%, periventricular T2 hyperintensity in 41%, brainstem involvement in 31%, leptomeningeal enhancement in 26%, and reversible splenial lesions in 4 cases. A total of 33 of 40 patients had a monophasic course, associated with a good outcome at last follow-up (Rankin Score ≤2: 89%), despite a severe clinical presentation. Adult and pediatric features are similar. Thirty-two patients were treated with immunotherapy. A total of 11/22 patients showed negative conversion of GFAP antibodies.DiscussionGFAP autoimmunity is mainly associated with acute/subacute meningoencephalomyelitis with prodromal symptoms, for which tumors and T-cell dysfunction are frequent triggers. The majority of patients followed a monophasic course with a good outcome.

Spontaneous intracranial hypotension (SIH) is a potentially debilitating condition resulting from a low cerebrospinal fluid (CSF) volume secondary to spinal CSF leakage. Characteristic clinical and radiological imaging findings are helpful in diagnosis. Herein, we present and discuss the magnetic resonance imaging (MRI) and CSF flow study of two patients with SIH and no CSF flow within the cerebral aqueduct, which is extremely rare in the literature.

BACKGROUND AND PURPOSE The aim of this study was to identify the long-term radiological changes, autoantibody specificities, and clinical course in a patient with kelch-like protein 11 (KLHL11)-associated paraneoplastic neurological syndrome (PNS). METHODS Serial brain magnetic resonance images were retrospectively assessed. To test for KLHL11 autoantibodies, longitudinal cerebrospinal fluid (CSF) and serum samples were screened by Phage-display ImmunoPrecipitation and Sequencing (PhIP-Seq). Immunohistochemistry was also performed to assess for the presence of KLHL11 in the patient's seminoma tissue. RESULTS A 42-year-old man presented with progressive ataxia and sensorineural hearing loss. Metastatic seminoma was detected 11 months after the onset of the neurological symptoms. Although immunotherapy was partially effective, his cerebellar ataxia gradually worsened over the next 8 years. Brain magnetic resonance imaging revealed progressive brainstem and cerebellar atrophy with a "hot-cross-bun sign", and low-signal intensity on susceptibility-weighted imaging (SWI) in the substantia nigra, red nucleus and dentate nuclei. PhIP-Seq enriched for KLHL11-derived peptides in all samples. Immunohistochemical staining of mouse brain with the patient CSF showed co-localization with a KLHL11 commercial antibody in the medulla and dentate nucleus. Immunohistochemical analysis of seminoma tissue showed anti-KLHL11 antibody-positive particles in cytoplasm. CONCLUSIONS This study suggests that KLHL11-PNS should be included in the differential diagnosis for patients with brainstem and cerebellar atrophy and signal changes not only on T2-FLAIR but also on SWI, which might otherwise be interpreted as secondary to a neurodegenerative disease such as multiple system atrophy.

The main causes for cerebrospinal fluid (CSF) leaks are known to be traumatic, iatrogenic, neoplastic, a meningoencephalocele, congenital bone defects, and spontaneous. Off-label intrathecal administration of fluorescein is widely used to localize a CSF leak. Complications are rare and low dose administration is described to be safe. In this case report, we present a case of a patient, who showed a CSF leak due to an encephalocele. Low dose fluorescein was applied intrathecally via lumbar catheter, the CSF leaks could be identified, and multilayered closure was performed. Postoperatively, the patient presented with motor and sensory deficits in the lower limbs which regressed only partially within 2 months. A possible explanation may be an increased local concentration of fluorescein, possibly on the basis of a preexisting lumbar spinal canal stenosis. To our knowledge, this is the first case in which a dose as low as 20 mg of fluorescein (2% saline mixture) led to persisting paraplegia. Therefore, the potential benefits and risks of the intrathecal fluorescein use in the detection of a CSF leak have to be discussed comprehensively prior to surgery.

This work aims to evaluate the changes in cerebrospinal fluid (CSF) hydrodynamics in patients diagnosed with communicating hydrocephalus. Besides, we establish the relationship between CSF flow dynamic parameters on the midbrain aqueduct and intracranial pressure (ICP). CSF hydrodynamics analysis was performed using Phase-Contrast Magnetic Resonance Imaging (PC‐MRI) techniques on the midbrain aqueduct of 41 patients diagnosed with communicating hydrocephalus and 22 healthy volunteers. The correlation between CSF average flow in the midbrain aqueduct and intracranial pressure measured by Lumbar Puncture (LP) was assessed in patients with hydrocephalus. Pearson correlation coefficient was used to establish the correction between the average CSF flow of midbrain aqueduct and ICP. CSF dynamic parameters of the midbrain aqueduct in hydrocephalus patients, including peak positive velocity (7.348 cm/s), average velocity (0.623 cm/s), average flow (50.799 mm3/s), and regions of interest (ROI) area (9.978 mm2) were significantly higher than in the healthy controls (p

Altres ajuts: Huntington's Disease Society of America Female Huntington's disease (HD) patients have consistently shown a faster clinical worsening than male, but the underlying mechanisms responsible for this observation remain unknown. Here, we describe how sex modifies the impact of neurodegeneration on brain atrophy and clinical severity in HD. Cerebrospinal fluid neurofilament light chain (NfL) levels were used as a biological measure of neurodegeneration, and brain atrophy was assessed by structural magnetic resonance imaging. We found that larger NfL values in women reflect higher brain atrophy and clinical severity than in men (p < 0.05 for an interaction model). This differential vulnerability could have important implications in clinical trials.

BackgroundNeurological manifestations of coronavirus disease 2019 (COVID-19) are increasingly recognized and include encephalopathy, although direct infection of the brain by SARS-CoV-2 remains controversial. We herein report the clinical course and cytokine profiles of a patient with severe SARS-CoV-2-related encephalopathy presenting aphasia.Case presentationAn 81-year-old man developed acute consciousness disturbance and status epileptics several days after SARS-CoV-2 infection. Following treatment with remdesivir and dexamethasone, his consciousness and epileptic seizures improved; however, amnestic aphasia and agraphia remained. Two months after methylprednisolone pulse and intravenous immunoglobulin, his neurological deficits improved. We found increased levels of interleukin (IL)-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1), but not IL-2 and IL-10 in the serum and cerebrospinal fluid (CSF), and the levels of serum IL-6 and MCP-1 were much higher than those in the CSF. The level of IL-8 in the CSF after immunotherapy was four times higher than that before immunotherapy.ConclusionThe cytokine profile of our patient was similar to that seen in severe SARS-CoV-2-related encephalopathy. We demonstrated (i) that the characteristic aphasia can occur as a focal neurological deficit associated with SARS-CoV-2-related encephalopathy, and (ii) that IL8-mediated central nervous system inflammation follows systemic inflammation in SARS-CoV-2-related encephalopathy and can persist and worsen even after immunotherapy. Monitoring IL-8 in CSF, and long-term corticosteroids may be required for treating SARS-CoV-2-related encephalopathy.

Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that has been reported as a potential marker for pre-dementia stages of Alzheimer's disease (AD). Longitudinal studies for its association with the conversion of mild cognitive impairment to AD is still lacking. This study included n = 268 study participants with subjective cognitive decline (SCD) (n = 82), mild cognitive impairment (MCI) (n = 98) and AD dementia (n = 88) at baseline and two-year follow-up clinical assessments. Serum and cerebrospinal fluid (CSF)NGAL, CSF amyloid beta(1-42), total-Tau, and phospho-Tau levels were measured with ELISA analysis. CSF NGAL levels were significantly lower in MCI participants compared to people with SCD at baseline. Lower baseline CSF NGAL levels predicted MCI converters to AD dementia vs. non-converters after 2-years follow-up. A positive correlation between CSF NGAL and amyloid beta(1-42) was found particularly in MCI participants at baseline. NGAL in CSF holds potential to be used as a predictive marker for the conversion of MCI to AD dementia and may reflect pathophysiological processes of prodromal AD neuropathology. (C) 2021 The Authors. Published by Elsevier Inc.