Cerebrospinal Fluid Changes Research Articles

Skogholt’s disease—A tauopathy precipitated by iron and copper?

BackgroundIt has been suggested that Skogholt’s disease is a new neurological disease entity. The disease, confined to a family line in Hedmark county, Norway, usually affects both the brain and peripheral nerves. Typical findings are white matter lesions in the brain, myelin damage in peripheral nerves, and discolored cerebrospinal fluid with high concentrations of protein, copper, and iron. Little is known about the natural progression of the disease and its underlying cause, but the high level of copper and iron in the cerebrospinal fluid may cause or exacerbate inflammation in the central nervous system. MethodsThe present clinical study further explores the disease progression with clinical chemistry analyses and mass spectrometry of blood and cerebrospinal fluid (CSF) from patients and controls. Findings are corroborated with cognitive assessments. ResultsPathological changes in CSF with low amyloid-β42 and high levels of tau proteins, total protein, copper, and iron, were discovered among Skogholt patients. The Montreal Cognitive Assessment identified 36 % of the patients as below normal range, while most patients performed slower than the norm mean time on the Trail Making Test. Mini-Mental Status Examination disclosed only minor deviations. ConclusionThe findings in the present study strengthen our initial suggestion that Skogholt’s disease most likely is a new neurological disorder and provide new clues to its cause: The disease may belong to the family of neurodegenerative disorders termed tauopathies. The increased level of copper and iron may contribute to neuroinflammation as these metals also have been associated with other neurodegenerative disorders. Although the causes of neurodegenerative disorders are currently largely unknown, studies on rare disease entities, such as the present one, may increase the understanding of neurodegeneration in general.

Next-Generation Sequencing and Proteomics of Cerebrospinal Fluid From COVID-19 Patients With Neurological Manifestations.

The SARS-CoV-2 and its variants are still hitting the world. Ever since the outbreak, neurological involvements as headache, ageusia, and anosmia in COVID-19 patients have been emphasized and reported. But the pathogenesis of these new-onset neurological manifestations in COVID-19 patients is still obscure and controversial. As difficulty always lay in the diagnosis of neurological infection, current reports to validate the presence of SARS-CoV-2 in cerebrospinal fluid (CSF) almost relied on the basic methods and warranted improvement. Here we reported a case series of 8 patients with prominent new-onset neurological manifestations, who were screened out from a patch of 304 COVID-19 confirmed patients. Next-generation sequencing (NGS) and proteomics were conducted in the simultaneously obtained CSF and serum samples of the selected patients, with three non-COVID-19 patients with matched demographic features used as the controls for proteomic analysis. SARS-CoV-2 RNA was detected in the CSF of four COVID-19 patients and was suspicious in the rest four remaining patients by NGS, but was negative in all serum samples. Proteomic analysis revealed that 185 and 59 proteins were differentially expressed in CSF and serum samples, respectively, and that only 20 proteins were shared, indicating that the proteomic changes in CSF were highly specific. Further proteomic annotation highlighted the involvement of complement system, PI3K-Akt signaling pathway, enhanced cellular interaction, and macrophages in the CSF proteomic alterations. This study, equipped with NGS and proteomics, reported a high detection rate of SARS-CoV-2 in the CSF of COVID-19 patients and the proteomic alteration of CSF, which would provide insights into understanding the pathological mechanism of SARS-CoV-2 CNS infection.

CSF tau phosphorylation occupancy at t217 increases in MAPT R406W mutation carriers without amyloid pathology

AbstractBackgroundTau hyperphosphorylation at Threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer disease (AD). However, it remains unclear whether pT217 could be modified in other tauopathies. Using immunoprecipitation and mass spectrometry, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid beta (Aβ) 42/40 ratio in cognitively normal controls, and individuals with AD, Progressive Supranuclear Palsy (PSP), Corticobasal Syndrome (CBS), and sporadic and familial Frontotemporal Dementia (FTD).MethodCSF Aβ, tau and phosphorylated tau (p‐tau) were measured using immunoprecipitation and quantitative mass spectrometry methods. Amyloid and tau Positron Emission Topography (PET) imaging were measured in a subset of participants and analyzed for correlation. Quadrant analyses were performed to assess amyloid and p‐tau positivity.ResultWe confirmed the strong association between CSF Aβ 42/40 and pT217 measures in most samples. Individuals with AD had high CSF pT217/T217 and low Aβ 42/40. In contrast, controls and the majority of patients with other tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio relative to controls. Most of these individuals were identified as MAPT R406W mutation carriers, a tau mutation leading to 3R+4R tauopathy similar to AD but without amyloid pathology. Diagnostic accuracies of CSF Aβ 42/40 alone, CSF pT217/T217 alone, and combination of both biomarkers were examined. We show that combination of both biomarkers can separate MAPT R406W carriers from control (AUC=0.960) and other tauopathies that are primarily 4R tauopathies (AUC=0.934).ConclusionWe demonstrate the importance of measuring both CSF Aβ 42/40 and pT217/T217 to improve AD diagnosis and differentiate MAPT R406W mutation carriers. This supports that changes in CSF pT217/T217 ratio is not a specific biomarker for AD but reflects common downstream tau pathology in these two 3R+4R tauopathies.

Cerebrospinal fluid and brain PET measures of synaptic density glycoprotein 2A: Biomarkers of synaptic density in Alzheimer’s disease

AbstractBackgroundSynaptic loss is linked with Alzheimer’s disease (AD) progression and provides a novel target for exploration with fluid and imaging biomarkers. Studies using [11C]UCB‐J–PET have shown significant reductions in synaptic glycoprotein 2A (SV2A) specific binding as a marker of synaptic density in early AD. The extent of these reductions indicates widespread neocortical synaptic loss that corroborates previous postmortem studies. This study examined the association between a SV2A measured with brain [11C]UCB‐J–PET and cerebrospinal fluid (CSF) levels of SV2A.MethodUsing [11C]UCB‐J binding to SV2A, synaptic density was measured in 21 participants with early AD (CDR=0.5‐1.0, PiB+) and 7 cognitively normal (CN) participants (CDR=0, PiB–). PET scans were performed on a HRRT after a bolus injection of [11C]UCB‐J. Synaptic density was calculated as the distribution volume ratio (DVR) using SRTM2 with a cerebellum reference region. CSF SV2A was measured by an in‐house ELISA method.ResultAs previously demonstrated, synaptic density measured with SV2A PET was significantly lower in AD participants in the hippocampus, entorhinal cortex, lateral parietal cortex, lateral temporal cortex, and lateral occipital cortex. CSF SV2A was also reduced in participants with AD (762 ± 148) pg/mL) compared to CN participants (935 ± 134 pg/mL, P = 0.01, Figure 1). Within the AD group (n = 21), CSF SV2A was significantly correlated with synaptic density measured with [11C]UCB‐J–PET in a composite of AD‐affected regions (r = 0.65, P = 0.001, Figure 2). A regional analysis showed that CSF and PET measures of SV2A were significantly correlated broadly in the neocortex, but not in medial temporal regions such as the hippocampus, entorhinal cortex, and amygdala.ConclusionThis study supports a previous report of decreased CSF SV2A in AD. In the primary analysis, SV2A measured in CSF and SV2A measured with brain PET were strongly correlated within a group of individuals with AD, indicating that decreases in both measures may reflect synaptic loss during disease progression. Further studies will focus on longitudinal changes in CSF and PET measures of SV2A, as well as other CSF measures of synaptic and neuronal damage to investigate the neurobiology of AD.

Longitudinal changes of multiple CSF phosphorylated tau sites in dominantly inherited Alzheimer disease

AbstractBackgroundRecent analyses of tau phosphorylation in cerebrospinal fluid (CSF) from dominantly inherited Alzheimer disease (DIAD) patients have pinpointed early modification of phosphorylated tau (p‐tau) at 217 (pT217) occurring simultaneously with emergence of amyloid plaques. This has opened new perspective in diagnosing AD pathology at preclinical stages using ptau in CSF and plasma. Tau is phosphorylated at many sites in brain and a subset of them is detectable in CSF. To date, we have investigated four p‐tau sites and demonstrated the modifications of pT217, pT181 and pT205 start respectively 21, 19 and 13 years before estimated year to symptom onset (EYO) when pS202 remained unchanged. We extend the list of monitored ptau sites in the DIAN cohort to ten tau residues.Method589 CSF samples from 370 participants in DIAD families were analyzed by tau immunopurification and multiplex‐targeted mass spectrometry using nanoLC‐Q‐LTQ‐Orbitrap instrument. We measured phosphorylation occupancy and ptau level at T111, T153, T175, T181, S199, S202, T205, S208, T217 and T231. For each ptau, we calculated area under curve (AUC) of receiver operating characteristic (ROC) to detect amyloidosis as measured by PiB‐PET. We determined phosphorylation amount and rate of change over the course of the disease based on EYO.ResultThe most to least sensitive phosphorylated sites for detecting amyloidosis in mutation carriers were T217, T181, T153, T111, T231, S208 and T205 with AUC ranging from 0.96 to 0.87. T175, S199 and S202 were not significantly modified. For the newly investigated sites pT111, pT153, pS208 and T231, we found significant hyperphosphorylation compared to non‐carriers at EYOs ranging from ‐22 to ‐19 years. Longitudinal analyses of pT153, pS208 and pT231 demonstrated a decreasing of the phosphorylation after symptoms as previously observed for pT217 and pT181. Separately, pT111 continued to increase after onset.ConclusionThis study corroborates the distinct response of tau residues to hyperphosphorylation over AD process. We confirm pT217 is the earliest abnormally modified phosphorylated site in AD amongst the 10 sites investigated in CSF. Our results support the use of pT153, pT111 pT231 and pS208 as additional ptau biomarkers for the diagnosis of asymptomatic AD.

Predictive Value of Cerebrospinal Fluid Lactate Level for the Diagnosis of Bacterial Meningitis following Cranial Surgery

Background:To distinguish post-neurosurgical bacterial meningitis (PNBM) from aseptic meningitis is difficult. Inflammatory and biochemical cerebrospinal fluid (CSF) changes mimic those classically observed after CNS surgery. CSF lactate assay has therefore been proposed as a useful PNBM marker. Objective:To determine the value of cerebrospinal fluid (CSF) lactate level for the identification of bacterial meningitis following cranial surgery. Methods:Between January 2016 and December 2016, a prospective clinical study was done in Department of Neurosurgery, in which all patients with clinical suspicion of PNBM were enrolled. Patients with clinical suspicion of bacterial meningitis BM were categorized, according to preset criteria, into 3 groups: (1) proven BM; (2) presumed BM, and (3) nonbacterial meningeal syndrome. CSF markers were plotted in a receiver operating curve (ROC) to evaluate their diagnostic accuracy. Results:The study included 70 patients. We obtained 65 CSF samples from patients with clinical suspicion of BM by CSF analysis. 20 corresponded to proven BM, 7 to probable BM and 38 to excluded BM. Mean lactate in CSF was: 8.4 ±3.0 mmol /l for proven BM, 4.8 ± 0.99 mmol /l for probable BM and 2.08 ± 0.822 mmol/l for excluded BM (P < .001). Conclusion: CSF lactate level has good predictive value to distinguish BM from aseptic meningitis with sensitivity of 90% and specificity: 87% at cut-off value: 4.0 mmol/l.

Neural Network Segmentation Algorithm-Based Magnetic Resonance Imaging to Explore the Relationship between Cerebrospinal Fluid Flow with Communicating Hydrocephalus after Decompressive Craniectomy for Craniocerebral Injury

This study aimed to explore the application value of magnetic resonance imaging optimized by neural network segmentation algorithm in analyzing the relationship between cerebrospinal fluid changes after decompressive craniectomy and the occurrence of communicating hydrocephalus. 100 patients with craniocerebral injury undergoing decompressive craniectomy in hospital were selected as research subjects. The collected MRI images were processed using the OTSU algorithm, the cerebrospinal fluid flow rate was calculated based on the observation results, and the MRI based on the neural network segmentation algorithm was used to analyze the relationship between the occurrence of communicating hydrocephalus with the cerebrospinal fluid flow after decompressive craniectomy for craniocerebral injury. Additionally, the dynamics of the flow of cerebrospinal fluid in the midbrain aqueduct was analyzed. After decompressive craniectomy for craniocerebral injury, of the 24 cases of cerebrospinal fluid accumulation, 23 cases had hydrocephalus; of the 55 cases of cerebrospinal fluid flow disorder, hydrocephalus occurred in 47 cases; and of the 21 cases of normal cerebrospinal fluid, no patients had hydrocephalus. For patients with communicating hydrocephalus, the cerebrospinal fluid flow at the aqueduct was obviously accelerated and the flow was increased. From this, the differential diagnosis of cerebrospinal fluid and communicating hydrocephalus can be further confirmed. The results showed that the third ventricle of the study group was significantly reduced, and the flow of cerebrospinal fluid was similar to that of normal people. It suggested that decompressive craniectomy can relieve communicating hydrocephalus. In patients with communicating hydrocephalus, the cerebrospinal fluid flow at the aqueduct was significantly accelerated, the flow amount was increased, and the blocked flow of cerebrospinal fluid can also lead to hydrocephalus, which further clarified the relationship between the occurrence of communicating hydrocephalus with the flow of cerebrospinal fluid. In short, the neural network segmentation algorithm-based magnetic resonance imaging demonstrated a good value in the analysis of craniocerebral injury, from which the doctor observed that the cerebrospinal fluid flow at the aqueduct was significantly accelerated. Its detection of brain complications after decompressive craniectomy was also effective.

In vivo monitoring of calcium ions in rat cerebrospinal fluid using an all-solid-state acupuncture needle based potentiometric microelectrode

Acupuncture needles are regarded as ideal materiel for the development of microelectrodes for in vivo sensing. In this work, an all-solid-state ion-selective microelectrode (ISμE) has been developed by coating a calcium ion-selective membrane on an acupuncture needle tip with a diameter of less than 80 μm, which is modified with poly(3,4-ethylenedioxythiophene)-poly(sodium 4-styrenesulfonate) as solid contact. The proposed Ca2+-ISμE shows a Nernstian response toward Ca2+ in the range from 1.0 × 10−6 to 3.1 × 10−3 M with a slope of 30.8 ± 0.9 mV/decade (R2 = 0.999), and the detection limit is 1.2 × 10−7 M. The Ca2+-ISμE has been used for in vivo monitoring of the calcium changes in rat cerebrospinal fluid (CSF) under the injury of spinal cord transection. The results demonstrate that the calcium concentration in CSF increases sharply from the normal level of 20.6 ± 1.72 μM (n = 3) to 133.2 ± 7.63 μM (n = 3) with a severe fluctuation after spinal cord damage. Thus, the proposed Ca2+-ISμE is available for in vivo monitoring of calcium ions with high temporal resolution and flexibility. The detection system can be extended to measure other ions in CSF by changing different ion-selective membranes.

Cerebrospinal fluid electrolytes and acid-base in diabetic patients.

BackgroundDiabetes mellitus (DM) has detrimental effects on the function of microvascular beds, resulting in blood–brain barrier (BBB) dysfunction. The objective of the study was to investigate whether DM affects the brain physiology through composition of cerebrospinal fluid (CSF) and compare gas tension and electrolyte levels in CSF between the diabetic and nondiabetic populations.MethodsPatients aged between 20 and 70 years scheduled for elective orthopedic or urologic surgery requiring spinal anesthesia were enrolled. They were assigned to either of the two groups (control or type 2 DM). Gas tension and electrolytes in the CSF and whole blood samples were measured in both groups.ResultsAll 49 enrolled patients (24 in the control and 25 in the DM group) completed the study. The concentrations of Na+ and Mg2+ in the blood were significantly lower in the DM group than those in the control. The levels of pCO2 and {text{HCO}}_{3}^{-}] in the CSF were lower in the DM group than in the control group. In addition, there was a marked increase in the glucose level in both the blood and CSF in the DM group.ConclusionThe results show that there were some homeostatic changes in blood and CSF in patients with DM.

Diet Effects on Cerebrospinal Fluid Amino Acids Levels in Adults with Normal Cognition and Mild Cognitive Impairment.

Background:Exploration of cerebrospinal fluid (CSF) amino acids and the impact of dietary intake on central levels may provide a comprehensive understanding of the metabolic component of Alzheimer’s disease.Objective:The objective of this exploratory study was to investigate the effects of two diets with varied nutrient compositions on change in CSF amino acids levels in adults with mild cognitive impairment (MCI) and normal cognition (NC). Secondary objectives were to assess the correlations between the change in CSF amino acids and change in Alzheimer’s disease biomarkers.Methods:In a randomized, parallel, controlled feeding trial, adults (NC, n = 20; MCI, n = 29) consumed a high saturated fat (SFA)/glycemic index (GI) diet [HIGH] or a low SFA/GI diet [LOW] for 4 weeks. Lumbar punctures were performed at baseline and 4 weeks.Results:CSF valine increased and arginine decreased after the HIGH compared to the LOW diet in MCI (ps = 0.03 and 0.04). This pattern was more prominent in MCI versus NC (diet by diagnosis interaction ps = 0.05 and 0.09), as was an increase in isoleucine after the HIGH diet (p = 0.05). Changes in CSF amino acids were correlated with changes in Alzheimer’s disease CSF biomarkers Aβ42, total tau, and p-Tau 181, with distinct patterns in the relationships by diet intervention and cognitive status.Conclusion:Dietary intake affects CSF amino acid levels and the response to diet is differentially affected by cognitive status.

Nosocomial meningitis laboratory criteria in ICU patients: 5-year surveillance

Introduction. Nosocomial meningitis (NM) is one of the leading complications in neurosurgery due to high mortality and disability rates.Objective. The study was aimed to determine the reference values of laboratory parameters to diagnose NM in neurosurgical patients in the intensive care unit (ICU).Results. The incidence of NM in neurosurgical patients in ICU was 8.4 (95% CI 6.8–10. 0) per 100 patients. The dominant microbial agents of NM were coagulase-negative staphylococci, A. baumannii, and K. pneumoniae. We revealed the increase in leukocytosis, C-reactive protein, and blood procalcitonin in patients with infectious complications of other systems, regardless of NM presence. Episodes of hyponatremia and an increase in body temperature ≥ 38.0 occurred signifcantly more often in patients with NM. Changes in cerebrospinal fluid (CSF) cytosis, glucose, lactate, and the CSF/blood glucose ratio can serve as reliable criteria in the NM diagnosis.Conclusions. The diagnosis of NM is most likely when the increase in CSF cytosis > 65 cells/μL, CSF lactate > 4.2 mmol/L is observed, the decrease in the CSF glucose < 2.6 mmol, and CSF/blood glucose ratio < 0.45 is found.

P‐tau235: a novel biomarker for staging preclinical Alzheimer’s disease

Alzheimer’s disease (AD) is characterised by a long preclinical phase. Although phosphorylated tau (p‐tau) species such as p‐tau217 and p‐tau231 provide accurate detection of early pathological changes, other biomarkers capable of staging disease progression during preclinical AD are still needed. Combining exploratory and targeted mass spectrometry methods in neuropathologically confirmed brain tissue, we observed that p‐tau235 is a prominent feature of AD pathology. In addition, p‐tau235 seemed to be preceded by p‐tau231, in what appeared to be a sequential phosphorylation event. To exploit its biomarker potential in cerebrospinal fluid (CSF), we developed and validated a new p‐tau235 Simoa assay. Using three clinical cohorts, we demonstrated that (i) CSF p‐235 increases early in AD continuum, and (ii) changes in CSF p‐tau235 and p‐tau231 levels during preclinical AD are consistent with the sequential phosphorylation evidence in AD brain. In conclusion, CSF p‐tau235 appears to be not only a highly specific biomarker of AD but also a promising staging biomarker for the preclinical phase. Thus, it could prove useful tracking disease progression and help enriching clinical trial recruitment.

Multi-Omics Approach to Elucidate Cerebrospinal Fluid Changes in Dogs with Intervertebral Disc Herniation.

Herniation of the intervertebral disc (IVDH) is the most common cause of neurological and intervertebral disc degeneration-related diseases. Since the disc starts to degenerate before it can be observed by currently available diagnostic methods, there is an urgent need for novel diagnostic approaches. To identify molecular networks and pathways which may play important roles in intervertebral disc herniation, as well as to reveal the potential features which could be useful for monitoring disease progression and prognosis, multi-omics profiling, including high-resolution liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and tandem mass tag (TMT)-based proteomics was performed. Cerebrospinal fluid of nine dogs with IVDH and six healthy controls were used for the analyses, and an additional five IVDH samples were used for proteomic data validation. Furthermore, multi-omics data were integrated to decipher a complex interaction between individual omics layers, leading to an improved prediction model. Together with metabolic pathways related to amino acids and lipid metabolism and coagulation cascades, our integromics prediction model identified the key features in IVDH, namely the proteins follistatin Like 1 (FSTL1), secretogranin V (SCG5), nucleobindin 1 (NUCB1), calcitonin re-ceptor-stimulating peptide 2 precursor (CRSP2) and the metabolites N-acetyl-D-glucosamine and adenine, involved in neuropathic pain, myelination, and neurotransmission and inflammatory response, respectively. Their clinical application is to be further investigated. The utilization of a novel integrative interdisciplinary approach may provide new opportunities to apply innovative diagnostic and monitoring methods as well as improve treatment strategies and personalized care for patients with degenerative spinal disorders.

Low soluble amyloid-β 42 is associated with smaller brain volume in Parkinson's disease

IntroductionWe sought to examine whether levels of soluble alpha-synuclein (α‐syn), amyloid-beta (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau), as measured in cerebrospinal fluid (CSF), are associated with changes in brain volume in Parkinson's disease. MethodsWe assessed the 4-year change in total brain volume (n = 99) and baseline CSF α‐syn, Aβ42, p-tau, and t-tau of Parkinson Progression Markers Initiative participants. We used linear mixed models to assess the longitudinal effect of baseline CSF biomarkers on total and regional brain volume and thickness as well as linear regression for cross-sectional analyses at baseline and year 2. All models were adjusted for age and gender; brain volume models also adjusted for baseline intracranial volume. Bonferroni correction was applied. ResultsThe 4-year change in total brain volume was −21.2 mm3 (95% confidence interval, −26.1, −16.3). There were no significant associations between the 4-year change in total brain volume and baseline levels of any CSF biomarker (all p-values > 0.05). On cross-sectional analyses, CSF Aβ42 was linearly associated with total brain volume at baseline (R2 = 0.60, p = 0.0004) and at year 2 (R2 = 0.66, p < 0.0001), with CSF Aβ42 < 1100 pg/ml, the threshold for brain amyloid pathology, associated with smaller total brain volume at baseline (p = 0.0010) and at year 2 (p = 0.0002). CSF α‐syn was linearly associated with total brain volume at baseline (R2 = 0.58, p = 0.0044) but not at year 2 (R2 = 0.58, p = 0.1342). ConclusionReduction in soluble Aβ42 is associated with lower total brain volume in Parkinson's disease.

Differential chemokine alteration in the variants of primary progressive aphasia\u2014a role for neuroinflammation

BackgroundThe primary progressive aphasias (PPA) represent a group of usually sporadic neurodegenerative disorders with three main variants: the nonfluent or agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). They are usually associated with a specific underlying pathology: nfvPPA with a primary tauopathy, svPPA with a TDP-43 proteinopathy, and lvPPA with underlying Alzheimer’s disease (AD). Little is known about their cause or pathophysiology, but prior studies in both AD and svPPA have suggested a role for neuroinflammation. In this study, we set out to investigate the role of chemokines across the PPA spectrum, with a primary focus on central changes in cerebrospinal fluid (CSF)MethodsThirty-six participants with sporadic PPA (11 svPPA, 13 nfvPPA, and 12 lvPPA) as well as 19 healthy controls were recruited to the study and donated CSF and plasma samples. All patients with lvPPA had a tau/Aβ42 biomarker profile consistent with AD, whilst this was normal in the other PPA groups and controls. We assessed twenty chemokines in CSF and plasma using Proximity Extension Assay technology: CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-1β), CCL7 (MCP-3), CCL8 (MCP-2), CCL11 (eotaxin), CCL13 (MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CX3CL1 (fractalkine), CXCL1, CXCL5, CXCL6, CXCL8 (IL-8), CXCL9, CXCL10, and CXCL11.ResultsIn CSF, CCL19 and CXCL6 were decreased in both svPPA and nfvPPA compared with controls whilst CXCL5 was decreased in the nfvPPA group with a borderline significant decrease in the svPPA group. In contrast, CCL2, CCL3 and CX3CL1 were increased in lvPPA compared with controls and nfvPPA (and greater than svPPA for CX3CL1). CXCL1 was also increased in lvPPA compared with nfvPPA but not the other groups. CX3CL1 was significantly correlated with CSF total tau concentrations in the controls and each of the PPA groups. Fewer significant differences were seen between groups in plasma, although in general, results were in the opposite direction to CSF, i.e. decreased in lvPPA compared with controls (CCL3 and CCL19), and increased in svPPA (CCL8) and nfvPPA (CCL13).ConclusionDifferential alteration of chemokines across the PPA variants is seen in both CSF and plasma. Importantly, these results suggest a role for neuroinflammation in these poorly understood sporadic disorders, and therefore also a potential future therapeutic target.

S100B as a biomarker of blood-brain barrier disruption after thoracoabdominal aortic aneurysm repair: a secondary analysis from a prospective cohort study.

The objective of this study was to determine whether the magnitude of the peripheral inflammatory response to cardiovascular surgery is associated with increases in blood-brain barrier (BBB) permeability as reflected by changes in cerebrospinal fluid (CSF)/plasma S100B concentrations. We conducted a secondary analysis from a prospective cohort study of 35 patients undergoing elective thoracoabdominal aortic aneurysm repair with (n = 17) or without (n = 18) cardiopulmonary bypass (CPB). Plasma and CSF S100B, interleukin-6 (IL-6), and albumin concentrations were measured at baseline (C0) and serially for up to five days. Following CPB, the median [interquartile range] plasma S100B concentration increased from 58 [32-88] pg·mL-1 at C0 to a maximum concentration (Cmax) of 1,131 [655-1,875] pg·mL-1 over a median time (tmax) of 6.3 [5.9-7.0] hr. In the non-CPB group, the median plasma S100B increased to a lesser extent. There was a delayed increase in CSF S100B to a median Cmax of 436 [406-922] pg·mL-1 in the CPB group at a tmax of 23.7 [18.5-40.2] hr. In the non-CPB group, the CSF concentrations were similar at all time points. In the CPB group, we did not detect significant correlations between plasma and CSF S100B with plasma IL-6 [r = 0.52 (95% confidence interval [CI], -0.061 to 0.84)] and CSF IL-6 [r = 0.53 (95% CI, -0.073 to 0.85)] concentrations, respectively. Correlations of plasma or CSF S100B levels with BBB permeability were not significant. The lack of parallel increases in plasma and CSF S100B following CPB indicates that S100B may not be a reliable biomarker for BBB disruption after thoracoabdominal aortic aneurysm repair employing CPB. www.clinicaltrials.gov (NCT00878371); registered 7 April 2009.

Non-invasive assessment of cerebrospinal fluid flow dynamics using phase-contrast magnetic resonance imaging in communicating hydrocephalus

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 < 0.05). This was after adjusting the age, gender, heart rate, systolic blood pressure, diastolic blood pressure, and body mass index. However, only the peak negative velocity of the midbrain aqueduct did not significantly differ between the groups (p = 0.209). A positive correlation was noted between the average flow (AF) of the midbrain aqueducts and ICP in hydrocephalus patients (y (AF) = 0.386× (ICP)−33.738, r = 0.787, p < 0.05). Reference data of CSF flow dynamic parameters was obtained through the PC-MRI in middle-aged healthy volunteers and communicating hydrocephalus patients. Although the sample size was constrained, this study has significant contributions. For instance, a significant correlation was noted between the average CSF flow of the aqueduct and ICP. This therefore provides a reference for clinicians to monitor ICP in patients with hydrocephalus.

Biological Significance of the Protein Changes Occurring in the Cerebrospinal Fluid of Alzheimer's Disease Patients: Getting Clues from Proteomic Studies.

The fact that cerebrospinal fluid (CSF) deeply irrigates the brain together with the relative simplicity of sample extraction from patients make this biological fluid the best target for biomarker discovery in neurodegenerative diseases. During the last decade, biomarker discovery has been especially fruitful for the identification new proteins that appear in the CSF of Alzheimer’s disease (AD) patients together with amyloid-β (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau). Thus, several proteins have been already stablished as important biomarkers, due to an increase (i.e., CHI3L1) or a decrease (i.e., VGF) in AD patients’ CSF. Notwithstanding this, only a deep analysis of a database generated with all the changes observed in CSF across multiple proteomic studies, and especially those using state-of-the-art methodologies, may expose those components or metabolic pathways disrupted at different levels in AD. Deep comparative analysis of all the up- and down-regulated proteins across these studies revealed that 66% of the most consistent protein changes in CSF correspond to intracellular proteins. Interestingly, processes such as those associated to glucose metabolism or RXR signaling appeared inversely represented in CSF from AD patients in a significant manner. Herein, we discuss whether certain cellular processes constitute accurate indicators of AD progression by examining CSF. Furthermore, we uncover new CSF AD markers, such as ITAM, PTPRZ or CXL16, identified by this study.

Morphological changes after cranial fractionated photon radiotherapy: Localized loss of white matter and grey matter volume with increasing dose

PurposeNumerous brain MR imaging studies have been performed to understand radiation-induced cognitive decline. However, many of them focus on a single region of interest, e.g. cerebral cortex or hippocampus. In this study, we use deformation-based morphometry (DBM) and voxel-based morphometry (VBM) to measure the morphological changes in patients receiving fractionated photon RT, and relate these to the dose. Additionally, we study tissue specific volume changes in white matter (WM), grey matter (GM), cerebrospinal fluid and total intracranial volume (TIV). Methods and materialsFrom our database, we selected 28 patients with MRI of high quality available at baseline and 1 year after RT. Scans were rigidly registered to each other, and to the planning CT and dose file. We used DBM to study non-tissue-specific volumetric changes, and VBM to study volume loss in grey matter. Observed changes were then related to the applied radiation dose (in EQD2). Additionally, brain tissue was segmented into WM, GM and cerebrospinal fluid, and changes in these volumes and TIV were tested. ResultsPerforming DBM resulted in clusters of dose-dependent volume loss 1 year after RT seen throughout the brain. Both WM and GM were affected; within the latter both cerebral cortex and subcortical nuclei show volume loss. Volume loss rates ranging from 5.3 to 15.3%/30 Gy were seen in the cerebral cortical regions in which more than 40% of voxels were affected. In VBM, similar loss rates were seen in the cortex and nuclei. The total volume of WM and GM significantly decreased with rates of 5.8% and 2.1%, while TIV remained unchanged as expected. ConclusionsRadiotherapy is associated with dose-dependent intracranial morphological changes throughout the entire brain. Therefore, we will consider to revise sparing of organs at risk based on future cognitive and neurofunctional data.

Concurrent central nervous system involvement in immunocompetent adults with pulmonary miliary TB: a prospective analysis.

Wallgren's tuberculosis (TB) timetable demonstrated co-occurrence of miliary TB and tuberculous meningitis in children. To verify the same in immunocompetent adults, we prospectively evaluated the prevalence and spectrum of central nervous system (CNS) involvement in patients with pulmonary miliary TB. This was a tertiary care, University hospital-based, prospective evaluation performed from December 2018 to June 2020. Newly diagnosed patients with pulmonary miliary TB were subjected to a detailed clinical, laboratory and MRI-based evaluation. All patients received treatment as per WHO guidelines. Out of 342 patients with pulmonary TB, 53 patients met the eligibility criteria. The median age at presentation was 32 y and approximately two-thirds of patients were female. Clinically, only two-fifths of patients had features of CNS involvement. Cerebrospinal fluid (CSF) and imaging abnormalities were noted in 46 patients each. Twelve (23.5%) patients were diagnosed with definite-category tuberculous meningitis. Presence of an infarct significantly correlated with neurological features. Mantoux positivity correlated significantly with the presence of choroid tubercles, CSF changes and brain tuberculomas. This is the first study to endorse Wallgren's observations in immunocompetent adults. A high index of suspicion, even in asymptomatic patients, may uncover tuberculous lesions involving the CNS and guide optimal monitoring of patients.