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Background/Objectives Healthcare-associated meningitis or ventriculitis ( HCAMV) is a serious and life-threatening complication of invasive neurosurgical procedures or penetrating head trauma. Older adults are at higher risk of adverse outcomes in community-acquired meningitis but studies of HCAMV are lacking. Therefore, we perform the study to define the differences in clinical outcomes between older and younger adults with HCAMV. Design Retrospective study. Setting A large tertiary care hospital in Houston, Texas, from July 2003 to November 2014. Participants Adults with a diagnosis of HCAMV (N = 160) aged ≥65 (n = 35), aged 18-64 (n = 125). Measurements Demographic characteristics, clinical presentation, laboratory results, treatments, and outcomes (Glasgow Outcome Scale). Results Older adults had more comorbidities and CSF abnormalities [pleocytosis, high cerebrospinal fluid ( CSF) protein, low CSF glucose) and were more likely to have altered mental status than younger adults ( P < .05). An adverse clinical outcome was seen in 142 participants (89%) (death (n = 18, 11%), persistent vegetative state (n = 26, 16%), severe disability (n = 68, 43%), moderate disability (n = 30, 19%). There was no difference in adverse outcomes between older (97%) and younger (86%) adults ( P = .13). On logistic regression analysis, abnormal neurological examination (adjusted odds ratio ( aOR) = 7.13, 95% confidence interval ( CI) = 2.15-23.63, P = .001) and mechanical ventilation ( aOR = 11.03, 95% CI = 1.35-90.51, P = .02) were associated with adverse clinical outcomes. Conclusion Older adults with HCAMV have more comorbidities and CSF abnormalities and are more likely to have altered mental status than younger adults but have similar high rates of adverse clinical outcomes. [ABSTRACT FROM AUTHOR]

Lanabecestat (AZD3293; LY3314814) is an orally active potent inhibitor of human β-secretase 1 in clinical development for the treatment of Alzheimer disease. In this first Japanese clinical study for an Alzheimer disease intervention to include cerebrospinal fluid (CSF) sampling in Japanese elderly healthy subjects, we report the pharmacokinetics and effects on plasma and CSF amyloid-β (Aβ) peptides of lanabecestat in a phase 1 study involving 40 healthy Japanese subjects (NCT02005211). No safety and tolerability concerns were identified in healthy Japanese subjects exposed to lanabecestat up to the highest doses given, which is consistent with observations in a US phase 1 study of lanabecestat. Exposure to lanabecestat was similar for young and elderly subjects and increased in a dose-dependent manner. For elderly subjects, plasma lanabecestat half-life after multiple dosing was 12 to 17 hours (on days 10 and 14). Robust plasma and CSF Aβ peptide reductions were also seen at all doses, with CSF Aβ42 concentrations reduced by 63% and 79% in the 15- and 50-mg lanabecestat groups, respectively. CSF soluble amyloid-β precursor protein β also decreased following lanabecestat treatment. Suppression of CSF Aβ peptides was similar in elderly healthy Japanese subjects and US patients with mild to moderate Alzheimer disease. Lanabecestat is a promising potentially disease-modifying treatment in phase 3 development for patients with early Alzheimer disease. [ABSTRACT FROM AUTHOR]

Objective To evaluate the relationship between CSF total protein concentration (CSF protein) and CSF opening pressure in idiopathic intracranial hypertension (IIH), and to explore the association of age, gender, race, BMI, and Humphrey visual field mean deviation (HVF MD) with CSF total protein. Methods The medical records of all IIH patients seen between 1989 and 2016 at one institution were systematically reviewed for demographics, CSF opening pressure, CSF contents, and HVF MD (at initial evaluation and most recent follow-up). Linear regression of CSF protein on CSF opening pressure was performed also considering BMI, age, gender, race, HVF MD, and year of lumbar puncture. Results We included 266 IIH patients (13 pre-pubertal children, 35 post-pubertal children, 218 adults). There was a negative linear association between CSF opening pressure and CSF protein: CSF protein decreased by 0.18 mg/dL for each 1 cm H 2 O increase in CSF opening pressure ( p < 0.001). After controlling for CSF opening pressure, mean CSF protein was 4.1 mg/dL higher in white patients than in black patients ( p < 0.001). Multivariable analysis found that CSF opening pressure ( p = 0.007), white race ( p < 0.001), and HVF MD (most recent follow-up, worst eye, p = 0.05) remained independently associated with CSF protein controlling for year of lumbar puncture and age. Conclusions There was a negative association between CSF protein and CSF opening pressure. After controlling for CSF opening pressure, CSF protein was higher in white patients and unaffected by age, gender, or BMI. Our findings help clarify inconsistent results of prior studies, but do not really help clarify IIH pathophysiology. [ABSTRACT FROM AUTHOR]

Objectives: To present detailed information regarding these aspects in Human Immunodeficiency Virus (HIV)-infected patients making an effort to improve the recognition of neurological complications of HIV infection. Methods: This retrospective study analyzed the clinical manifestations, laboratory and neuroimaging results of HIV-infected patients with neurological complications at Xuanwu hospital, Beijing, China from January 2011 to December 2014, one of top-rated hospitals in Beijing, China. Results: A diverse range of clinical diagnoses was identified, including encephalopathy, meningoencephalitis, peripheral neuropathy, multiple sclerosis, cerebral infarction and lymphoma associated with HIV infection. The mostly observed neurological disorders were motor/sensory deficits in the limbs (75%), cognitive impairments (42%) and fever (33%). Non-specific results of laboratory tests, including elevated erythrocyte sedimentation rate (ESR), cerebrospinal fluid (CSF) protein concentration and IgG, were found. Brain Magnetic Resonance Imaging (MRI) abnormalities displayed a variety of patterns and distributions due to diverse clinical profiles. Conclusion: The clinical scenarios of HIV-infected patients are remarkably diverse and complex. Etiological tests would be cardinal to make more definitive diagnosis for HIV-infected patients. Prospective studies with follow-up were needed to bring more accurate information. [ABSTRACT FROM AUTHOR]

Background: Subependymal giant cell astrocytomas (SEGA) are slow-growing tumors, which can cause obstructive hydrocephalus in patients with tuberous sclerosis complex (TSC). These tumors require routine surveillance with magnetic resonance imaging. Current consensus guidelines recommend treatment of asymptomatic SEGAs with an mechanistic target of rapamycin (mTOR) inhibitor because these medications have demonstrated efficacy and safety in multiple prospective clinical trials. For symptomatic SEGAs, standard therapy typically involves surgical resection of the tumor to relieve mass effect and resolve hydrocephalus. However, resection can be associated with significant perioperative morbidity and complications. There are anecdotal reports of using mTOR inhibitors to reduce tumor size in preparation for surgery, but prospective studies comparing sole mTOR inhibitor therapy with surgical management have not been completed.Methods: Here, we present a seven-year-old boy with a large, symptomatic SEGA which was treated acutely with everolimus.Results: Everolimus treatment resulted in rapid reduction in tumor size, symptomatic improvement, and decrease in cerebrospinal fluid protein.Conclusions: Everolimus can effectively reduce tumor size, decrease cerebrospinal fluid protein, and allow successful ventriculoperitoneal shunt placement without the need for surgical resection of a symptomatic SEGA. [ABSTRACT FROM AUTHOR]

Sperm competition is pervasive and fundamental to determining a male's overall fitness. Sperm traits and seminal fluid proteins (Sfps) are key factors. However, studies of sperm competition may often exclude females that fail to remate during a defined period. Hence, the resulting data sets contain fewer data from the potentially fittest males that have most success in preventing female remating. It is also important to consider a male's reproductive success before entering sperm competition, which is a major contributor to fitness. The exclusion of these data can both hinder our understanding of the complete fitness landscapes of competing males and lessen our ability to assess the contribution of different determinants of reproductive success to male fitness. We addressed this here, using the Drosophila melanogaster model system , by (i) capturing a comprehensive range of intermating intervals that define the fitness of interacting wild-type males and (ii) analysing outcomes of sperm competition using selection analyses. We conducted additional tests using males lacking the sex peptide ( SP) ejaculate component vs. genetically matched ( SP +) controls. This allowed us to assess the comprehensive fitness effects of this important Sfp on sperm competition. The results showed a signature of positive, linear selection in wild-type and SP + control males on the length of the intermating interval and on male sperm competition defence. However, the fitness surface for males lacking SP was distinct, with local fitness peaks depending on contrasting combinations of remating intervals and offspring numbers. The results suggest that there are alternative routes to success in sperm competition and provide an explanation for the maintenance of variation in sperm competition traits. [ABSTRACT FROM AUTHOR]

Background: Combining PET amyloid-β (Aβ) and tau imaging may be critical for tracking disease progression in Alzheimer's disease (AD).Objective: We sought to characterize the relationship between Aβ and tau ligands as well as with other measures of pathology.Methods: We conducted a multi-center observational study in early AD (MMSE >20) participants aged 50 to 85 y. The schedule included cognitive assessments (ADAS-Cog) and CSF measurement of Aβ and tau at baseline and 6 months; PET-CT imaging with Aβ ([18F]AV45) and tau ([18F]AV1451) ligands at baseline.Results: 22 participants took part in the study with 20 completing its 6-month duration and 12 having both tau and amyloid PET. The PET biomarker analysis revealed a strong negative correlation between age and tau in multiple regions. Entorhinal cortex tau and age interacted significantly in terms of cognitive change over 6 months which may have been to older participants deteriorating faster despite lower levels of cortical tau. Cortical Aβ associated with entorhinal cortex tau while CSF tau/Aβ ratio correlated strongly with cortical tau but not Aβ.Conclusion: The negative relationship between age and cortical tau whereby younger patients with mild AD had relatively greater tau burden is potentially important. It suggests that younger-age onset AD may be primarily driven by tau pathology while AD developing later may depend on a multitude of pathological mechanisms. These data also suggest that PET-tau performs better than PET-amyloid in predicting the best validated AD diagnostic marker- the CSF total tau/Aβ ratio. [ABSTRACT FROM AUTHOR]

Guillain Barré syndrome (GBS) is a post-infectious acute autoimmune polyradiculopathy. Cerebrospinal fluid (CSF) total protein level and plasma neutrophil/lymphocyte ratio (NLR) are related with autoimmune response. We aimed to reach a prognostic indicator for GBS by using electrophysiological findings, protein level of CSF, and plasma NLR based on Medical Research Council (MRC) sum score data. Cases who met diagnostic criteria of GBS and followed at least six months were enrolled in the study. Nerve conduction study (NCS) and lumbar puncture were performed one week after symptom onset. Routine CSF findings and complete blood count were recorded. Plasma NLR was calculated as the ratio of neutrophil cell count to lymphocyte cell count. All patients received intravenous immunoglobulin. MRC sum scores were calculated on administration time (1st) and six months later (2nd) for evaluation of recovery. Mean values of baseline CSF protein level, NCS parameters and NLR were compared with mean scores of MRC1st and MRC2nd. Increased CSF protein levels showed negative correlation with MRC2nd scores but no correlation with NCS. Increased NLR levels were positively correlated with age, MRC2nd scores and NCS. Facial diplegia was observed in 42% of patients. A positive correlation was found between high level of NLR and MRC1st, and there was no relationship with MRC2nd. Regression analyses showed that only CSF protein level was an independent factor on both MRC1st and MRC2nd. A positive association was found between baseline data included young age high plasma NLR, low level of CSF protein and good prognosis in our study. Also a positive correlation was found between high level of NLR and baseline disability in GBS cases with facial diplegia. Calculation of NLR is an easy and inexpensive method. On the other hand it may be influenced by age and immunotherapy. Our results showed that CSF protein level is still a liable parameter for prognosis. NLR could be a candidate prognostic marker of GBS cases. Further investigations including more cases are needed. [ABSTRACT FROM AUTHOR]

Introduction Increased cytokine expression is a prominent finding in amyotrophic lateral sclerosis (ALS). Due to their interdependence and pleiotropism, interpretation of CSF concentrations of a single cytokine is challenging. We describe a cytokine analysis in ALS patients using a pathway-based statistical method to identify changes in the whole cytokine network. Methods We analyzed 19 cytokines in CSF of ALS patients and controls. An equality of concentration matrices was conducted that allowed us to evaluate disturbances in the relationship of cytokines between controls and ALS patients with less and more than 12 months of disease length. MANOVA assessed differences in cytokines and interdependence was compared by partial correlations among specific pairs of cytokines. Results Seventy-seven ALS patients and 13 control subjects were included. Significant differences were identified in the cytokine pathway between controls and ALS patients with less (p < 0.0001) and more than 12 months of disease length (p < 0.0001), and between ALS patients with less than 12 months and those with more than 12 months (p = 0.0058). In ALS patients with a shorter disease length, IL4 and IL6 were negatively correlated (−0.3571), whereas in ALS > 12 months, a positive correlation was detected (0.4080). Conclusions The pathway-based statistical method revealed remarkable variations in the whole cytokine pathway in ALS patients and controls. Cytokine-network changes and the positive correlation between IL4 and IL6 were related to disease length; these variations might explain the deleterious immunological effects on motor neurons. A further analysis using this method is needed to confirm the exact interaction among cytokines in ALS. [ABSTRACT FROM AUTHOR]

Background: Amyloid-β (Aβ) degradation in brains of Alzheimer disease patients is a crucial focus for the clarification of disease pathogenesis. Nevertheless, the mechanisms underlying Aβ degradation in the human brain remain unclear. Objective: This study aimed to quantify the levels of small C-terminal Aβ fragments generated upon Aβ degradation in human cerebrospinal fluid (CSF). Methods: A fraction containing small peptides was isolated and purified from human CSF by high-pressure liquid chromatography. Degradation products of Aβ C termini were identified and measured by liquid chromatography-tandem mass spectrometry. The C-terminal fragments of Aβ in the conditioned medium of cultured cells transfected with the Swedish variant of βAPP (sw βAPP) were analyzed. These fragments in brains of PS1 I213T knock-in transgenic mice, overexpressing sw βAPP, were also analyzed. Results: The peptide fragments GGVV and GVV, produced by the cleavage of Aβ40, were identified in human CSF as well as in the brains of the transgenic mice and in the conditioned medium of the cultured cells. Relative to Aβ40 levels, GGVV and GVV levels were 7.6 ± 0.81 and 1.5 ± 0.18%, respectively, in human CSF. Levels of the GGVV fragment did not increase by the introduction of genes encoding neprilysin and insulin-degrading enzyme to the cultured cells. Conclusion: Our results indicate that a substantial amount of Aβ40 in human brains is degraded via a neprilysin-or insulin-degrading enzyme-independent pathway. [ABSTRACT FROM AUTHOR]

Although the use of cerebrospinal fluid (CSF) amyloid β1-42 (Aβ42), tau (T-tau), and phosphorylated tau (p-tau181) gives added diagnostic and prognostic values, the diffusion is still limited in clinical practice and only a restricted number of patients receive an integrated clinico-biological diagnosis. By a survey, we aimed to do a "selfie" of the use and diffusion of CSF biomarkers of dementia in Italy, the standardization of pre-analytical procedures, the harmonization of ranges, and the participation to Quality Control programs. An online questionnaire was sent to the members of SIBioC and SINdem-ITALPLANED and to main neurological clinics all over Italy. In Italy, 25 laboratories provide biomarkers analysis in addition to a network of 15 neighboring hospitals. In sum, 40 neurological centers require CSF analyses. 7/20 regions (35%) lack CSF laboratories. Standardization of pre-analytical procedures is present in 62.02% of the laboratories; only 56.00% of the laboratories participate in International Quality Control. There is no harmonization of cut-offs. In Italy, the use of CSF biomarkers is still limited in clinical practice. Standardization and harmonization of normal ranges are needed. To optimize and expand the use of CSF biomarkers, a cost-benefit analysis should be promoted by scientific societies and national health services. [ABSTRACT FROM AUTHOR]

AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of ≥5 mg, a ≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing. [ABSTRACT FROM AUTHOR]

Background: Currently available biomarkers of Alzheimer's disease (AD) include cerebrospinal fluid (CSF) protein analysis and amyloid PET imaging, each of which has limitations. The discovery of extracellular microRNAs (miRNAs) in CSF raises the possibility that miRNA may serve as novel biomarkers of AD.Objective: Investigate miRNAs in CSF obtained from living donors as biomarkers for AD.Methods: We profiled miRNAs in CSF from 50 AD patients and 49 controls using TaqMan® arrays. Replicate studies performed on a subset of 32 of the original CSF samples verified 20 high confidence miRNAs. Stringent data analysis using a four-step statistical selection process including log-rank and receiver operating characteristic (ROC) tests, followed by random forest tests, identified 16 additional miRNAs that discriminate AD from controls. Multimarker modeling evaluated linear combinations of these miRNAs via best-subsets logistic regression, and computed area under the ROC (AUC) curve ascertained classification performance. The influence of ApoE genotype on miRNA biomarker performance was also evaluated.Results: We discovered 36 miRNAs that discriminate AD from control CSF. 20 of these retested in replicate studies verified differential expression between AD and controls. Stringent statistical analysis also identified these 20 miRNAs, and 16 additional miRNA candidates. Top-performing linear combinations of 3 and 4 miRNAs have AUC of 0.80-0.82. Addition of ApoE genotype to the model improved performance, i.e., AUC of 3 miRNA plus ApoE4 improves to 0.84.Conclusions: CSF miRNAs can discriminate AD from controls. Combining miRNAs improves sensitivity and specificity of biomarker performance, and adding ApoE genotype improves classification. [ABSTRACT FROM AUTHOR]

AZD3293 (LY3314814) is a promising new potentially disease-modifying BACE1 (β-secretase) inhibitor in Phase III clinical development for the treatment of Alzheimer's disease. Reported here are the first two Phase I studies: (1) a single ascending dose study evaluating doses of 1-750 mg with a food-effect component (n = 72), and (2) a 2-week multiple ascending dose study evaluating doses of 15 or 50 mg once daily (QD) or 70 mg once weekly (QW) in elderly subjects (Part 1, n = 31), and 15, 50, or 150 mg QD in patients with mild to moderate Alzheimer's disease (Part 2, n = 16). AZD3293 was generally well tolerated up to the highest doses given. No notable food effects were observed. PK following multiple doses (Part 2) were tmax of 1 to 3 h and mean t1/2 of 16 to 21 h across the 15 to 150 mg dose range. For single doses of≥5 mg, a≥70% reduction was observed in mean plasma Aβ40 and Aβ42 concentrations, with prolonged suppression for up to 3 weeks at the highest dose level studied. Following multiple doses, robust reductions in plasma (≥64% at 15 mg and ≥78% at ≥50 mg) and cerebrospinal fluid (≥51% at 15 mg and ≥76% at ≥50 mg) Aβ peptides were seen, including prolonged suppression even with a QW dosing regimen. AZD3293 is the only BACE1 inhibitor for which prolonged suppression of plasma Aβ with a QW dosing schedule has been reported. Two Phase III studies of AZD3293 (AMARANTH, NCT02245737; and DAYBREAK-ALZ, NCT02783573) are now ongoing. [ABSTRACT FROM AUTHOR]

Delirium is a common postoperative complication among older patients with many adverse outcomes. Due to a lack of validated biomarkers, prediction and monitoring of delirium by biological testing is not currently feasible. Circulating proteins in cerebrospinal fluid (CSF) may reflect biological processes causing delirium. Our goal was to discover and investigate candidate protein biomarkers in preoperative CSF that were associated with the development of postoperative delirium in older surgical patients. We employed a nested case-control study design coupled with high multiplex affinity proteomics analysis to measure 1305 proteins in preoperative CSF. Twenty-four matched delirium cases and non-delirium controls were selected from the Healthier Postoperative Recovery (HiPOR) cohort, and the associations between preoperative protein levels and postoperative delirium were assessed using t -test statistics with further analysis by systems biology to elucidate delirium pathophysiology. Proteomics analysis identified 32 proteins in preoperative CSF that significantly associate with delirium ( t -test p < 0.05). Due to the limited sample size, these proteins did not remain significant by multiple hypothesis testing using the Benjamini-Hochberg correction and q-value method. Three algorithms were applied to separate delirium cases from non-delirium controls. Hierarchical clustering classified 40/48 case-control samples correctly, and principal components analysis separated 43/48. The receiver operating characteristic curve yielded an area under the curve [95% confidence interval] of 0.91 [0.80-0.97]. Systems biology analysis identified several key pathways associated with risk of delirium: inflammation, immune cell migration, apoptosis, angiogenesis, synaptic depression and neuronal cell death. Proteomics analysis of preoperative CSF identified 32 proteins that might discriminate individuals who subsequently develop postoperative delirium from matched control samples. These proteins are potential candidate biomarkers for delirium and may play a role in its pathophysiology.

Cerebrospinal fluid (CSF) is an essential matrix for the discovery of neurological disease biomarkers. However, the high dynamic range of protein concentrations in CSF hinders the detection of the least abundant protein biomarkers by untargeted mass spectrometry. It is thus beneficial to gain a deeper understanding of the secretion processes within the brain. Here, we aim to explore if and how the secretion of brain proteins to the CSF can be predicted. By combining a curated CSF proteome and the brain elevated proteome of the Human Protein Atlas, brain proteins were classified as CSF or non-CSF secreted. A machine learning model was trained on a range of sequence-based features to differentiate between CSF and non-CSF groups and effectively predict the brain origin of proteins. The classification model achieves an area under the curve of 0.89 if using high confidence CSF proteins. The most important prediction features include the subcellular localization, signal peptides, and transmembrane regions. The classifier generalized well to the larger brain detected proteome and is able to correctly predict novel CSF proteins identified by affinity proteomics. In addition to elucidating the underlying mechanisms of protein secretion, the trained classification model can support biomarker candidate selection.

Background: Alzheimer's disease (AD) cerebrospinal fluid (CSF) core biomarkers (Aβ42/40 ratio, p-tau, and t-tau) provide high diagnostic accuracy, even at the earliest stage of disease. However, these markers do not fully reflect the complex AD pathophysiology. Recent large scale CSF proteomic studies revealed several new AD candidate biomarkers related to metabolic pathways. In this study we measured the CSF levels of four metabolism-related proteins not directly linked to amyloid- and tau-pathways (i.e., pyruvate kinase, PKM; aldolase, ALDO; ubiquitin C-terminal hydrolase L1, UCHL1, and fatty acid-binding protein 3, FABP3) across the AD continuum. We aimed at validating the potential value of these proteins as new CSF biomarkers for AD and their possible involvement in AD pathogenesis, with specific interest on the preclinical phase of the disease., Methods: CSF PKM and ALDO activities were measured with specific enzyme assays while UCHL1 and FABP3 levels were measured with immunoassays in a cohort of patients composed as follows: preclinical AD (pre-AD, n = 19, cognitively unimpaired), mild cognitive impairment due to AD (MCI-AD, n = 50), dementia due to AD (ADdem, n = 45), and patients with frontotemporal dementia (FTD, n = 37). Individuals with MCI not due to AD (MCI, n = 30) and subjective cognitive decline (SCD, n = 52) with negative CSF AD-profile, were enrolled as control groups., Results: CSF UCHL1 and FABP3 levels, and PKM activity were significantly increased in AD patients, already at the pre-clinical stage. CSF PKM activity was also increased in FTD patients compared with control groups, being similar between AD and FTD patients. No difference was found in ALDO activity among the groups. UCHL1 showed good performance in discriminating early AD patients (pre-AD and MCI-AD) from controls (AUC ~ 0.83), as assessed by ROC analysis. Similar results were obtained for FABP3. Conversely, PKM provided the best performance when comparing FTD vs. MCI (AUC = 0.80). Combination of PKM, FABP3, and UCHL1 improved the diagnostic accuracy for the detection of patients within the AD continuum when compared with single biomarkers., Conclusions: Our study confirmed the potential role of UCHL1 and FABP3 as neurodegenerative biomarkers for AD. Furthermore, our results validated the increase of PKM activity in CSF of AD patients, already at the preclinical phase of the disease. Increased PKM activity was observed also in FTD patients, possibly underlining similar alterations in energy metabolism in AD and FTD., (© 2023. The Author(s).)

Syndromic CLN3-Batten is a fatal, pediatric, neurodegenerative disease caused by variants in CLN3 , which encodes the endolysosomal transmembrane CLN3 protein. No approved treatment for CLN3 is currently available. The protracted and asynchronous disease presentation complicates the evaluation of potential therapies using clinical disease progression parameters. Biomarkers as surrogates to measure the progression and effect of potential therapeutics are needed. We performed proteomic discovery studies using cerebrospinal fluid (CSF) samples from 28 CLN3-affected and 32 age-similar non-CLN3 individuals. Proximal extension assay (PEA) of 1467 proteins and untargeted data-dependent mass spectrometry [MS; MassIVE FTP server (ftp://MSV000090147@massive.ucsd.edu)] were used to generate orthogonal lists of protein marker candidates. At an adjusted p -value of <0.1 and threshold CLN3/non-CLN3 fold-change ratio of 1.5, PEA identified 54 and MS identified 233 candidate biomarkers. Some of these (NEFL, CHIT1) have been previously linked with other neurologic conditions. Others (CLPS, FAM217B, QRICH2, KRT16, ZNF333) appear to be novel. Both methods identified 25 candidate biomarkers, including CHIT1, NELL1, and ISLR2 which had absolute fold-change ratios >2. NELL1 and ISLR2 regulate axonal development in neurons and are intriguing new candidates for further investigation in CLN3. In addition to identifying candidate proteins for CLN3 research, this study provides a comparison of two large-scale proteomic discovery methods in CSF.

Alzheimer's disease (AD) is the most common form of dementia, with cerebrospinal fluid (CSF) β-amyloid (Aβ), total Tau, and phosphorylated Tau (pTau) providing the most sensitive and specific biomarkers for diagnosis. However, these diagnostic biomarkers do not reflect the complex changes in AD brain beyond amyloid (A) and Tau (T) pathologies. Here, we report a selected reaction monitoring mass spectrometry (SRM-MS) method with isotopically labeled standards for relative protein quantification in CSF. Biomarker positive (AT+) and negative (AT-) CSF pools were used as quality controls (QCs) to assess assay precision. We detected 62 peptides (51 proteins) with an average coefficient of variation (CV) of ~13% across 30 QCs and 133 controls (cognitively normal, AT-), 127 asymptomatic (cognitively normal, AT+) and 130 symptomatic AD (cognitively impaired, AT+). Proteins that could distinguish AT+ from AT- individuals included SMOC1, GDA, 14-3-3 proteins, and those involved in glycolysis. Proteins that could distinguish cognitive impairment were mainly neuronal proteins (VGF, NPTX2, NPTXR, and SCG2). This demonstrates the utility of SRM-MS to quantify CSF protein biomarkers across stages of AD., (© 2023. The Author(s).)

Cerebrospinal fluid (CSF) proteins are very important because they can serve as biomarkers for central nervous system diseases. Although many CSF proteins have been identified with wet experiments, the identification of CSF proteins is still a challenge. In this paper, we propose a novel method to predict proteins in CSF based on protein features. A two-stage feature-selection method is employed to remove irrelevant features and redundant features. The deep neural network and bagging method are used to construct the model for the prediction of CSF proteins. The experiment results on the independent testing dataset demonstrate that our method performs better than other methods in the prediction of CSF proteins. Furthermore, our method is also applied to the identification of glioma biomarkers. A differentially expressed gene analysis is performed on the glioma data. After combining the analysis results with the prediction results of our model, the biomarkers of glioma are identified successfully.

Neurologic manifestations are among the most frequently reported complications of COVID-19. However, given the paucity of tissue samples and the highly infectious nature of the etiologic agent of COVID-19, we have limited information to understand the neuropathogenesis of COVID-19. Therefore, to better understand the impact of COVID-19 on the brain, we used mass-spectrometry-based proteomics with a data-independent acquisition mode to investigate cerebrospinal fluid (CSF) proteins collected from two different nonhuman primates, Rhesus Macaque and African Green Monkeys, for the neurologic effects of the infection. These monkeys exhibited minimal to mild pulmonary pathology but moderate to severe central nervous system (CNS) pathology. Our results indicated that CSF proteome changes after infection resolution corresponded with bronchial virus abundance during early infection and revealed substantial differences between the infected nonhuman primates and their age-matched uninfected controls, suggesting these differences could reflect altered secretion of CNS factors in response to SARS-CoV-2-induced neuropathology. We also observed the infected animals exhibited highly scattered data distributions compared to their corresponding controls indicating the heterogeneity of the CSF proteome change and the host response to the viral infection. Dysregulated CSF proteins were preferentially enriched in functional pathways associated with progressive neurodegenerative disorders, hemostasis, and innate immune responses that could influence neuroinflammatory responses following COVID-19. Mapping these dysregulated proteins to the Human Brain Protein Atlas found that they tended to be enriched in brain regions that exhibit more frequent injury following COVID-19. It, therefore, appears reasonable to speculate that such CSF protein changes could serve as signatures for neurologic injury, identify important regulatory pathways in this process, and potentially reveal therapeutic targets to prevent or attenuate the development of neurologic injuries following COVID-19., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Vestibular schwannoma is a common pathology encountered by neurosurgeons worldwide. Often vestibular schwannoma presents with obstructive hydrocephalus. Papilledema is present in 8% of the patients with vestibular schwannoma, primarily due to obstructive hydrocephalus. Hyperproteinorrhachia is believed to be responsible for papilledema in the absence of hydrocephalus in vestibular schwannoma. However, there is a paucity of literature on the mechanism of papilledema in vestibular schwannoma patients with hydrocephalus., Objective: The aim of this study was to conduct a scoping review of scientific literature on papilledema in vestibular schwannoma patients without hydrocephalus., Methods: Design: This was a systematic scoping review and critical appraisal. Literature Search from PubMed was done following PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) and Joanna Briggs Institute guidelines for conducting and reporting scoping reviews., Results: A total of seven studies, including eight patients, were identified for inclusion in the review. The studies were heterogeneous in terms of reporting for various variables. All the included studies were case reports, with the earliest publication in 1954 and the latest publication in 2020. The mean age of the patients in the included studies was 35 years, with a minimum age of 20 years and maximum age of 64 years. Approximately 62.5% were females, and 37.5% were males in the included study. Only three studies have studied cerebrospinal fluid (CSF) proteins levels in these patients., Conclusions: There is paucity in literature and a lack of evidence to conclusively state hyperproteinorrhachia as an antecedent to the development of papilledema in vestibular schwannoma patients without hydrocephalus. Younger age and female gender are risk factors for developing papilledema in the absence of hydrocephalus in vestibular schwannoma patients. Brainstem compression due to the large size of vestibular schwannoma can still have a patent aqueduct of Sylvius and no obstruction to CSF flow. The development of papilledema in vestibular schwannoma is a complex interplay of multiple factors that must be studied comprehensively for complete understanding.