Cerebrospinal Fluid Patterns Research Articles

Temporal Immune Profiling in the CSF and Blood of Patients with Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) is a significant complication of aneurysmal subarachnoid hemorrhage (aSAH). This study profiled immune responses after aSAH and evaluated their association with DCI onset. Twelve aSAH patients were enrolled. Leukocyte populations and cytokine levels were analyzed in cerebrospinal fluid (CSF) and peripheral blood (PB) on days 3, 5, 7, 10, and 14 post-aSAH. Peripheral blood mononuclear cells (PBMCs) were collected and their cytokine production quantified following stimulation. Mixed-effects models revealed distinct immune cell dynamics in CSF compared to blood. Natural killer T cell frequency increased over time in CSF only, while monocyte/macrophage numbers increased in both CSF and PBMCs. CD4+ HLA II+ T cells increased in circulation. Unstimulated PBMCs showed increased IL-1β, IL-6, and TNFα production, peaking at 7 days post-aSAH, coinciding with typical DCI onset. Ex vivo stimulation of PBMCs showed that only IL-6 significantly changed over time. In CSF, cytokines peaked 5 days post-injury, preceding immune cell profile alterations. Our findings reveal a time-dependent immune response following aSAH, with distinct within-patient patterns in CSF and PB. The early CSF cytokine peak preceding immune cell changes suggests a potential mechanistic link and identifies the cytokine response as a promising therapeutic target. This cytokine surge may drive immune cell expansion and prime PBMCs for increased inflammatory activity, potentially contributing to DCI risk. Future studies should explore the importance and sources of specific cytokines in driving immune activation. These insights may inform the development of targeted immunomodulatory strategies for preventing or managing DCI in aSAH patients.

Findings Related to Cerebrospinal Fluid and Central Nervous System Disorders in Small Ruminants-A Retrospective Study on Sheep and Goats.

Small ruminants often suffer from central nervous system (CNS) disorders, and cerebrospinal fluid (CSF) analysis can be used as a diagnostic tool in this regard. In small animals and cattle, specific CSF patterns have been defined for specific disease categories. No data exist regarding CSF results obtained from small ruminants and their association with certain CNS diseases. The objective of this study was to retrospectively investigate CSF findings obtained from sheep and goats and to identify possible CSF patterns associated with disease categories. CSF samples and medical records from 44 sheep and 27 goats were included in this study. All animals were presented to the Veterinary Teaching Hospital Zurich of the Veterinary Teaching Hospital Zurich of the Vetsuisse Faculty of the University of Zurich between 2003 and 2016 and had either a confirmed CNS diagnosis or showed CSF changes without a specific CNS diagnosis. Mixed mononuclear pleocytosis was the most common CSF pattern in sheep (25%), followed by monocytic pleocytosis (21%). Lymphocytic pleocytosis was most frequently found in goats (37%). In 75% of sheep and 56% of goats, infectious CNS diseases were diagnosed, with listeriosis being the most common infectious disease in both species, followed by parasitic disorders (nematodiasis and coenurosis). The cytologic CSF patterns in small ruminants are mainly based on the increased presence of monocytic and lymphocytic cells with variable quantitative expression, whereas neutrophilic pleocytosis and cytoalbuminologic dissociation were rare findings. Infectious diseases of bacterial origin were the most common underlying causes for CSF alterations in sheep and goats, followed by parasitic disorders. The pleocytosis type is not helpful for differentiating disease types.

Lower CSF ApoE glycosylation associates with measures of Alzheimer's disease biomarkers

AbstractBackgroundThe mechanisms of how APOE4 allele (APOE4) increases the risk of Alzheimer’s disease (AD) pathology have not been fully elucidated. In cerebrospinal fluid (CSF), apoE is heavily glycosylated but its contribution to AD pathology is not known. The objective of this study was to determine the impact of APOE genotype and cognitive status on the relative abundance of apoE protein isoforms and their specific glycosylation patterns in CSF and plasma.MethodTotal glycosylation and ApoE isoform‐specific glycosylation were analyzed in plasma and CSF from a group of older individuals (n = 106) from the USC ADRC cohort, grouped into cognitively normal, with mild cognitive impairment, and with AD dementia. We used a new mass spectrometric immunoassay that simultaneously detects the apoE isoforms and glycoforms (O‐linked GalNAc(‐Sia)‐Gal‐Sia, and various combinations thereof).ResultIn heterozygous individuals, the apoE3/E2, E4/E2, and E4/E3 isoform ratios were all significantly lower in plasma compared to CSF. For all individuals, a single O‐linked glycan was observed in plasma, while two glycans (of the same type) per apoE were observed in CSF. The ratio of glycosylated to total apoE was greater in CSF compared to plasma for all apoE isoforms. In CSF, ApoE4 was 35% and 25% less glycosylated (P<0.001) than ApoE2 and ApoE3 carriers respectively. The % of secondary glycosylation was positively correlated with CSF Aβ42 levels (R=0.55, p<0.001) and negatively correlated with CSF total Tau (R=‐0.38, p=0.001). Patients with AD dementia had lower % glycosylation than individuals with MCI (p=0.008).ConclusionCSF glycosylation is lower in CSF apoE4 isoform and in those with dementia, and correlate with markers of AD pathology. Ongoing experiments are delineating the effects of ApoE glycosylation on its functions. ApoE4 glycosylation may represent a newer target of treatment in AD.

Subtle cognitive deficits assessed by means of CANTAB in a cohort of subjects with CSF AD profile

AbstractBackgroundIn order to make successful disease‐modifying treatments, it is needed to shift Alzheimer’s disease (AD) diagnosis toward individuals with subtle cognitive deficits not yet fulfilling MCI criteria (pre‐MCI), entity associated with AD biomarkers positivity and increased risk of progression (Parnetti et al.,2019). This might allow to identify the individuals candidate to biomarker assessment. The detection of subtle cognitive impairment is limited by the sensitivity of standard neuropsychological measures (Wolfsgruber et al.,2020; Chipi et al.,2019). Cambridge Neuropsychological Test Automated Battery (CANTAB) represents an advanced computerized tool for the assessment of non‐verbal frontal‐subcortical functioning (Robbins et al.,1994). We aimed to explore the frequency of cerebrospinal fluid (CSF) AD‐like profile in pre‐MCI subjects defined as those obtaining low scores (≥‐1 SD) in at least one CANTAB test.MethodWe retrospectively analyzed 64 consecutive subjects (31 males, 33 females, mean age = 67±7.9) referring to our Memory Clinic for subjective cognitive complaints. All participants performed a comprehensive standard neuropsychological battery, reporting normal scores, and tests from CANTAB (Paired Associated Learning‐PAL; Pattern Recognition Memory‐PRM; Spatial Working Memory‐SWM). Pathological performance at CANTAB (CANTAB+) was defined as scores ≥‐1 SD in at least one task. All of them underwent lumbar puncture for the analysis of CSF core AD biomarkers (Aβ42/Aβ40 ratio, total tau, phospho‐tau). By applying the A/T/(N) classification scheme (Jack et al.,2018), AD CSF profile was defined as A+/T+. As A biomarker, we considered the Aβ42/40 ratio.ResultOut of 64 subjects, 43 performed ≥‐1SD in at least one test from CANTAB. In those 43 CANTAB+ subjects, 10 (23%) were A+/T+, 4 (9%) A+, and 22 (51%) A‐/T‐. Among CANTAB‐ (N = 21), 3 (14%) were A+/T+; 3 (14%) A+; 13 (61%) A‐/T‐. Among CANTAB+ subjects with A+/T+ (N = 10), 8 (80%) showed deficit in PAL, 4 at SWM and none of them showed altered scores at PRM.ConclusionConsistent proportion (23%) of pre‐MCI subjects with at least one altered score at CANTAB showed a CSF pattern compatible with AD. Since PAL test was altered in 80% of these subjects, if confirmed in independent cohorts, it might represent a sensitive neuropsychological measure to identify subjects with subtle cognitive deficits who may deserve CSF analysis for detecting preclinical AD.

Longitudinal ventricular cerebrospinal fluid profile in patients with spontaneous subarachnoid hemorrhage.

BackgroundSpontaneous subarachnoid hemorrhage (SAH) is a severe neurological disease that frequently requires placement of external ventricular drainage (EVD). Cerebrospinal fluid (CSF) obtained via the drain is used to detect potential complications of SAH.ObjectiveThis study aimed to describe the longitudinal profile of routine CSF parameters in patients with SAH and to identify associations with neurological complications.MethodsA total of thirty-three patients with spontaneous SAH who required an EVD and had at least three consecutive CSF samples collected over a period of more than 7 days were included in this study.ResultsA median of 6 longitudinally collected CSF samples per patient were available within 1–22 days after SAH onset. Overall, red blood cells (RBC) steadily decreased over time, whereas white blood cells (WBC) and total protein (TP) increased until days 6 and 13, respectively, and decreased thereafter. The estimated decay rates of RBC, WBC, and TP were 28, 22, and 6% per day. Distinct CSF patterns over time were linked to known complications after SAH. Patients with rebleeding showed increased RBC, TP, and phagocytosing cells compared to patients without re-bleeding. For ventriculitis, an elevated cell index with a higher proportion of granulocytes was characteristic. CSF of patients with delayed cerebral ischemia showed increased RBC and WBC compared to patients without DCI. Early CSF WBC and cell index were predictive for the occurrence of DCI and ventriculitis later during the disease course. The amount of daily CSF drainage via EVD had no impact on routine CSF parameters.ConclusionLongitudinal CSF characteristics are associated with SAH-related complications.

Ventricular volume in relation to lumbar CSF levels of amyloid-β 1–42, tau and phosphorylated tau in iNPH, is there a dilution effect?

BackgroundLevels of the biomarkers amyloid-β 1–42 (Aβ42), tau and phosphorylated tau (p-tau) are decreased in the cerebrospinal fluid (CSF) of patients with idiopathic normal pressure hydrocephalus (iNPH). The mechanism behind this is unknown, but one potential explanation is dilution by excessive CSF volumes. The aim of this study was to investigate the presence of a dilution effect, by studying the relationship between ventricular volume (VV) and the levels of the CSF biomarkers.MethodsIn this cross-sectional observational study, preoperative magnetic resonance imaging (MRI) and lumbar CSF was acquired from 136 patients with a median age of 76 years, 89 men and 47 females, selected for surgical treatment for iNPH. The CSF volume of the lateral and third ventricles was segmented on MRI and related to preoperative concentrations of Aβ42, tau and p-tau.ResultsIn the total sample VV (Median 140.7 mL) correlated weakly (rs = − 0.17) with Aβ42 (Median 534 pg/mL), but not with tau (Median 216 pg/mL) nor p-tau (Median 31 pg/mL). In a subgroup analysis, the correlation between VV and Aβ42 was only present in the male group (rs = − 0.22, p = 0.038). Further, Aβ42 correlated positively with tau (rs = 0.30, p = 0.004) and p-tau (rs = 0.26, p = 0.012) in males but not in females.ConclusionsThe findings did not support a major dilution effect in iNPH, at least not in females. The only result in favor for dilution was a weak negative correlation between VV and Aβ42 but not with the other lumbar CSF biomarkers. The different results between males and females suggest that future investigations of the CSF pattern in iNPH would gain from sex-based subgroup analysis.

Patterns of Cerebrospinal Fluid Alzheimer's Dementia Biomarkers in People Living with HIV: Cross-Sectional Study on Associated Factors According to Viral Control, Neurological Confounders and Neurocognition.

People living with HIV (PLWH) age with an excess burden of comorbidities that may increase the incidence of age-related complications. There is controversy surrounding the hypothesis that HIV can accelerate neurodegeneration and Alzheimer’s dementia (AD). We performed a retrospective study to analyze the distribution of cerebrospinal fluid (CSF) AD biomarkers (beta amyloid 1–42 fragment, tau, and phosphorylated tau) in adult PLWH (on cART with undetectable viremia, n = 136, with detectable viremia, n = 121, and with central nervous system CNS disorders regardless of viremia, n = 72) who underwent a lumbar puncture between 2008 to 2018; HIV-negative controls with AD were included (n = 84). Five subjects (1.5%) presented CSF biomarkers that were compatible with AD: one was diagnosed with AD, whereas the others showed HIV encephalitis, multiple sclerosis, cryptococcal meningitis, and neurotoxoplasmosis. Regardless of confounders, 79.6% of study participants presented normal CSF AD biomarkers. Isolated abnormalities in CSF beta amyloid 1–42 (7.9%) and tau (10.9%) were associated with age, biomarkers of intrathecal injury, and inflammation, although no HIV-specific feature was associated with abnormal CSF patterns. CSF levels of AD biomarkers very poorly overlapped between HIV-positive clinical categories and AD controls. Despite the correlations with neurocognitive performance, the inter-relationship between amyloid and tau proteins in PLWH seem to differ from that observed in AD subjects; the main driver of the isolated increase in tau seems represented by non-specific CNS inflammation, whereas the mechanisms underlying isolated amyloid consumption remain unclear.

Cerebrospinal fluid proteome maps detect pathogen-specific host response patterns in meningitis.

Meningitis is a potentially life-threatening infection characterized by the inflammation of the leptomeningeal membranes. Many different viral and bacterial pathogens can cause meningitis, with differences in mortality rates, risk of developing neurological sequelae, and treatment options. Here, we constructed a compendium of digital cerebrospinal fluid (CSF) proteome maps to define pathogen-specific host response patterns in meningitis. The results revealed a drastic and pathogen-type specific influx of tissue-, cell-, and plasma proteins in the CSF, where, in particular, a large increase of neutrophil-derived proteins in the CSF correlated with acute bacterial meningitis. Additionally, both acute bacterial and viral meningitis result in marked reduction of brain-enriched proteins. Generation of a multiprotein LASSO regression model resulted in an 18-protein panel of cell- and tissue-associated proteins capable of classifying acute bacterial meningitis and viral meningitis. The same protein panel also enabled classification of tick-borne encephalitis, a subgroup of viral meningitis, with high sensitivity and specificity. The work provides insights into pathogen-specific host response patterns in CSF from different disease etiologies to support future classification of pathogen type based on host response patterns in meningitis.

Cerebrospinal fluid analysis in dogs: Main patterns and prevalence of albuminocytological dissociation.

Albuminocytological dissociation (ACD) of the cerebrospinal fluid (CSF) is defined as an increased total protein concentration with normal total nucleated cell count. It is suspected to occur in diseases that alter the blood-brain barrier, increase the production of protein or obstruct the flow of CSF. The purposes of this study were to review the CSF analysis results of a large cohort of dogs with neurological conditions, to analyse the total prevalence of ACD and to describe which diseases have a higher prevalence of ACD. Medical records were retrospectively searched for dogs whom CSF was sampled from 2012-2019. Data collected included signalment, body weight, site of collection of the CSF, CSF analysis results, and final diagnosis. A total of 497 dogs met the inclusion criteria. ACD was identified in 16.5% (82/497) of dogs. The diseases with higher proportion of ACD were cranial nerve neuropathy (6/10; 60.0%), brain tumour (10/24; 41.7%), idiopathic vestibular disease (7/17; 41.2%) and brain vascular disease (4/13; 30.8%). This study describes the CSF patterns of the most common neurological conditions in dogs, also characterizing, for the first time in dogs, the prevalence and causes of ACD, which was identified in 16.5% of the samples. The diseases with highest proportions of ACD were cranial nerve neuropathy, brain tumour, idiopathic vestibular disease and brain vascular disease.

Pulsatile cerebrospinal fluid dynamics in Chiari I malformation syringomyelia: Predictive value in posterior fossa decompression and insights into the syringogenesis.

Background:Pathophysiological mechanisms underlying the syringomyelia associated with Chiari I malformation (CM-1) are still not completely understood, and reliable predictors of the outcome of posterior fossa decompression (PFD) are lacking accordingly. The reported prospective case-series study aimed to prove the existence of a pulsatile, biphasic systolic–diastolic cerebrospinal fluid (CSF) dynamics inside the syrinx associated with CM-1 and to assess its predictive value of patients' outcome after PFD. Insights into the syringogenesis are also reported.Methods:Fourteen patients with symptomatic CM-1 syringomyelia underwent to a preoperative neuroimaging study protocol involving conventional T1/T2 and cardiac-gated cine phase-contrast magnetic resonance imaging sequences. Peak systolic and diastolic velocities were acquired at four regions of interest (ROIs): syrinx, ventral, and dorsal cervical subarachnoid space and foramen magnum region. Data were reported as mean ± standard deviation. After PFD, the patients underwent a scheduled follow-up lasting 3 years. One-way analysis of variance with Bonferroni Post hoc test of multiple comparisons was performed P was <0.001.Results:All symptoms but atrophy and spasticity improved. PFD caused a significant velocity changing of each ROI. Syrinx and premedullary cistern velocities were found to be decreased within the 1st month after PFD (<0.001). A caudad and cephalad CSF jet flow was found inside the syrinx during systole and diastole, respectively.Conclusion:Syrinx and premedullary cistern velocities are related to an early improvement of symptoms in patients with CM-1 syringomyelia who underwent PFD. The existence of a biphasic pulsatile systolic–diastolic CSF pattern inside the syrinx validates the “transmedullary” theory about the syringogenesis.

Non-invasive epigenomic molecular phenotyping of the human brain via liquid biopsy of cerebrospinal fluid and next generation sequencing.

Our goal was to undertake a genome-wide epigenomic liquid biopsy of cerebrospinal fluid (CSF) for the comprehensive analysis of cell-free DNA (cfDNA) methylation signatures in the human central nervous system (CNS). Solution-phase hybridization and massively parallel sequencing of bisulfite converted human DNA was employed to compare methylation signatures of cfDNA obtained from CSF with plasma. Recovery of cfDNA from CSF was relatively low (68-840pg/mL) compared to plasma (2720-8390pg/mL) and cfDNA fragments from CSF were approximately 20bp shorter than their plasma-derived counterparts. Distributions of CpG methylation signatures were significantly altered between CSF and plasma, both globally and at the level of functional elements including exons, introns, CpG islands, and shores. Sliding window analysis was used to identify differentially methylated regions.We found numerous gene/locus-specific differences in CpG methylation between cfDNA from CSF and plasma. These loci were more frequently hypomethylated in CSF compared to plasma. Differentially methylated CpGs in CSF were identified in genes related to branching of neurites and neuronal development.Using the GTEx RNA expression database, we found clear association between tissue-specific gene expression in the CNS and cfDNA methylation patterns in CSF. Ingenuity pathway analysis of differentially methylated regions identified an enrichment of functional pathways related to neurobiology. In conclusion, we present a genome-wide analysis of DNA methylation in human CSF. Our methods and the resulting data demonstrate the potential of epigenomic liquid biopsy of the human CNS for molecular phenotyping of brain-derived DNA methylation signatures.

Simple and Fast Assay for Apolipoprotein E Phenotyping and Glycotyping: Discovering Isoform-Specific Glycosylation in Plasma and Cerebrospinal Fluid.

Background:The mechanisms of how APOE ɛ4 allele (APOE4) increases the risk of Alzheimer’s disease (AD) pathology have not been fully elucidated. In cerebrospinal fluid (CSF), apoE is heavily glycosylated.Objective:To determine the impact of APOE genotype on the relative abundance of apoE protein isoforms and their specific glycosylation patterns in CSF and plasma via a newly developed mass spectrometric immunoassay (MSIA) assay.Methods:Total glycosylation and isoform-specific glycosylation were analyzed in plasma and CSF from a group of non-demented older individuals (n = 22), consisting of homozygous ɛ3 and ɛ4 or heterozygous ɛ3/ɛ4, ɛ2/ɛ3, or ɛ2/ɛ4 carriers. The glycan structures were further confirmed after treatment with sialidase.Results:In heterozygous individuals, the apoE3/E2, E4/E2, and E4/E3 isoform ratios were all significantly lower in plasma compared to CSF. For all individuals, a single O-linked glycan was observed in plasma, while two glycans (of the same type) per apoE were observed in CSF. The ratio of glycosylated to total apoE was greater in CSF compared to plasma for all apoE isoforms. In plasma and CSF, a trend of decreasing glycosylation was observed from apoE2 > apoE3 > apoE4. The difference in the percentage of secondary glycosylation in CSF was significantly greater in apoE4 compared to the other isoforms.Conclusion:The new MSIA apoE assay robustly distinguishes among apoE isoforms and glycoforms in plasma and CSF. ApoE4 is the predominant isoform and least glycosylated in CSF. Assessing apoE isoform-specific glycosylation by MSIA may help clarify brain apoE metabolism and AD risk.

Innate Immune Responses in Serum and Cerebrospinal Fluid From Neonates and Infants Infected With Parechovirus-A3 or Enteroviruses.

Parechovirus (PeV)-A3 and enteroviruses (EV) are the most common viruses causing sepsis and meningoencephalitis in neonates and young infants. Clinical manifestations of PeV-A3 infection are more severe than those of EV infection, and no pleocytosis with a positive polymerase chain reaction (PCR) result for PeV-A3 in cerebrospinal fluid (CSF) are characteristic findings. We hypothesized that innate immune responses to PeV-A3 and EV are distinct in serum and CSF. We evaluated 22 cytokines/chemokines in serum and CSF from PeV-A3- or EV-infected patients younger than 4 months in Niigata, Japan, from 2015 through 2018. Infection was diagnosed with real-time PCR followed by sequencing. Febrile neonates and infants with sepsis-like syndrome who had negative bacterial culture and viral PCR for both PeV-A and EV were also included (non-PeV-A/EV patients). Among 192 febrile patients, we evaluated 16 PeV-A3-infected, 15 EV-infected, and 8 non-PeV-A/EV patients. Serum pro-/anti-inflammatory cytokine/chemokine levels were higher in PeV-A3-infected patients than in EV-infected patients (P < .02). Although most cytokine/chemokine were elevated in CSF from EV-infected patients, levels were low or undetectable in PeV-A3-infected and non-PeV-A/EV patients (P < .001). Distinct cytokine/chemokine patterns in serum and CSF may explain the different clinical manifestations of PeV-A3-infected and EV-infected neonates and young infants.

Elemental fingerprint: Reassessment of a cerebrospinal fluid biomarker for Parkinson's disease

The aim of the study was to validate a predictive biomarker machine learning model for the classification of Parkinson's disease (PD) and age-matched controls (AMC), based on bioelement abundance in the cerebrospinal fluid (CSF). For this multicentric trial, participants were enrolled from four different centers. CSF was collected according to standardized protocols. For bioelement determination, CSF samples were subjected to inductively coupled plasma mass spectrometry. A predefined Support Vector Machine (SVM) model, trained on a previous discovery cohort was applied for differentiation, based on the levels of six different bioelements. 82 PD patients, 68 age-matched controls and 7 additional Normal Pressure Hydrocephalus (NPH) patients were included to validate a predefined SVM model. Six differentiating elements (As, Fe, Mg, Ni, Se, Sr) were quantified. Based on their levels, SVM was successfully applied to a new local cohort (AUROC 0.76, Sensitivity 0.80, Specificity 0.83), without taking any additional features into account. The same model did not discriminate PD and AMCs / NPH from three external cohorts, likely due to center effects. However, discrimination was possible in cohorts with a full elemental data set, now using center-specific discovery cohorts and a cross validated approach (AUROC 0.78 and 0.88, respectively). Pooled PD CSF iron levels showed a clear correlation with disease duration (p = .0001). In summary, bioelemental CSF patterns, obtained by mass spectrometry and integrated into a predictive model yield the potential to facilitate the differentiation of PD and AMC. Center-specific biases interfere with application in external cohorts. This must be carefully addressed using center-defined, local reference values and models.

Linked CSF reduction of phosphorylated tau and IL-8 in HIV associated neurocognitive disorder

HIV-associated neurocognitive disorder (HAND) is a common condition in both developed and developing nations, but its cause is largely unknown. Previous research has inconsistently linked Alzheimer’s disease (AD), viral burden, and inflammation to the onset of HAND in HIV-infected individuals. Here we simultaneously measured cerebrospinal fluid (CSF) levels of established amyloid and tau biomarkers for AD, viral copy numbers, and six key cytokines in 41 HIV-infected individuals off combination anti-retroviral therapy (14 with HAND) who underwent detailed clinical and neuropsychological characterization, and compared their CSF patterns with those from young healthy subjects, older healthy subjects with normal cognition, and older people with AD. HAND was associated with the lowest CSF levels of phosphorylated tau (p-Tau181) after accounting for age and race. We also found very high CSF levels of the pro-inflammatory interferon gamma-induced protein 10 (IP-10/CXCL10) in HIV regardless of cognition, but elevated CSF interleukin 8 (IL-8/CXCL8) only in HIV-NC but not HAND. Eleven HIV-infected subjects underwent repeat CSF collection six months later and showed strongly correlated longitudinal changes in p-Tau181 and IL-8 levels (R = 0.841). These data suggest reduced IL-8 relative to IP-10 and reduced p-Tau181 to characterize HAND.

Validation of the Erlangen Score Algorithm for the Prediction of the Development of Dementia due to Alzheimer's Disease in Pre-Dementia Subjects.

In previous studies, a dichotomous stratification of subjects into "cerebrospinal fluid (CSF) normal" and "CSF pathologic" was used to investigate the role of biomarkers in the prediction of progression to dementia in pre-dementia/mild cognitive impairment subjects. With the previously published Erlangen Score Algorithm, we suggested a division of CSF patterns into five groups, covering all possible CSF result combinations based on the presence of pathologic tau and/or amyloid-β CSF values. This study aimed to validate the Erlangen Score diagnostic algorithm based on the results of biomarkers analyses obtained in different patients cohorts, with different pre-analytical protocols, and with different laboratory analytical platforms. We evaluated the algorithm in two cohorts of pre-dementia subjects: the US-Alzheimer's Disease Neuroimaging Initiative and the German Dementia Competence Network. In both cohorts, the Erlangen scores were strongly associated with progression to Alzheimer's disease. Neither the scores of the progressors nor the scores of the non-progressors differed significantly between the two projects, in spite of significant differences in the cohorts, laboratory methods, and the samples treatment. Our findings confirm the utility of the Erlangen Score algorithm as a useful tool in the early neurochemical diagnosis of Alzheimer's disease.

Peculiar Cytological Cerebrospinal Fluid Pattern in a Case of Encephalomyelitis During Anti-Tumor Necrosis Factor-α Therapy.

IntroductionTumor necrosis factor-α (TNF-α) blocking agents may be associated with neurological adverse events, including demyelinating syndromes, that can be difficult to differentiate from multiple sclerosis (MS) and clinically isolated syndrome (CIS) as neither the clinical nor laboratory distinctive features have been reported. Usually clinicians mainly examine the diagnostic value of immunoglobulin G oligoclonal bands underestimating the value of other cerebrospinal fluid (CSF) parameters (such as CSF cytology).Case ReportWe present a case of a patient who acutely developed mild pyramidal and sensory impairment of lower limbs and urinary hesitancy during treatment with adalimumab, a monoclonal antibody to TNF-α, for psoriatic arthritis. Magnetic resonance imaging demonstrated a widespread area of hyperintense signal extending from C5 to D8 level in T2-weighted images. Two consecutive CSF examinations showed an intense activation of monocyte/macrophage lineage (88% and 90%, respectively) with some giant and binucleated cells that notably decreased five months after TNF-α blocker cessation. We compared the results of CSF examinations of our patient with CSF results of 20 patients with MS and 20 patients with CIS that demonstrated activation of both lymphocytic and monocytic lineage (MS: 48% and 52%, respectively, CIS: 54.5% and 43.5%, respectively) that were very different from the findings in adalimumab-related encephalomyelitis in acute phase (11% and 89%, respectively). CSF cytology in two patients with neuromyelitis optica during the relapse (n = 3) showed minor monocyte/macrophage activation (9%) and an increased number of granulocytes (77%).ConclusionProminent activation of monocyte/macrophage lineage with some binucleated giant cells in CSF could be induced by anti-TNF-α treatment. The peculiar CSF pattern, never found in MS, CIS, and NMO, can help in differential diagnosis and stresses the importance of careful CSF cytology evaluation in the course of demyelinating diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s40120-015-0027-z) contains supplementary material, which is available to authorized users.

Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease.

Alterations in cerebrospinal fluid (CSF) have been found in Parkinson disease (PD) and in PD dementia (PDD), but the prognostic importance of such changes is not well known. In vivo biomarkers for disease processes in PD are important for future development of disease-modifying therapies. To assess the diagnostic and prognostic value of a panel of CSF biomarkers in patients with early PD and related disorders. Regional population-based, prospective cohort study of idiopathic parkinsonism that included patients diagnosed between January 1, 2004, and April 30, 2009, by a movement disorder team at a university hospital that represented the only neurology clinic in the region. Participants were 128 nondemented patients with new-onset parkinsonism (104 with PD, 11 with multiple system atrophy, and 13 with progressive supranuclear palsy) who were followed up for 5 to 9 years. At baseline, CSF from 30 healthy control participants was obtained for comparison. Cerebrospinal fluid concentrations of neurofilament light chain protein, Aβ1-42, total tau, phosphorylated tau, α-synuclein, and heart fatty acid-binding protein were quantified by 2 blinded measurements (at baseline and after 1 year). Follow-up included an extensive neuropsychological assessment. As PD outcome variables, mild cognitive impairment and incident PDD were diagnosed based on published criteria. Among the 128 study participants, the 104 patients with early PD had a different CSF pattern compared with the 13 patients with progressive supranuclear palsy (baseline area under the receiver operating characteristic curve, 0.87; P < .0001) and the 30 control participants (baseline area under the receiver operating characteristic curve, 0.69; P = .0021). A CSF biomarker pattern associated with the development of PDD was observed. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PDD as analyzed by Cox proportional hazards regression models. Combined, these early biomarkers predicted PDD with high accuracy (hazard ratio, 11.8; 95% CI, 3.3-42.1; P = .0001) after adjusting for possible confounders. The analyzed CSF biomarkers have potential usefulness as a diagnostic tool in patients with parkinsonism. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein were related to future PDD, providing new insights into the etiology of PDD.

The use of electrical stimulation to guide epidural and intrathecal needle advancement at the L5-L6 intervertebral space in dogs

ObjectiveTo determine the minimal electrical threshold (MET) necessary to elicit appropriate muscle contraction when the tip of an insulated needle is positioned epidurally or intrathecally at the L5-6 intervertebral space (phase-I) and to determine whether the application of a fixed electrical current during its advancement could indicate needle entry into the intrathecal space (phase-II) in dogs. Study designProspective, blinded study. AnimalsThirteen (phase-I) and seventeen (phase-II) dogs, scheduled for a surgical procedure where L5-6 intrathecal administration was indicated. MethodsUnder general anesthesia, an insulated needle was first inserted into the L5-6 epidural space and secondly into the intrathecal space and the MET necessary to obtain a muscular contraction of the pelvic limb or tail at each site was determined (phase-I). Under similar conditions, in dogs of phase-II an insulated needle was inserted through the L5-6 intervertebral space guided by the use of a fixed electrical current (0.8 mA) until muscular contraction of the pelvic limb or tail was obtained. Intrathecal needle placement was confirmed by either free flow of cerebrospinal fluid (CSF) or myelography. ResultsThe current required to elicit a motor response was significantly lower (p < 0.0001) when the tip of the needle was in the intrathecal space (0.48 ± 0.10 mA) than when it was located epidurally (2.56 ± 0.57). The use of a fixed electrical stimulation current of 0.8 mA resulted in correct prediction of intrathecal injection, corroborated by either free flow of CSF (n = 12) or iohexol distribution pattern (n = 5), in 100% of the cases. Conclusion and clinical relevanceNerve stimulation may be employed as a tool to distinguish epidural from intrathecal insulated needle position at the L5-6 intervertebral space in dogs. This study demonstrates the feasibility of using an electrical stimulation test to confirm intrathecal needle position in dogs.

CSF and clinical hallmarks of subcortical dementias: focus on DLB and PDD

Dementia has become a relevant problem associated with the elderly in our countries. Increased interest in the field has yielded a copious literature, so far mostly centered on Alzheimer's dementia. Cerebrospinal fluid (CSF) analysis combined with neuropsychology, even in absence of neuroimaging, represents the gold standard to reach a diagnosis when cortical cognitive impairment prevails. In view of this, low levels of CSF amyloid peptides β (Aβ) and high tau/Aβ protein ratio, despite prominent impairment of executive functions or concomitant vascular burden, facilitate the diagnosis of Alzheimer's disease. Conversely, an early cognitive impairment occurring in patients suffering from Parkinson's disease (PD) or Lewy body disorders (LBDs), both diagnoses posed on pure clinical grounds, remains quite elusive in term of biomarkers or neuropsychological assessment. Whether PD with dementia (PDD) and dementia with Lewy bodies (DLB) represent further steps along with a continuum of the same progressive degeneration due to Lewy bodies deposition, rather then the association of Lewy bodies and Aβ pathology, remains a challenging issue. Aim of this work is to set a state-of-the-art on the neuropsychological profiles of both or DLB. Then, we will focus on the ongoing controversies about the specificity of the standard CSF biomarkers if applied to extrapyramidal disorders. Our conclusions are that the CSF pattern, in PDD and DLB, can certainly be distinct from that in AD, though mechanisms leading to dementia could be shared among them. It is possible that, by combining imaging tracers, neuropsychologically careful assessment and renewed CSF biomarkers, DLB can be better distinguished in subgroups, depending on the presence or absence of a relevant amyloid burden. However, more complete data, possibly collected in fieri during the progressive derangement of cognitive abilities, are needed to improve our ability to decipher and treat these entities.