CSF Levels Research Articles

Associations of dietary patterns and CSF biomarkers for Alzheimer’s disease in a population‐based sample of 70‐year‐olds

AbstractBackgroundDiet could be a modifiable factor in the prevention of Alzheimer’s disease (AD). Western‐style dietary patterns are considered to increase the risk, while Mediterranean‐style dietary patterns are considered protective. The aim of this study was to investigate the relation between dietary patterns and CSF biomarkers of relevance for AD.MethodData was derived from the population based Gothenburg H70 Birth Cohort Studies, Sweden (n=1203). CSF levels of β‐amyloid (Aβ)42, total tau, and phosphorylated tau were measured with ELISA. Dietary intake was determined by the diet history method (n=861). Principal component analysis were performed to reduce 21 food groups into factors representing dietary patterns. Logistic regression analyses, with CSF biomarkers as dependent variables (pathological, yes/no), and linear regression analyses with CSF biomarkers as continuous variables, were performed on the dementia‐free participants with both CSF and dietary data (n=269, 49% women). Analyses were adjusted for APOE ε4 status, energy intake, education, BMI and physical activity and sex. Analyses were also performed stratified by sex.ResultFour dietary patterns were derived from the principal component analysis. A western‐style dietary pattern, a Mediterranean‐style dietary pattern, a mixed dietary pattern with alcoholic beverages and a dietary pattern of high fat dairy products, eggs and refined cereal products. The odds ratio of having pathological values of total tau was higher among those with a higher compliance to a western‐style dietary pattern (OR 1.37; 95%CI 1.02‐1.85). The linear regression model indicate the same trend (r2=0.06, B=0.04, p=0.08). When stratified by sex, the odds ratio of having pathological values of phosphorylated tau was higher for men with a higher intake of high fat dairy products, eggs and refined cereal products (OR 3.38; 95%CI 1.22‐9.36). There were no associations between the other dietary patterns and CSF biomarkers.ConclusionOur results indicate an association between western‐style dietary patterns and increased levels of total tau and phosphorylated tau. There was no relation between a healthier Mediterranean‐style dietary pattern and CSF biomarkers for AD, however.

Association between polygenic risk score of Alzheimer’s disease and CSF amyloid beta 42 in a cohort of 70‐year‐olds from the general population

AbstractBackgroundRecently, it was reported that as much as 45% of cognitively normal 70‐year olds from the general population had pathological CSF levels of either amyloid beta or tau, and the APOE e4 allele was significantly more common among these individuals. However, very few studies have investigated the effect of non‐APOE polygenic risk score (PRS) for Alzheimer’s disease (AD) on CSF biomarkers in representative population‐based samples. The aim of the present study was thus to investigate the relation between AD‐PRS and CSF biomarkers for AD and neurodegeneration in a representative sample of 70‐year‐olds.MethodA total of 303 individuals belonging to the Gothenburg H70 Birth Cohort Studies were included in the study. Genotyping was performed using the NeuroChip (Illumina) and imputation was done with the Sanger imputation service using the reference panel of Haplotype Reference Consortium data (HRC1.1). A PRS was calculated based on the allele counts of 23 AD risk‐variants multiplied with effect sizes (β‐coefficients) from IGAP. CSF levels of amyloid beta 42, total‐tau, phosphorylated tau, neurogranin and neurofilament light were measured with ELISA. Linear regression models, adjusted for sex and APOE e4 status, were used to analyze the association between AD‐PRS and CSF biomarkers.ResultAn association was found between the AD‐PRS and amyloid beta 42 (p = 0.003), showing a decreasing level of the biomarker with an increasing level of the PRS. No associations were found between the AD‐PRS and any of the other biomarkers. When only including cognitively healthy individuals (CDR = 0; n = 247), the association with amyloid beta 42 was still significant (p = 0.03). There was an interaction between the AD‐PRS and APOE e4 status (p = 0.04); the association between the PRS and amyloid beta 42 was present in e4 carriers only.ConclusionOur results show that genetic risk for AD beyond the APOE locus is associated with CSF‐amyloid beta 42, but not with any of the other investigated CSF‐biomarkers, among cognitively healthy 70‐year‐olds recruited from the general population. This finding is in line with the amyloid cascade hypothesis, showing that changed levels of CSF amyloid beta 42 is one of the earliest biomarkers related to AD.

The cerebrospinal fluid fractalkine as a biomarker in mild cognitive impairment (MCI)

AbstractBackgroundMild cognitive impairment (MCI) is a neurological disorder that occurs in older adults and could be a very early phase of AD dementia. It is not only medical but also socioeconomic and legal problem. Since the MCI symptoms are not yet associated with such serious memory problems as in dementia, it may be difficult to assess the patient's legal capacity. This is an extremely important issue, among others, from the point of view of the patient's decision about his/her treatment process. His ability to fully understand his health situation and the ability to make rational decisions, including being aware of its effects, can be difficult to assess, which has significant legal effects. Therefore, the biomarkers of early stage of dementia are critically important. Growing body of evidence indicated that overexpression of CX3CL‐1 may influence on tau pathology and modulate the dementia disorders development. In our investigation we aim to measure the cerebrospinal fluid concentration of fractalkine to assess the potential usefulness of this protein in the diagnosis of MCI patients. Moreover, the CSF CX3CL‐1 level was compared to the concentrations of classical AD biomarkers, including Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181.MethodThe study included 18 patients with MCI and 18 non‐demented controls. The cerebrospinal fluid levels of CX3CL‐1 and classical AD biomarkers, such as Aβ‐42, Aβ‐42/Aβ‐40, tau and pTau181, were assessed by immunoenzyme assays.ResultThe concentration of fractalkine was significantly higher in cerebrospinal fluid of MCI patients when compared to non‐demented controls. The increased CSF levels of CX3CL‐1 were observed to significantly correlate with amyloid beta 1‐42 (Aβ‐42) and phosphorylated tau protein (pTau181) in mild cognitive impairment MCI subjects. Moreover, similar association between CX3CL‐1 concentrations and Aβ‐42/Aβ‐40 ratio was revealed in the control group.ConclusionPresented findings indicate a potential role of CX3CL‐1 in the pathology of MCI and possible usefulness of this protein in the early diagnosis of patients with cognitive impairment. The study was conducted with the use of equipment purchased by Medical University of Białystok as part of the RPOWP 2007‐2013 funding, Priority I, Axis 1.1, contract No. UDA‐RPPD.01.01.00‐20‐001/15‐00 dated 26.06.2015.

Sex differences of innate immune activation in amyloid positive predementia cases

AbstractBackgroundInnate immunity is linked to Alzheimer’s disease, as shown by genome‐wide association studies and experimental data. There is, however, a sexual dimorphism in the activation of the innate immune system. Here, we investigate sex‐differences in immune activation by comparing glial activation markers in CSF from males and females with amyloid pathology as compared to healthy controls.MethodA total of 110 CSF Aβ‐ healthy controls (n=52 males and n=58 females), and 121 CSF Aβ+ (n=70 males and n=51 females) non‐demented cases with cognitive symptoms from the Dementia Disease Initiation (DDI) cohort were included in the analyses. CSF levels of sTREM2, YKL‐40 and MCP‐1 were determined using Mesoscale Discovery. Amyloid pathology was determined using CSF Aβ1‐42 threshold of 708 pg/mL. CSF total tau was included in our models to investigate potential sex differences of active neurodegeneration. We compared CSF concentrations using three‐way ANCOVA with age as a covariate, investigating main effects, two‐way interaction effects between sex and CSF Aβ status and three‐way APOE‐ε4 interactions with sex and CSF Aβ.ResultSignificant interaction effects between sex and CSF Aβ status showed lower CSF YKL‐40 (p<.001), sTREM2 (p<.05) and MCP‐1 (p<.0001) levels in Aβ+ women as compared to males. No differences in levels were found between male and female healthy controls. Furthermore, we found that only Aβ+ males had increased YKL‐40 (p<.001), sTREM2 (p<.05) and MCP‐1 (p<.05) levels compared to healthy controls, whilst Aβ+ females showed no significant differences in levels. Men had slightly higher levels of CSF total tau as compared to women, however, this difference did not reach the threshold for statistical significance (p=.07). No main effects or interaction effects with APOE‐ε4 were found.ConclusionWe found consistent differences in innate immune activation in Aβ+ females, but not related to APOE‐ε4 genotype. However, a slight non‐significant increase in a CSF marker of neurodegeneration in men may in part contribute to the observed differences in immune activation in our sample. The low level of innate immune activation has yet to be linked to differences in disease progression.

Time course of phosphorylated-tau181 in blood across the Alzheimer's disease spectrum.

Tau phosphorylated at threonine 181 (p-tau181) measured in blood plasma has recently been proposed as an accessible, scalable, and highly specific biomarker for Alzheimer's disease. Longitudinal studies, however, investigating the temporal dynamics of this novel biomarker are lacking. It is therefore unclear when in the disease process plasma p-tau181 increases above physiological levels and how it relates to the spatiotemporal progression of Alzheimer's disease characteristic pathologies. We aimed to establish the natural time course of plasma p-tau181 across the sporadic Alzheimer's disease spectrum in comparison to those of established imaging and fluid-derived biomarkers of Alzheimer's disease. We examined longitudinal data from a large prospective cohort of elderly individuals enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 1067) covering a wide clinical spectrum from normal cognition to dementia, and with measures of plasma p-tau181 and an 18F-florbetapir amyloid-β PET scan at baseline. A subset of participants (n = 864) also had measures of amyloid-β1-42 and p-tau181 levels in CSF, and another subset (n = 298) had undergone an 18F-flortaucipir tau PET scan 6 years later. We performed brain-wide analyses to investigate the associations of plasma p-tau181 baseline levels and longitudinal change with progression of regional amyloid-β pathology and tau burden 6 years later, and estimated the time course of changes in plasma p-tau181 and other Alzheimer's disease biomarkers using a previously developed method for the construction of long-term biomarker temporal trajectories using shorter-term longitudinal data. Smoothing splines demonstrated that earliest plasma p-tau181 changes occurred even before amyloid-β markers reached abnormal levels, with greater rates of change correlating with increased amyloid-β pathology. Voxel-wise PET analyses yielded relatively weak, yet significant, associations of plasma p-tau181 with amyloid-β pathology in early accumulating brain regions in cognitively healthy individuals, while the strongest associations with amyloid-β were observed in late accumulating regions in patients with mild cognitive impairment. Cross-sectional and particularly longitudinal measures of plasma p-tau181 were associated with widespread cortical tau aggregation 6 years later, covering temporoparietal regions typical for neurofibrillary tangle distribution in Alzheimer's disease. Finally, we estimated that plasma p-tau181 reaches abnormal levels ∼6.5 and 5.7 years after CSF and PET measures of amyloid-β, respectively, following similar dynamics as CSF p-tau181. Our findings suggest that plasma p-tau181 increases are associated with the presence of widespread cortical amyloid-β pathology and with prospective Alzheimer's disease typical tau aggregation, providing clear implications for the use of this novel blood biomarker as a diagnostic and screening tool for Alzheimer's disease.

BACE inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain.

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.

Biomarkers and phenotypic expression in Alzheimer\u2019s disease: exploring the contribution of frailty in the Alzheimer\u2019s Disease Neuroimaging Initiative

The present study aimed at investigating if the main biomarkers of Alzheimer’s disease (AD) neuropathology and their association with cognitive disturbances and dementia are modified by the individual’s frailty status. We performed a cross-sectional analysis of data from participants with normal cognition, mild cognitive impairment (MCI), and AD dementia enrolled in the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI2) study. Frailty was operationalized by computing a 40-item Frailty Index (FI). The following AD biomarkers were considered and analyzed according to the participants’ frailty status: CSF Aβ1-42, 181P-tau, and T-tau; MRI-based hippocampus volume; cortical glucose metabolism at the FDG PET imaging; amyloid deposition at the 18F-AV-45 PET imaging. Logistic regression models, adjusted for age, sex, and education, were performed to explore the association of biomarkers with cognitive status at different FI levels. Subjects with higher FI scores had lower CSF levels of Aβ1-42, hippocampus volumes at the MRI, and glucose metabolism at the FDG PET imaging, and a higher amyloid deposition at the 18F-AV-45 PET. No significant differences were observed among the two frailty groups concerning ApoE genotype, CSF T-tau, and P-tau. Increasing frailty levels were associated with a weakened relationship between dementia and 18F-AV-45 uptake and hippocampus volume and with a stronger relationship of dementia with FDG PET. Frailty contributes to the discrepancies between AD pathology and clinical manifestations and influences the association of AD pathological modifications with cognitive changes. AD and dementia should increasingly be conceived as “complex diseases of aging,” determined by multiple, simultaneous, and interacting pathophysiological processes.

Chitinase 3-like 1 and neurofilament light chain in CSF and CNS atrophy in MS.

ObjectiveTo investigate cross-sectional associations of CSF levels of neurofilament light chain (NfL) and of the newly emerging marker chitinase 3–like protein 1 (CHI3L1) with brain and spinal cord atrophy, which are established MRI markers of disease activity in MS, to study CHI3L1 and NfL in relapsing (RMS) and progressive MS (PMS), and to assess the expression of CHI3L1 in different cell types.MethodsIn a single-center study, 131 patients with MS (42 RMS and 89 PMS) were assessed for NfL and CHI3L1 concentrations in CSF, MRI-based spinal cord and brain volumetry, MS subtype, age, disease duration, and disability. We included 42 matched healthy controls receiving MRI. CHI3L1 expression of human brain cell types was examined in 2 published single-cell RNA sequencing data sets.ResultsCHI3L1 was associated with spinal cord volume (B = −1.07, 95% CI −2.04 to −0.11, p = 0.029) but not with brain volumes. NfL was associated with brain gray matter (B = −7.3, 95% CI −12.0 to −2.7, p = 0.003) but not with spinal cord volume. CHI3L1 was suitable to differentiate between progressive or relapsing MS (p = 0.015, OR 1.0103, CI for OR 1.002–1.0187), and its gene expression was found in MS-associated microglia and macrophages and in astrocytes of MS brains.ConclusionsNfL and CHI3L1 in CSF were differentially related to brain and spinal cord atrophy. CSF CHI3L1 was associated with spinal cord volume loss and was less affected than NfL by disease duration and age, whereas CSF NfL was associated with brain gray matter atrophy. CSF NfL and CHI3L1 measurement provides complementary information regarding brain and spinal cord volumes.Classification of evidenceThis study provides Class II evidence that CSF CHI3L1 is associated with spinal cord volume loss and that CSF NfL is associated with gray matter atrophy.

Diagnosis-to-Treatment Interval Is an Important Prognostic Factor with a Time-Dependent Effect Predicting Event-Free Survival after 12 Months from First-Line Treatment in Newly Diagnosed Diffuse Large B-Cell Primary CNS Lymphoma

Diagnosis-to-Treatment Interval Is an Important Prognostic Factor with a Time-Dependent Effect Predicting Event-Free Survival after 12 Months from First-Line Treatment in Newly Diagnosed Diffuse Large B-Cell Primary CNS Lymphoma

Final Report of Reduced Anthracycline Dose Intensity with the Addition of Dose Dense Rituximab in Children, Adolescents and Young Adults with De Novo Good Risk Mature B-Cell Non Hodgkin Lymphoma (B-NHL)

Background: Previous studies have demonstrated excellent results with FAB/LMB86 chemotherapy alone and in combination with rituximab in children, adolescents and young adults with mature B-NHL. (Cairo et al, JCO 2012, Goldman et al, Leukemia, 2013, Goldman et al, BJH 2014) The intermediate risk FAB/LMB Group B arm consists of 180mg/m2 of doxorubicin. This was reduced to 120mg/m2 with the addition of dose-dense rituximab. Other standard NHL regimens more commonly used in young adults with advanced stage mature B-NHL, such as R-CHOP, have a total dose doxorubicin of 360mg/m2. These approaches are associated with short term morbidities and long-term health conditions, including anthracycline induced cardiac toxicities.Dose-dense rituximab containing chemoimmunotherapy in high risk mature B-NHL has shown significant improvements in outcomes. We tested the hypothesis that rituximab can be used to even further reduce the burden of anthracycline from 120mg/m2 to 50mg/m2 in patients with good risk B-NHL. Objective: To safely reduce the burden of therapy by reducing the number of IT injections and reducing the total dose of doxorubicin from 120mg/m2 to 50mg/m2 with the addition of liposomal cytarabine and dose-dense rituximab to our prior chemotherapy backbone in children with good risk mature B-NHL. Design/Methods: Multi-institutional Phase II study (NCT01859819). Patients (3-31 years) with CD20+ B-NHL with good risk (FAB Group B GR=Stage I/II, Stage III with any LDH and Stage IV {BM tumor &amp;lt; 25%)}) were eligible. Staging was defined per the IPNHLSS as previously described. (Roselen et al, JCO 2015) All patients received FAB backbone chemotherapy with the addition of six rituximab (375mg/m2) doses; two doses prior to each of two induction courses and one dose prior to each of two consolidation courses. Cumulative doxorubicin was reduced from 120 to 50 mg/m2 (25mg/m2 per dose) total. After systemic methotrexate clearance, patients received age-based dosing of IT liposomal cytarabine resulting in a reduction of IT injections from nine to five. The primary outcome was safety and toxic deaths with an estimated 3-year survival above 90%, monitored by an independent DSMB. Response was defined per the IPNHLRC as previously described. (Sandlund et al, JCO 2015) Results: Twenty-five FAB Group B patients were enrolled at 5 treatment centers in the United States. Histology included DLBCL in 13 patients and Burkitt in 12 patients. Table 1. All patients had at least a 20% tumor decrease after the reduction phase. Two patients were upstaged to intensified Group C therapy after residual imaging findings post first consolidation. Therefore, 23/25 patients had a cumulative doxorubicin exposure of 50 mg/m2 while the two patients who received augmented treatment had a total exposure of 170 mg/m2. There were no serious adverse events reported with rituximab administration and no reported CNS or other toxicity reported with liposomal cytarabine intrathecal prophylaxis. During the two induction cycles there were no readmissions for febrile neutropenia or other causes and no reported grade III or higher mucositis. Follow up immune globulin levels on a smaller cohort of patients revealed median IgG levels of 821 (range, 362-1172) at a median follow up of 24 months. All patients are alive and in first remission with an EFS/OS = 100% at a median follow up of 4 years (range, 2-7yr). Figure 1. Echocardiograms revealed stable left ventricular function. Rituximab CSF levels were measured as we previously described and were extremely low (&amp;lt; 10µg/ml) compared to peak serum levels (250-400µg/ml). Conclusions: Our results demonstrate the feasibility of careful reduction of anthracycline dose intensity with the addition of dose-dense rituximab immunotherapy in children, adolescents and young adults with good risk mature B-NHL. Our results demonstrate a 100% EFS/OS with a reduction to only 50mg/m2 total dose of anthracycline. This is consistent with published standard of care outcomes utilizing much higher doses of 120-550mg/m2 of doxorubicin. Our treatment strategy benefits good risk patients with mature B-NHL by using dose-dense rituximab to reduce the cumulative exposure of anthracycline associated short- and long-term toxicities as well as the number of required intrathecal injections. These excellent results require the investigation of this approach in a larger cohort in the future to confirm these preliminary findings. Disclosures Goldman: Jazz Pharmaceuticals, Inc.: Speakers Bureau. Harker-Murray:Regerenon Pharmaceuticals: Consultancy. Cairo:Miltenyi: Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Dihydrotestosterone in Amyotrophic lateral sclerosis-The missing link?

ObjectiveTestosterone has been postulated to be involved in ALS causation.Materials and methodsCSF levels of free testosterone and dihydrotestosterone were measured in 13 ALS patients [7 males, 6 females] and 22 controls [12 males, 10 females].ResultsCSF free testosterone levels did not show any significant differences but CSF dihydrotestosterone levels were significantly decreased in all male and female ALS patients.ConclusionsDHT is probably integral to survival of motor neurons. In patients predisposed to develop ALS, there is possibly a sort of “testosterone resistance” at level of blood–brain barrier [BBB] existing right from birth and is likely the result of dysfunctional transport protein involved in testosterone transfer across the BBB. In these patients, lesser amount of testosterone is able to breach the BBB and enter the central neural axis. Lesser amount of testosterone is available to 5 α reductase in the anterior pituitary to be converted to DHT and lesser amount of DHT is generated. There is inadequate negative feedback suppression of LH at the level of anterior pituitary by DHT. As a result of higher LH levels, testosterone levels rise in the peripheral testosterone fraction [the fraction outside the BBB] and this explains the various physical attributes of ALS patients like lower Ratio of the index and ring finger lengths (2D:4D ratio), increased incidence of early onset alopecia etc. This deficiency of DHT leads to motor neuron death causing ALS.

Association of Enlarged Perivascular Spaces and Measures of Small Vessel and Alzheimer Disease

To investigate the relationship between enlarged perivascular spaces (EPVS) and measures of Alzheimer disease (AD), small vessel disease (SVD), cognition, vascular risk factors, and neuroinflammation, we tested associations between EPVS and different relevant neuroimaging, biochemical, and cognitive variables in 778 study participants. Four hundred ninety-nine cognitively unimpaired (CU) individuals, 240 patients with mild cognitive impairment, and 39 patients with AD from the Swedish Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably (BioFINDER) study were included. EPVS with diameter >1 mm in centrum semiovale (CSO), basal ganglia (BG), and hippocampus (HP); hippocampal volume; white matter lesions (WML); and other SVD markers were determined from MRI. CSF levels of β-amyloid42 (Aβ42), phosphorylated tau, total tau, and neuroinflammatory markers; amyloid accumulation determined with [18F]-flutemetamol PET; and vascular risk factors and results from cognitive tests were determined and collected. EPVS in CSO, BG, and HP were associated with WML volume and Fazekas score in individuals without dementia. No associations were found between EPVS and CSF Aβ42, total tau and phosphorylated tau, neuroinflammatory markers, vascular risk factors, and cognitive tests. EPVS in HP were associated with hippocampal atrophy. In a matched group of individuals with AD and CU, EPVS in HP were associated with AD diagnosis. EPVS are related to SVD, also in early disease stages, but the lack of correlation with cognition suggests that their importance is limited. Our data do not support a role for EPVS in early AD pathogenesis.

Prevalence of pyogenic meningitis in a Tertiary Care Hospital of Sindh.

Objectives: The current study aimed to find out the prevalence of pyogenic meningitis in the local population of Peoples University of Medical and Health Sciences Hospital Nawabshah. Study Design: Descriptive Cross Sectional study. Setting: Pediatric Ward of People University of Medical and Health Sciences Hospital, Nawabshah. Period: 1 year from November 2018 to October 2019. Material &amp; Methods: Using self-designed questionnaire. Patient’s samples were send for relevant investigations i.e. Blood culture and CSF examination and their results were recorded in proforma. Statistical Package for Social Science (SPSS) version 21 was used for data analysis. Results: Mean age of the children was 7 Years with a standard deviation of 2.4 years. 57% of the sample consist of boys while 43% were girls. Diagnosis of pyogenic meningitis was confirmed in 52.08% of the cases and fever was present in 100% cases and was the most common clinical presentation followed by headache (67%), Vomiting (44%) and fits (28%). Mean protein level was 235 mg/dl in the diagnosed cases. Mean sugar level in CSF of diseased children was 35 mg/dl with significant p-value of 0.0005. Conclusion: Pyogenic meningitis is highly prevalent that is 52.08% in current study. Its morbidity and mortality can be reduced by early recognition and prompt treatment.

Patterns of CSF Inflammatory Markers in Non-demented Older People: A Cluster Analysis.

ObjectiveIn this study, we aimed to examine if patterns of CSF inflammatory markers are correlated with global cognition, episodic memory, hippocampal volume, and CSF AD-related pathologies among non-demented older people.MethodsWe included 217 non-demented older individuals, including 87 subjects with normal cognition (NC) and 130 subjects with mild cognitive impairment (MCI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. Hierarchical cluster analysis including nine inflammatory markers in CSF [Tumor necrosis factor-α(TNF-α), TNF-R1, TNF-R2, transforming growth factor-β1 (TGF-β1), TGF-β2, TGF-β3, Interleukin-21 (IL-21), IL-6, and IL-7] was conducted.ResultsWe identified two clusters among non-demented older people based on nine inflammatory markers in CSF. Compared to the first cluster, the second cluster showed significantly higher levels of CSF inflammatory markers (TNF-R1, TNF-R2, TGF-β1, TGF-β3, and IL-6). Further, the second cluster was also associated with higher levels of t-tau and p-tau levels in CSF.ConclusionWe observed a subgroup of non-demented older people characterized by increased levels of inflammatory markers in CSF. Further, this subgroup showed higher levels of t-tau and p-tau levels in CSF.

O08 Neurosarcoidosis mimicking CNS lymphoma

Case report - IntroductionSarcoidosis is a multisystem disease which involves formation of inflammatory lesions known as granulomas. Central nervous system’s involvement is rare. Clinical neurologic complications occur in approximately 5% of patients.Diagnostic criteria for neurosarcoidosis in the absence of central nervous system (CNS) histology are not firmly established. A clinically compatible picture, exclusion of other neurological diseases, and histological confirmation of disease elsewhere are generally required. We present a case report of neurosarcoidosis presenting as a lymphoma mimic. Case report - Case descriptionA 45-year-old right-handed white male with past medical history of obstructive sleep apnoea, presented to the acute neurology clinic with several weeks’ history of cognitive decline and severe L facial pain. He had lost 2 stone in weight and there was loss of appetite over 2 months. Neurology examination (including cranial nerves) was unremarkable except for a mini mental state score of 25/30, where he lost points on the attention and recall tasks. CT head revealed a mass in the L cavernous sinus. Brain MRI with contrast revealed an enhancing lesion in the left. suspicious of lymphoma. Additional work up included whole body FDG-PET/CT scan, lumbar puncture. Lumbar puncture showed normal CSF. Serum ACE was normal and a paraneoplastic panel. Whole body PET/CT scan showed FDG avid areas in the bilateral neck, axillary regions, chest and pelvis and inguinal regions, highly consistent with lymphoma. Bone marrow biopsy was negative for lymphoma. Further EBUS biopsy before start of prednisolone revealed multiple non caseating granulomas, diagnostic of sarcoidosis. The patient was treated with oral prednisolone, followed by anti-tumour necrosis factor-a infliximab infusion.A repeat brain MRI with contrast done at five months after initiation of steroids, methotrexate and infliximab showed complete resolution of the intracranial lesion. Neurological and neuropsychological evaluation three months after diagnosis demonstrated resolution of facial pain and cognitive decline. Case report - DiscussionThere exists several mimics of neurosarcoidosis. Both clinically and radiographically, neurosarcoidosis can be difficult to diagnose. MRI and PET scan in neurosarcoidosis can often mimic malignancy. Early symptomatic treatment is advised for neurosarcoidosis, thus there is a clear need for more prompt diagnosis to allow commencement of the appropriate therapy. There is no known cure for neurosarcoidosis. Immunosuppression is the primary means of controlling the disease, and corticosteroids are the cornerstone of therapy. Treatment options are limited; however, there is more evidence suggesting that steroids and immunomodulatory agents such as infliximab may improve clinical outcomes, which may be due to the anti-TNF-α effect on reducing oxidative stress. Case report - Key learning pointsOur patient had a clinical presentation suspicious of lymphoma, however he did not have lymphoma and had a good response to corticosteroids and infliximab. Often, FDG PET/CT scan can be misleading and may appear to be neoplastic rather than inflammatory. ACE levels in both CSF and serum are not always positive. Biopsy in these cases is necessary to establish correct diagnosis. Prompt treatment can lead to significant reduction in mortality and morbidity

Adenosine deaminase and lactate dehydrogenase levels in serum and cerebrospinal fluid of patients with tuberculous meningitis

Meningitis is an active inflammatory condition of CNS. However prompt and precise aetiological diagnosis remains a challenge. Often a thorough CSF examination may not give a precise diagnosis.There is considerable urgency in establishing correct diagnosis in patients with tuberculous meningitis because specific therapy is most effective when initiated early in course of illness, delay may cause irreversible brain damage.Diagnosis often rests on circumstantial evidence such as history, typical CSF findings and other evidence for presence of tuberculosis such as acid fast bacilli in sputum, positive tuberculosis test and suspicious Chest x-ray. Under present study the role of enzymes such as adenosine deaminase and lactate dehydrogenase has been evaluated in diagnosis of tuberculous meningitis. Result of the study suggest that adenosine deaminase level in CSF and serum may be a useful parameter along with other routine estimations. The enzyme activity is high in disease such as tuberculosis where cellular mediated immunity is stimulated.Estimation of lactate dehydrogenase levels may not be a specific parameter for tuberculous meningitis this requires further studies in patients of meningitis with different aetiological diagnosis.

Effect of escitalopram dose and treatment duration on CSF Aβ levels in healthy older adults: A controlled clinical trial.

To determine whether treatment with escitalopram compared with placebo would lower CSF β-amyloid 42 (Aβ42) levels. Serotonin signaling suppresses Aβ42 in animal models of Alzheimer disease (AD) and young healthy humans. In a prospective study in older adults, we examined dose and treatment duration effects of escitalopram. Using lumbar punctures to sample CSF levels before and after a course of escitalopram treatment, cognitively normal older adults (n = 114) were assigned to placebo, 20 mg escitalopram × 2 weeks, 20 mg escitalopram × 8 weeks, or 30 mg escitalopram × 8 weeks; CSF sampled pretreatment and posttreatment and within-subject percent change in Aβ42 was used as the primary outcome in subsequent analyses. An overall 9.4% greater reduction in CSF Aβ42 was found in escitalopram-treated compared with placebo-treated groups (p < 0.001, 95% confidence interval [CI] 4.9%-14.2%, d = 0.81). Positive baseline Aβ status (CSF Aβ42 levels <250 pg/mL) was associated with smaller Aβ42 reduction (p = 0.006, 95% CI -16.7% to 0.5%, d = -0.52) compared with negative baseline amyloid status (CSF Aβ42 levels >250 pg/mL). Short-term longitudinal doses of escitalopram decreased CSF Aβ42 in cognitively normal older adults, the target group for AD prevention. NCT02161458. This study provides Class II evidence that for cognitively normal older adults, escitalopram decreases CSF Aβ42.

NFL and CXCL13 may reveal disease activity in clinically and radiologically stable MS

BackgroundCerebrospinal fluid (CSF) levels of neurofilament light (NFL), a biomarker of axonal damage, and CXCL13, a chemokine involved in B-cell regulation, are both associated with disease activity in multiple sclerosis (MS). ObjectiveTo explore the potential of NFL and CXCL13 to detect residual disease activity in patients with no signs of clinical or ongoing radiological activity and to study the clinical relevance of such activity. MethodsNFL and CXCL13 concentrations were determined with ELISA in CSF obtained from 90 relapsing-remitting (RR) MS and 47 Progressive (Pr) MS (including primary and secondary PrMS) at baseline and after 12 months of follow-up. The patients were assessed at baseline, before initiating or switching disease modifying therapy (DMT) and again after 12 and 27 months of follow-up. ResultsAll patients with ongoing disease activity (relapse or contrast-enhancing lesions on MRI) had increased NFL or CXCL13. The proportion of RRMS and PrMS patients without ongoing disease activity with elevation of either NFL or CXCL13 (residual disease activity) was 39% and 50%, respectively, and both were increased in 11% and 16%, respectively. The treatment with DMTs decreased the proportion with residual disease activity in both RRMS and PrMS significantly. We could not show any significant association between residual disease activity and clinical or MRI measures at 12 or 27 months of follow-up. ConclusionsAlthough most of this real-world study population had been treated with second-line DMTs and achieved clinical and radiological stability, a significant proportion of patients still displayed increased CSF levels of both NFL and CXCL13, indicating residual disease activity. Thus, these markers seemed considerably more sensitive to disease activity than clinical and MRI measures. However, the long-term clinical significance of such activity remains to be determined.

Cerebrospinal Fluid Levels of Kininogen-1 Indicate Early Cognitive Impairment in Parkinson's Disease.

Cognitive impairment is common in patients with PD. Core markers of Alzheimer's dementia have been related also to PD dementia, but no disease-specific signature to predict PD dementia exists to date. The aim of this study was to investigate CSF markers associated with cognition in early PD. A high-throughput suspension bead array examined 216 proteins in CSF of 74 PD patients in the AETIONOMY project. Cognitive function was assessed with Repeatable Battery for the Assessment of the Neuropsychological Status, Montreal Cognitive Assessment, and Mini-Mental State Examination. Of 69 patients with complete data, 34 had high (≥90) and 35 had low Repeatable Battery for the Assessment of the Neuropsychological Status total score (<90). Of 14 proteins in CSF that differed in levels between groups, increased kininogen-1, validated with several antibodies, was independently associated with lower Repeatable Battery for the Assessment of the Neuropsychological Status and Montreal Cognitive Assessment scores after adjustment for confounders. Kininogen-1 levels in CSF may serve as a marker of cognitive impairment in PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Endocannabinoid levels in patients with Parkinson's disease with and without levodopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) are frequent complications, and the endocannabinoid system has a role on its pathophysiology. To test the hypothesis that the functioning of the endocannabinoid system would be altered in PD and in LID by measuring plasma and CSF levels of α-N-arachidonoylethanolamine (AEA) and 2-arachidonoyl-glycerol (2-AG) in patients with PD with and without LID and in healthy controls. Blood and CSF samples were collected from 20 healthy controls, 23 patients with PD without LID, and 24 patients with PD with LID. The levels of AEA and 2-AG were measured using a highly sensitive column switching ultrahigh-performance liquid chromatography-tandem mass spectrometry method. When pooled together, patients with PD had lower plasma and CSF levels of 2-AG and higher CSF levels of AEA compared to healthy controls (Mann-Whitney statistics = 303.0, p = 0.02). Patients with PD without LID had lower CSF levels of 2-AG (Kruskal-Wallis statistics = 7.76, p = 0.02) and higher CSF levels of AEA levels than healthy controls (Kruskal-Wallis statistics = 8.81, p = 0.01). The findings suggest that the endocannabinoid system participates in the pathophysiology of PD symptoms, but its role in the pathophysiology of LID is still unclear.