Cerebral Spinal Fluid Biomarkers Research Articles

Sex modifies effects of imaging and CSF biomarkers on cognitive and functional outcomes: a study of Alzheimer's disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory and functional impairments. Two of 3 patients with AD are biologically female; therefore, the biological underpinnings of this diagnosis disparity may inform interventions slowing the AD progression. To bridge this gap, we conducted analyses of 1078 male and female participants from the Alzheimer’s Disease Neuroimaging Initiative to examine associations between levels of cerebral spinal fluid (CSF)/neuroimaging biomarkers and cognitive/functional outcomes. The Chow test was used to quantify sex differences by determining if biological sex affects relationships between the studied biomarkers and outcomes. Multiple magnetic resonance imaging (whole brain, entorhinal cortex, middle temporal gyrus, fusiform gyrus, hippocampus), position emission tomography (AV45), and CSF (P-TAU, TAU) biomarkers were differentially associated with cognitive and functional outcomes. Post-hoc bootstrapped and association analyses confirmed these differential effects and emphasized the necessity of using separate, sex-stratified models. The studied imaging/CSF biomarkers may account for some of the sex-based variation in AD pathophysiology. The identified sex-varying relationships between CSF/imaging biomarkers and cognitive/functional outcomes warrant future biological investigation in independent cohorts.

Longitudinal hippocampal subfields, CSF biomarkers, and cognition in patients with Parkinson disease

ObjectiveHippocampal atrophy is an indicator of emerging dementia in PD, though it is unclear whether cerebral spinal fluid (CSF) Abeta-42, t-tau, or alpha-syn predict hippocampal subfield atrophy in a de novo cohort of PD patients. To examine whether levels of CSF alpha-synuclein (alpha-syn), beta-amyloid 1–42 (Abeta-42), or total-tau (t-tau) are associated with hippocampal subfield volumes over time. MethodsWe identified a subset of Parkinson’s Progression Markers Initiative (PPMI) de novo PD patients with longitudinal T1-weighted imaging (baseline plus at least two additional visits across 12, 24, and 48 months) and CSF biomarkers available at baseline. We performed cross-sectional, regression, and linear mixed model analyses to evaluate the baseline and longitudinal CSF biomarkers, hippocampal subfields, and cognition. A false discovery rate (FDR) was used to correct for multiple comparisons. Results88 PD-CN and 21 PD-MCI had high quality longitudinal data. PD-MCI patients exhibited reduced bilateral CA1 volumes relative to PD-CN, though there were no significant differences in CSF biomarkers between these groups. Relationships between CSF biomarkers and hippocampal subfields changed over time, with a general pattern that lower CSF Abeta-42, higher t-tau and higher alpha-syn were associated with smaller hippocampal subfields, primarily in the right hemisphere. ConclusionWe replicated prior reports that demonstrated reduced CA1 volumes in PD-MCI in a de novo PD cohort. CSF biomarkers were associated with individual subfields, with evidence that the increased CSF t-tau was associated with smaller subiculum volumes at baseline and over time, though there was no clear indication that the subfields associated with cognition (CA1 and HATA) were associated with CSF biomarkers.

Diagnosing Alzheimer Disease: Which Dementia Screening Tool to Use in Elderly Puerto Ricans with Mild Cognitive Impairment and Early Alzheimer Disease?

AbstractBackgroundMost of the time, Alzheimer Disease (AD)’s diagnosis is not made at its earliest periods and prodromal stages, for instance at Mild Cognitive Impairment (MCI) and Early Alzheimer Disease (E‐AD) stage. Commonly, AD’s diagnosis is made when significant impairment interferes with the habitual daily activities (1). Our pilot study, serves to demonstrate a correlation between the screening tools, including the Mini‐mental Status Exam (MMSE), Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating Scale (CDR), and the biological biomarkers in the cerebral spinal fluid (CSF) (Amyloid Beta 1‐42 (Aβ42 pg/mL), Tau proteins (tTau (pg/mL) and tTau/Aβ42 ratio in Puerto Ricans > 55 years old with MCI and E‐AD. To our knowledge, this is the first study trying to create a correlation between memory tests scores and underlying AD pathology to improve early detection in elderly Puerto Ricans.MethodThirty participants were evaluated including, demographics, clinical characteristics, memory scales and CSF biomarkers. CSF biomarkers (Aβ42, tTau protein, and tTau/Aβ42 ratio) were determined using the Meso Scale Discovery Platform (MSD). Associations between memory scales (MOCA, MMSE, CDR) and CSF markers were performed using Spearman’s rho correlation.ResultOur study revealed statistical association in favor of a direct relationship between MMSE and tTau/Aβ42 ratio in CSF (p= .022, 95.00% CI = [‐.69, ‐.07] (Figure 1). We found a trend towards significance with an inverse relationship with MMSE and Aβ42 (p=.069) (Figure 2) and a direct relationship with MMSE and tTau (p= .098) (Figure 3). Besides, MoCA and tTau/Aβ42 ratio had a statistically significant direct relationship (p = 0.035) (Figure 4). There was no significant statistical association between CDR test with CSF biomarkers in elderly Puerto Ricans.ConclusionMMSE was the dementia screening test consistently identifying a statistically significant or a‐trend‐towards a significant association with the CSF Alzheimer Disease’ s biomarkers (Aβ42, tTau protein, and tTau/Aβ42 ratio) in elderly Puerto Ricans with MCI and E‐AD. Clinically, > 55 y/o Puerto Rican patients with MCI and E‐AD should be screened with MMSE for a higher likelihood of earlier detection and, thus, initiation of disease‐modifying treatment.

Plasma pTau181/Aβ42 identifies cognitive change earlier than CSF pTau181/Ab42

AbstractBackgroundPlasma biomarkers now show an accuracy in detecting Amyloid Beta (Aβ) similar to AD biomarkers derived from cerebral spinal fluid (CSF). However, the ability of plasma AD biomarkers, alone or in combination, to predict cognitive decline has not yet been compared to that of CSF AD biomarkers.MethodPlasma biomarker data from 233 participants’ first visit in the Australian Imaging, Biomarkers and Lifestyle study (AIBL) was submitted to linear mixed effects models (LME) to quantify the relationship with change in cognition (measured using the AIBL PACC) and in clinical disease stage (CDR SoB) in both PET Aβ‐ (Centiloid value <20CL) and Aβ+ (Centiloid value ≥20CL) participant subgroups. Separate models were used to assess CSF (Elecsys) and plasma (ADx NeuroSciences) data for Aβ42, pTau181 and the pTau181/Aβ42 ratio. Biomarker values were classified into low vs high levels based on ROC‐derived thresholds optimizing separation of PET Aβ status (low vs high at 20 CL). Changes in cognitive and clinical symptoms were then compared between the low/high plasma biomarker groups.ResultIn Aβ‐ participants, no significant interactions between binary biomarker classification and time were observed for AIBL PACC or CDR SoB, for either CSF or plasma biomarkers. In the Aβ+ participants, interactions between the binary plasma biomarker classification and change in cognition were greater in magnitude that those detected for CSF biomarker classification. For plasma, abnormally high values of both pTau181 and the pTau181/Aβ42 ratio predicted a significant increase over time in CDR SoB (Figure 1H & 1L) and a significant decrease over time in the AIBL PACC score (Figure 1F & 1J), compared the group with low values on the same biomarkers. In cognitively unimpaired Aβ‐ participants, the AIBL PACC score declined in those with abnormally high values of the pTau181 and the pTau181/Aβ42 ratio (Figure 1F & 1J).ConclusionAssays to measure pTau181 and Aβ42 in the plasma possess an accuracy equivalent to those derived from CSF. In particular, abnormally high levels of plasma pTau181 or the ratio of pTau181 to Aβ42 ratio provide a strong prediction of early cognitive changes, even in those with normal PET Aβ status.

Multimodal magnetic resonance imaging reveals distinct sensitivity of hippocampal subfields in asymptomatic stage of Alzheimer's disease.

While hippocampal atrophy and its regional susceptibility to Alzheimer’s disease (AD) are well reported at late stages of AD, studies of the asymptomatic stage of AD are limited but could elucidate early stage pathophysiology as well as provide predictive biomarkers. In this study, we performed multi-modal magnetic resonance imaging (MRI) to estimate morphometry, functional connectivity, and tissue microstructure of hippocampal subfields in cognitively normal adults including those with asymptomatic AD. High-resolution resting-state functional, diffusion and structural MRI, cerebral spinal fluid (CSF), and neuropsychological evaluations were performed in healthy young adults (HY: n = 40) and healthy older adults with negative (HO−: n = 47) and positive (HO+ : n = 25) CSF biomarkers of AD. Morphometry, functional connectivity, and tissue microstructure were estimated from the structural, functional, and diffusion MRI images, respectively. Our results indicated that normal aging affected morphometry, connectivity, and microstructure in all hippocampal subfields, while the subiculum and CA1-3 demonstrated the greatest sensitivity to asymptomatic AD pathology. Tau, rather than amyloid-β, was closely associated with imaging-derived synaptic and microstructural measures. Microstructural metrics were significantly associated with neuropsychological assessments. These findings suggest that the subiculum and CA1-3 are the most vulnerable in asymptomatic AD and tau level is driving these early changes.

Assessment of cerebral spinal fluid biomarkers and microRNA-mediated disease mechanisms in spinal muscular atrophy patient samples.

Cerebral spinal fluid (CSF) is a promising biospecimen for the detection of central nervous system biomarkers to monitor therapeutic efficacy at the cellular level in neurological diseases. Spinal muscular atrophy (SMA) patients receiving intrathecal antisense oligonucleotide (nusinersen) therapy tend to show improved motor function, but the treatment effect on cellular health remains unknown. The objective of this study was to assess the potential of extracellular RNAs and microRNAs in SMA patient CSF as indicators of neuron and glial health following nusinersen treatment. Extracellular RNA analysis of CSF samples revealed ongoing cellular stress related to inflammation and glial differentiation, even after treatment administration. Downregulated microRNA expression associated with SMA-specific or general motor neuron dysfunction in animal and cellular models, tended to increase in nusinersen-treated patient CSF samples and correlated with SMA Type 1 and 2 motor functioning improvements. However, miR-146a, known to be upregulated in SMA-induced pluripotent stem cell (iPSC)-derived astrocytes, showed increased expression in nusinersen-treated CSF samples. We then used mRNA sequencing and multi-electrode arrays to assess the transcriptional and functional effects of miR-146a on healthy and SMA iPSC-derived motor neurons. miR-146a treatment on iPSC-derived motor neurons led to a downregulation of extracellular matrix genes associated with synaptic perineuronal net and alterations in spontaneous electrophysiological activity. Altogether, this study suggests that extracellular RNAs and microRNAs may serve as useful biomarkers to monitor cellular health during nusinersen treatment. Moreover, these data highlight the importance of addressing astrocyte health and response to nusinersen in SMA pathogenesis and treatment strategies.

A phase 1 study of AL002 in healthy volunteers

AbstractBackgroundTriggering receptor expressed on myeloid cells ‐2 (TREM2) is a prominent Alzheimer’s disease (AD) risk gene that is expressed by microglia in the brain; reduced function of TREM2 is associated with a 3‐fold increase in AD risk. AL002 is a humanized monoclonal IgG1 antibody. The proposed mechanism of action is that it binds to TREM2 and activates the TREM2 signaling pathway to increase the ability of microglia to clear pathology and protect neurons with the goal of treating patients suffering from AD. INVOKE was a first‐in‐human Phase 1 study designed to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenously administered AL002 in healthy volunteers (HV).MethodINVOKE was a randomized, placebo‐controlled, double‐blind investigation of AL002 in healthy volunteers (HV). The SAD portion of the study, which included a total of 64 HV receiving a single dose of 0.003 to 60 mg/kg AL002 or matching placebo is complete. Blood and CSF biomarkers were measured before dosing and at multiple timepoints after dosing.ResultIn the SAD portion of the INVOKE study, AL002 was generally well tolerated in HV. AL002 decreased sTREM2 in cerebral spinal fluid (CSF), in a dose‐dependent manner, demonstrating proof of target engagement in the brain. Microglia biomarkers of TREM2 activation, such as CSF1R, SPP1 and IL1RN, were identified with in vitro and in vivo non‐clinical experiments. Consistent with these findings, treatment of HV with AL002 caused an increase in CSF levels of CSF1R, SPP1 and IL1RN in a dose‐dependent manner, suggesting proof of microglia activity through the TREM2 pathway.ConclusionAL002 treatment resulted in TREM2 target engagement and proof of activity in the CSF of HVs. These results have supported progressing AL002 to an ongoing Phase 2 study (INVOKE‐2) to investigate its effects on cognitive decline and neurodegeneration in subjects with early AD.

BRAF-V600E in Peripheral Mononuclear Cells and Microglia-like Brain Cells Suggest Hematopoietic Origin of Langerhans Cell Histiocytosis-Associated Neurodegeneration

Introduction: Langerhans cell histiocytosis (LCH) is a myeloid neoplasia characterized by inflammatory lesions with pathologic CD207+ myeloid dendritic cells (DC). Activation of ERK occurs in all patients with the most common somatic driver mutation being BRAF-V600E being found in up to 60% of patients.Mononuclear cells harboring the BRAF-V600E mutation have been found in peripheral blood of patients with involvement of the liver, spleen, or bone marrow, known as high risk organs. LCH involvement of the brain may include mass lesions in 25% of patients, most commonly the pituitary gland, or a progressive neurodegenerative syndrome (LCH-ND) that arises in approximately 5% of patients. LCH-ND may arise years after the initial LCH episode was presumed to have been cured and may lead to permanent neurologic deficits. The pathogenesis of LCH-ND is poorly understood, but is believed to be due to an autoimmune or paraneoplastic process. No standard approaches to surveillance or therapy exist. In order to define the etiology of LCH-ND, develop clinical tools for identifying patients at risk for LCH-ND, and to identify potential targets for novel therapies, we evaluated cerebral spinal fluid (CSF) proteins, extracellular BRAF- V600E DNA in CSF, and BRAF-V600E + cells in peripheral blood and brain biopsies.Methods: CSF biomarkers, including 121 unique proteins associated with inflammation and/or neurodegeneration and extracellular BRAF- V600E, were evaluated in 40 patients with LCH brain lesions and/or LCH-ND. CSF samples from 29 patients with acute lymphoblastic leukemia in remission and 25 patients with pediatric brain tumors represented control samples. Peripheral mononuclear cells were evaluated for BRAF-V600E by qPCR in blood samples collected pre-therapy (14 LCH-ND, 140 non-ND LCH), post-therapy at the time of relapse (14 LCH-ND, 28 non-ND LCH) and post-therapy with no evidence of active disease (35 LCH-ND, 25 non-ND LCH). Brain biopsy specimens were tested for the presence of cells harboring BRAF-V600E and relative expression of osteopontin.Results: Osteopontin was significantly elevated and S100B was decreased in CSF from patients with LCH compared to patients with brain tumors and other neurodegenerative conditions. While extracellular BRAF-V600E was detected in CSF of only 2/23 patients with LCH CNS lesions or LCH-ND, peripheral blood mononuclear cells with the BRAF- V600E mutation were more frequently found in patients with LCH-ND. In pre-therapy samples, mononuclear cells harboring the BRAF-V600E mutation were identified in 10/17 LCH-ND patients (3/9 with LCH limited to the CNS and 7/8 with active LCH beyond the CNS) vs 21/140 non-ND LCH patient samples. Comparing pre-therapy samples from patients with active LCH outside of the CNS, circulating BRAF-V600E was associated with LCH-ND with a sensitivity of 0.875 and specificity of 0.85 (P=<0.0001). In post-therapy blood collected at a time of relapsed non-CNS LCH, BRAF-V600E was detected in 6/14 LCH-ND samples and 2/28 non-ND LCH samples (sensitivity 0.4286, specificity 0.9286, P=0.0105). In post-therapy blood collected in patients with no active non-CNS LCH, circulating BRAF-V600E was detected in 8/29 LCH-ND samples vs 0/43 non-ND LCH samples (sensitivity 0.2162, specificity 1, P=0.0013). Brain biopsies of patients with LCH-ND demonstrate diffuse infiltration by BRAF-V600E + cells with a transformed microglial phenotype and elevated osteopontin expression, surrounded by CD3+ T cells. Three of four patients with LCH-ND treated with BRAF inhibitors experienced significant clinical and radiologic improvement.Conclusions: Prior theories of LCH-ND pathogenesis include autoimmune or inflammatory mechanisms. Our results support a model of LCH lesions and LCH-ND arising from a common hematopoietic precursor: whereas ERK-activated myeloid precursors differentiate into CD207+ DCs in non CNS LCH lesions, they may migrate to the brain and differentiate into hyper activated inflammatory microglia-like cells in LCH-ND. This revised model of pathogenesis supports evaluation for LCH mutations in serial blood samples prospectively along with long-term clinical surveillance to identify patients at risk for LCH-ND who may benefit from early initiation of therapy directed against the clonal reservoir of myeloid precursors with activated ERK. DisclosuresBaiocchi:Prelude therapeutics: Research Funding; viracta: Membership on an entity's Board of Directors or advisory committees, Research Funding; essanex: Research Funding; Theravectys: Consultancy.

Retinal ganglion cell dysfunction in preclinical Alzheimer\u2019s disease: an electrophysiologic biomarker\xa0signature

The current study evaluated retinal function using electroretinography (ERG) in cognitively healthy (CH) participants with preclinical Alzheimer’s disease (AD), as classified by cerebral spinal fluid (CSF) Aβ42/Tau ratio. Individuals with normal retinal morphology ascertained by spectral-domain optical coherence tomography were enrolled. Full-field ERG, pattern PERG, and photopic negative response (PhNR) were performed in 29 adult participants (58 eyes). Amplitude and implicit times of the ERG wave components were analyzed. Preclinical AD participants showed marked retinal ganglion cell dysfunction relative to controls. The PhNR was significantly diminished in preclinical AD relative to controls. PhNR amplitude and N95 implicit time differentiated CH individuals with CSF biomarkers of AD pathology with 87% sensitivity and 82% specificity. These quantitative electrophysiologic findings expand our understanding of early retinal functional changes that precede cognitive decline in AD. Retinal ganglion cell dysfunction, as detected by ERG, may be a clinically useful, non-invasive in vivo biomarker for early disease detection, which is necessary for ultimately pursuing early intervention.

Intranasal Insulin Reduces White Matter Hyperintensity Progression in Association with Improvements in Cognition and CSF Biomarker Profiles in Mild Cognitive Impairment and Alzheimer\u2019s Disease

BackgroundIntranasally administered insulin has shown promise in both rodent and human studies in Alzheimer’s disease; however, both effects and mechanisms require elucidation.ObjectiveWe assessed the effects of intranasally administered insulin on white matter health and its association with cognition and cerebral spinal fluid biomarker profiles in adults with mild cognitive impairment or Alzheimer’s disease in secondary analyses from a prior phase 2 clinical trial (NCT01767909).DesignA randomized (1:1) double-blind clinical trial.SettingTwelve sites across the United States.ParticipantsAdults with mild cognitive impairment or Alzheimer’s disease.InterventionParticipants received either twice daily placebo or insulin (20 IU Humulin R U-100 b.i.d.) intranasally for 12 months. Seventy-eight participants were screened, of whom 49 (32 men) were enrolled.MeasurementsChanges from baseline in global and regional white matter hyperintensity volume and gray matter volume were analyzed and related to changes in cerebral spinal fluid biomarkers, Alzheimer’s Disease Assessment Scale-Cognition, Clinical Disease Rating-Sum of Boxes, Alzheimer’s Disease Cooperative Study-Activities of Daily Living Scale, and a memory composite.ResultsThe insulin-treated group demonstrated significantly reduced changes in white matter hyperintensity volume in deep and frontal regions after 12 months, with a similar trend for global volume. White matter hyperintensity volume progression correlated with worsened Alzheimer’s disease cerebral spinal fluid biomarker profile and cognitive function; however, patterns of correlations differed by treatment group.ConclusionIntranasal insulin treatment for 12 months reduced white matter hyperintensity volume progression and supports insulin’s potential as a therapeutic option for Alzheimer’s disease.

Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia

Individuals with tuberous sclerosis complex can develop a progressive neuropsychiatric syndrome known as tuberous sclerosis-associated neuropsychiatric disorders. Tuberous sclerosis-associated neuropsychiatric disorders symptoms overlap with clinical criteria for frontotemporal dementia, yet the association between the 2 has not been explored. To investigate the potential association between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia. Case-control study that enrolled patients with tuberous sclerosis complex with normal IQs in an observational clinical study at the University of California, San Francisco, from 2017 to 2019 where they underwent a comprehensive clinical evaluation including neuropsychologic testing, cerebral spinal fluid biomarker profiling, and structural neuroimaging. The study included adults who fulfilled the clinical criteria for tuberous sclerosis complex and had normal IQs, had frontotemporal dementia, or were healthy control individuals. Tuberous sclerosis-associated neuropsychiatric disorders checklist severity score, neuropsychologic test scores, cerebral spinal fluid concentrations of phosphorylated tau181, total tau, amyloid-β 42, and neurofilament light chain. Amyloid and tau positron emission tomography scans were obtained in a subset of patients. Eighteen patients with tuberous sclerosis complex (mean [SD] age, 48 years [9.54]; 13 women [72%]), 16 with frontotemporal dementia (60 [6.93] years; 7 women [44%]) and 18 healthy control individuals (63 [3.85] years; 9 women [50%]) were included. The tuberous sclerosis-associated neuropsychiatric disorders checklist and neuropsychological test results were not significantly different when the tuberous sclerosis complex and frontotemporal dementia cohorts were compared. The tuberous sclerosis complex cohort exhibited elevated cerebral spinal fluid phosphorylated tau181 and neurofilament light chain with a mean of 32 pg/mL and 2300 pg/mL, respectively, when compared to healthy control individuals. All 3 patients with tuberous sclerosis complex who underwent fluorine 1B-labeled flortaucipir tau positron emission tomographic neuroimaging showed punctate foci of elevated [18F]flortaucipir binding in the frontal and temporal regions. Adults with tuberous sclerosis complex showed phenotypic overlap with frontotemporal dementia. The results support a possible clinical continuum between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia and highlights a potential pathophysiological link between neurodevelopmental and neurodegenerative processes. Quantitative neuropsychological testing and the tuberous sclerosis-associated neuropsychiatric disorders checklist, potentially supplemented by cerebral spinal fluid and imaging biomarkers, could be used to screen and prognosticate for risk of a neurodegenerative process in adult patients with tuberous sclerosis complex.

UTILITY OF EXECUTIVE FUNCTION TO IDENTIFY EARLY COGNITIVE IMPAIRMENT IN AFRICAN AMERICANS

Within diverse cohorts, African Americans (AA) demonstrate higher rates of Alzheimer’s dementia (AD) and Alzheimer’s dementia combined with multiple comorbid conditions. AA are also two times more likely to develop late-onset AD than whites and less likely to be diagnosed. Yet, our understanding of this disparity in cognition remains limited. Cognitive impairment (CI) and dementia are both underdiagnosed and underreported in primary care patients. The lack of early detection of cognitive and functional decline in high risk populations results in failure to provide care and interventions to members of vulnerable groups. This talk will focus on research that seeks to identify a more sensitive cognitive marker for early identification of cognitive impairment for AA and advances this objective by linking the cognitive marker to AD cerebral spinal fluid biomarkers (Aβ1-42, p-tau) and testing whether this association differs between AA and whites.

The predictive value of CSF multiple assay in multiple sclerosis: A single center experience

BackgroundMultiple sclerosis (MS) is a chronic, immune-mediated, inflammatory, neurodegenerative disorder. Many studies are investigating the potential role of body fluid biomarkers as prognostic factors for early identification of patients presenting with clinical isolated syndrome (CIS) at high risk for conversion to MS or to recognize RRMS patients at high risk for progression. ObjectivesTo evaluate the correlation between levels of BAFF, chitinase 3-like 1 (CHI3L1), sCD163, Osteopontin (OPN), both on serum and cerebral spinal fluid (CSF), and the disease activity and progression. We also want to explore a possible relationship between serological and CSF biomarker's levels. Patients and methodsWe enrolled 82 patients between June 2014 and June 2016. Seventy-one received a diagnosis of demyelinating disease of CNS (46 RRMS and 25 CIS), while 11 were affected by other neurological diseases. All patients underwent a neural axis MRI, lumbar puncture and blood samples. Levels of BAFF, CHI3L1, sCD163, OPN on serum and CSF were analyzed by Luminex xMAP system, with a kit 11-plex ad hoc. ResultsThe CSF CHI3L1, sCD163 and OPN levels were significantly higher in MS patients than in controls. We did not find significant differences in serum CHI3L1, sCD163 and OPN levels, nor CSF or serum BAFF levels between patient and control groups.We found significantly higher CSF level of sCD163 and CHI3L1 in all patients’ subgroups compared with controls, while OPN was higher in CIS and RR subgroups. We did not find significant differences for serum and CSF levels of all the markers between patients with or without clinical or radiological disease activity.CSF sCD163 and CHI3L1 levels was significant higher in CIS patients who converted to MS (p < 0.05).Using ROC curve analysis, CSF sCD163 resulted the best predictive factor. CSF CHI3L1 and OPN levels resulted useful independent predictors too. Combined ROCs of those three analytes demonstrated a better predictive value, with sCD163 and CHI3L1 resulting as the best combination. ConclusionsCSF sCD163 CHI3L1 and OPN levels were higher in MS patients whereas serum CHI3L1, sCD163 and OPN levels did not show differences compared with controls. This finding confirms the high CSF specificity with regards to the analysis of processes, inflammatory and non-inflammatory, that occur within the CNS.

Preconditioning in the Rhesus Macaque Induces a Proteomic Signature Following Cerebral Ischemia that Is Associated with Neuroprotection.

Each year, thousands of patients are at risk of cerebral ischemic injury, due to iatrogenic responses to surgical procedures. Prophylactic treatment of these patients as standard care could minimize potential neurological complications. We have shown that protection of brain tissue, in a non-human primate model of cerebral ischemic injury, is possible through pharmacological preconditioning using the immune activator D192935. We postulate that preconditioning with D192935 results in neuroprotective reprogramming that is evident in the brain following experimentally induced cerebral ischemia. We performed quantitative proteomic analysis of cerebral spinal fluid (CSF) collected post-stroke from our previously published efficacy study to determine whether CSF protein profiles correlated with induced protection. Four groups of animals were examined: naïve animals (no treatment or stroke); animals treated with vehicle prior to stroke; D192935 treated and stroked animals, further delineated into two groups, ones that were protected (small infarcts) and those that were not protected (large infarcts). We found that distinct protein clusters defined the protected and non-protected animal groups, with a 16-member cluster of proteins induced exclusively in D192935 protected animals. Seventy percent of the proteins induced in the protected animals have functions that would enhance neuroprotection and tissue repair, including several members associated with M2 macrophages, a macrophage phenotype shown to contribute to neuroprotection and repair during ischemic injury. These studies highlight the translational importance of CSF biomarkers in defining mechanism and monitoring responses to treatment in development of stroke therapeutics.

Biomarker assessment and combination with differential covariate effects and an unknown gold standard, with an application to Alzheimer’s disease

The continued efforts to evaluate biomarkers’ predictive abilities and identify optimal biomarker combinations are often challenged by the absence of a gold standard, that is, the true disease status. Current methods that address this issue are mostly developed for binary or ordinal diagnostic tests, which do not fully utilize information provided by continuous biomarkers, or require strong parametric assumptions. Moreover, limited methods exist to allow for the inclusion of covariates—despite their crucial role in facilitating the accurate evaluation of biomarkers. In this paper, we proposed a latent profile approach to evaluating diagnostic accuracy of biomarkers without a gold standard. The method allows for flexible biomarker distributions and incorporation of previous knowledge about risk factors while simultaneously permitting researchers to model paticipants’ characteristics that putatively affect biomarker levels, and therefore provides information needed to develop more personalized diagnostic procedures. Additionally, the proposed method presents a potential strategy for biomarker combination when gold standard information is unavailable, as it derives a composite risk score for the underlying disease status. The method is applied to evaluate different cerebral spinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) detection. The results show that CSF biomarkers hold significant potential for facilitating early AD detection and for continuous disease monitoring. Furthermore, they call attention to biomarker variability in subgroups and reexamination of CSF biomarker distributions. Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.

A single center study: Aβ42/p-Tau181 CSF ratio to discriminate AD from FTD in clinical setting.

Abnormal levels of beta amyloid (Aβ42) and tau protein concentrations in the cerebral spinal fluid (CSF) have been largely described in Alzheimer's disease (AD). Thus, CSF analysis of these biomarkers has been incorporated in recent AD diagnostic criteria, and it is increasingly performed for neurodegenerative dementia diagnostic workout in clinical setting. Nevertheless, the precise biomarkers CSF features in neurodegenerative dementia, either AD or Frontotemporal dementia (FTD), are still not fully clear today. This is mainly due to lack of CSF clear cutoff values due to a well-known intersite (but even intrasite) variability of CSF procedures, ranging from collection to analysis. Applying CSF biomarker ratios, rather than their single values could represent a useful tool, especially for the differential diagnosis of different forms of dementia. We explored clinical values of six CSF ratios (by combining Aβ42 and tau) in order to better discriminate between AD and FTD; we identified Aβ42/p-Tau181 ratio as a potential good candidate for helping differentiating AD from FTD in the clinical practice.

Elevated cerebral spinal fluid biomarkers in children with mucopolysaccharidosis I-H

Mucopolysaccharidosis (MPS) type-IH is a lysosomal storage disease that results from mutations in the IDUA gene causing the accumulation of glycosaminoglycans (GAGs). Historically, children with the severe phenotype, MPS-IH (Hurler syndrome) develop progressive neurodegeneration with death in the first decade due to cardio-pulmonary complications. New data suggest that inflammation may play a role in MPS pathophysiology. To date there is almost no information on the pathophysiologic changes within the cerebral spinal fluid (CSF) of these patients. We evaluated the CSF of 25 consecutive patients with MPS-IH. While CSF glucose and total protein were within the normal range, we found a significantly mean elevated CSF opening pressure at 24 cm H2O (range 14–37 cm H2O). We observed a 3-fold elevation in CSF heparan sulfate and a 3–8 fold increase in MPS-IH specific non-reducing ends, I0S0 and I0S6. Cytokine analyses in CSF of children with MPS-IH showed significantly elevated inflammatory markers including: MCP-1 SDF-1a, IL-Ra, MIP-1b, IL-8, and VEGF in comparison to unaffected children. This is the largest report of CSF characteristics in children with MPS-IH. Identification of key biomarkers may provide further insight into the inflammatory-mediated mechanisms related to MPS diseases and perhaps lead to improved targeted therapies.

Intrinsic functional connectivity alterations in cognitively intact elderly APOE ε4 carriers measured by eigenvector centrality mapping are related to cognition and CSF biomarkers: a preliminary study.

Apolipoprotein E (APOE) ε4 allele is the best established genetic risk factor for sporadic Alzheimer's disease (AD). However, there is a need to understand the effects of this genotype on the brain by simultaneously assessing intrinsic brain network and cerebral spinal fluid (CSF) biomarkers changes in healthy older ε4 carriers. Thirteen cognitively intact, elderly APOE ε4 carriers and 22 ε3 homozygotes were included in the present study. Eigenvector centrality mapping (ECM) was used to identify brain network hub organization based on resting-state functional MRI (rsfMRI). We evaluated comprehensive cognitive ability and tested levels of Aβ1-42, total-tau (t-tau) and phosphorylated-tau (p-tau181) in CSF. Comparisons of ECM between two groups were conducted, followed by correlations analyses between EC values with significant group differences and cognitive ability/CSF biomarkers. APOE ε4 carriers showed significantly decreased EC values in left medial temporal lobe (MTL), left lingual gyrus (LG) and increased EC values in left middle frontal gyrus (MFG) as compared to non-carriers. Correlation analysis demonstrated that left LG EC value correlated with Rey Auditory Verbal Learning Test total learning (RAVLT, r=0.57, p<0.05) and t-tau level (r=-0.57, p<0.05), while left MFG EC values correlated with log-transformed Trail-Making Test B (TMT-B, r=-0.67, p<0.05) in APOE ε4 carriers. This study suggests the APOE ε4 allele contributes to disruption of brain connectedness in certain functional nodes, which may result from neuronal death caused by toxicity of neurofibrillary tangles.

Identification of novel CSF biomarkers for neurodegeneration and their validation by a high-throughput multiplexed targeted proteomic assay.

BackgroundCurrently there are no effective treatments for many neurodegenerative diseases. Reliable biomarkers for identifying and stratifying these diseases will be important in the development of future novel therapies. Lewy Body Dementia (LBD) is considered an under diagnosed form of dementia for which markers are needed to discriminate LBD from other forms of dementia such as Alzheimer’s Disease (AD). This work describes a Label-Free proteomic profiling analysis of cerebral spinal fluid (CSF) from non-neurodegenerative controls and patients with LBD. Using this technology we identified several potential novel markers for LBD. These were then combined with other biomarkers from previously published studies, to create a 10 min multiplexed targeted and translational MRM-LC-MS/MS assay. This test was used to validate our new assay in a larger cohort of samples including controls and the other neurodegenerative conditions of Alzheimer’s and Parkinson’s disease (PD).ResultsThirty eight proteins showed significantly (p < 0.05) altered expression in LBD CSF by proteomic profiling. The targeted MRM-LC-MS/MS assay revealed 4 proteins that were specific for the identification of AD from LBD: ectonucleotide pyrophosphatase/phosphodiesterase 2 (p < 0.0001), lysosome-associated membrane protein 1 (p < 0.0001), pro-orexin (p < 0.0017) and transthyretin (p < 0.0001). Nineteen proteins were elevated significantly in both AD and LBD versus the control group of which 4 proteins are novel (malate dehydrogenase 1, serum amyloid A4, GM2−activator protein, and prosaposin). Protein-DJ1 was only elevated significantly in the PD group and not in either LBD or AD samples. Correlations with Alzheimer-associated amyloid β-42 levels, determined by ELISA, were observed for transthyretin, GM2 activator protein and IGF2 in the AD disease group (r2 ≥ 0.39, p ≤ 0.012). Cystatin C, ubiquitin and osteopontin showed a strong significant linear relationship (r2 ≥ 0.4, p ≤ 0.03) with phosphorylated–tau levels in all groups, whilst malate dehydrogenase and apolipoprotein E demonstrated a linear relationship with phosphorylated-tau and total-tau levels in only AD and LBD disease groups.ConclusionsUsing proteomics we have identified several potential and novel markers of neurodegeneration and subsequently validated them using a rapid, multiplexed mass spectral test. This targeted proteomic platform can measure common markers of neurodegeneration that correlate with existing diagnostic makers as well as some that have potential to show changes between AD from LBD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0059-y) contains supplementary material, which is available to authorized users.

Pulse pressure in relation to tau-mediated neurodegeneration, cerebral amyloidosis, and progression to dementia in very old adults.

Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear. To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia. In this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months tracked progression to dementia. Regression and analysis of covariance analyses investigated relationships between pulse pressure and distinct cerebral spinal fluid biomarker profiles. Very old participants (80 years or older) were compared with younger participants (55-79 years of age) on clinical measures and pulse pressure × age group interactions were investigated. Survival analysis examined the effect of baseline pulse pressure on progression to dementia. Covariates were age, sex, apolipoprotein E genotype, body mass index, vascular risk factors, and antihypertensive medication use. Individuals with a P-tau-positive biomarker profile exhibited mean (SD) elevated pulse pressure regardless of age (62.0 [15.6] mm Hg for a P-tau-positive biomarker vs 57.4 [14.0] mm Hg for P-tau-negative biomarker; P = .04). In very old participants, a further increase in pulse pressure was observed in those exhibiting both P-tau elevation and β-amyloid 1-42 reduction vs either biomarkers alone (69.7 [16.0] mm Hg for both positive biomarkers vs 63.18 [13.0] mm Hg for P-tau alone vs 60.1 [16.4] mm Hg for β-amyloid 1-42 alone vs 56.6 [14.5] mm Hg for negative biomarkers; P = .003). Those with higher baseline pulse pressure progressed to dementia more rapidly (95% CI, 1.000-1.048; P = .05; hazard ratio = 1.024). Systolic pressure exhibited similar relationships with Alzheimer disease biomarkers and progression to dementia in the very old subgroup (P < .05) but showed no associations in the young old subgroup (P > .10). Diastolic pressure was reduced in young old participants with isolated phosphorylated tau elevation (P = .04). Pulse pressure, an index of vascular aging, was associated with neurodegenerative change prior to the onset of dementia across a broad age range. Among those with more advanced age, higher pulse pressure was also associated with cerebral amyloidosis in the presence of neurodegeneration and more rapid progression to dementia. Diastolic contributions to these biomarker associations were limited to young old participants whereas systolic contributions were found only in very old participants.