Cerebrospinal Fluid Biomarker Studies Research Articles

The role of the complement system in Multiple Sclerosis: A review.

The complement system has been involved in the pathogenesis of multiple neuroinflammatory and neurodegenerative conditions. In this review, we evaluated the possible role of complement activation in multiple sclerosis (MS) with a focus in progressive MS, where the disease pathogenesis remains to be fully elucidated and treatment options are limited. The evidence for the involvement of the complement system in the white matter plaques and gray matter lesions of MS stems from immunohistochemical analysis of post-mortem MS brains, in vivo serum and cerebrospinal fluid biomarker studies, and animal models of Experimental Autoimmune Encephalomyelitis (EAE). Complement knock-out studies in these animal models have revealed that this system may have a “double-edge sword” effect in MS. On the one hand, complement proteins may aid in promoting the clearance of myelin degradation products and other debris through myeloid cell-mediated phagocytosis. On the other, its aberrant activation may lead to demyelination at the rim of progressive MS white matter lesions as well as synapse loss in the gray matter. The complement system may also interact with known risk factors of MS, including as Epstein Barr Virus (EBV) infection, and perpetuate the activation of CNS self-reactive B cell populations. With the mounting evidence for the involvement of complement in MS, the development of complement modulating therapies for this condition is appealing. Herein, we also reviewed the pharmacological complement inhibitors that have been tested in MS animal models as well as in clinical trials for other neurologic diseases. The potential use of these agents, such as the C5-binding antibody eculizumab in MS will require a detailed understanding of the role of the different complement effectors in this disease and the development of better CNS delivery strategies for these compounds.

Clinical correlations of cerebrospinal fluid biomarkers including neuron-glia 2 and neurofilament light chain in patients with multiple system atrophy

BackgroundMultiple system atrophy (MSA) is a progressive neurodegenerative disorder. The usefulness of biomarkers in diagnosing MSA has been recently reported, but few studies have investigated the correlations among cerebrospinal fluid (CSF) biomarkers or the relationship between CSF biomarkers and the clinical parameters of patients with MSA. Thus, this was the aim of our study. MethodsWe performed cross-sectional study of CSF biomarkers in 50 patients with MSA and 20 control subjects. Ten of the patients with MSA were longitudinally followed for a period of 2 ± 1 years (mean ± standard deviation) as a substudy. We quantified CSF biomarkers including α-synuclein (α-syn), β-amyloid42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau), neurofilament light chain (NfL), and neuron-glia2 (NG2), and assessed their relationship with clinical parameters (clinical subtypes, motor symptoms, nonmotor symptoms, and disease progression). ResultsThe levels of CSF α-syn, Aβ42, and p-tau were significantly lower, while those of NfL were higher in the patients with MSA than in the control subjects. Importantly, we found the significant elevation of soluble NG2 in the CSF of patients with MSA. CSF NfL showed the optimal diagnostic performance for MSA with levels at baseline significantly associated with longitudinal motor progression. With the exception of t-tau, there were no differences in the levels of CSF biomarkers between the MSA-parkinsonism and MSA-cerebellar subtypes. ConclusionsOur results suggest CSF levels of NG2 and NfL as possible diagnostic and prognostic biomarkers in MSA. Further study is necessary to validate these findings.

Clinical, cognitive and biomarker profiles in dominantly‐inherited versus sporadic early‐onset Alzheimer’s disease

AbstractBackgroundApproximately 5% of Alzheimer disease (AD) occurs before the age of 65, known as early onset AD (EOAD); 5‐10% of the patients with EOAD are caused by dominantly inherited mutations (DIAD) and the remainder appear to be sporadic EOAD (sEOAD). The extent to which clinical presentations, cognitive and biomarker profiles in DIAD and sEOAD overlap remains unknown.MethodsWe compared the clinical presentation, cognitive performance and cerebrospinal fluid (CSF) AD biomarker concentrations in DIAD and sEOAD. We included all DIAD symptomatic (CDR>0) participants (n=92) from the Dominantly Inherited Alzheimer Network (DIAN) cohort and 120 sEAOD symptomatic participants from the UCSF Alzheimer’s Disease Research Center. All EOAD cases were amyloid‐positive via PIB‐PET. All participants completed clinical measures, a battery of cognitive tests and CSF biomarker studies (Aβ‐42, p‐tau‐181, t‐tau). Baseline differences in clinical and biomarkers variables between sEOAD and DIAD were compared using t‐tests, and differences in the rates of decline on clinical and cognitive measures were compared using linear mixed effects models.ResultsDIAD participants had an earlier age at symptom onset compared to the sEOAD group (42.9y (±8.1) and 54.8y (±5.1) respectively, p<0.001). The sEOAD group showed a lower performance on executive measures, including verbal fluency (p=0.001), Trail making test (p=0.001) and digit span (p<0.001). CSF Aβ‐42 levels were significantly lower in DIAD compared to sEOAD participants (242.0 pg/ml [IQR=164.5, 318.8] vs 295.0 pg/ml [IQR=243.9, 364.1] respectively, p=0.014). Ptau‐181 levels were higher in the DIAD cohort (p=0.003), but no significant differences were found for t‐tau levels (p=0.11). Longitudinal analyses did not reveal significant differences in the rates of functional (CDRTM‐SB) and cognitive (MMSE) decline between two groups.ConclusionsAlthough sporadic and inherited EOAD differed in AD core pathological CSF biomarkers concentrations and baseline cognitive profiles, the rates of functional and cognitive changes were similar across these groups. These findings provide unique insights into the similarities and differences between DIAD and sEOAD and may inform the design of future clinical trials.

Comparison of the blood, bone marrow, and cerebrospinal fluid metabolomes in children with b-cell acute lymphoblastic leukemia

Metabolomics may shed light on treatment response in childhood acute lymphoblastic leukemia (ALL), however, most assessments have analyzed bone marrow or cerebrospinal fluid (CSF), which are not collected during all phases of therapy. Blood is collected frequently and with fewer risks, but it is unclear whether findings from marrow or CSF biomarker studies may translate. We profiled end-induction plasma, marrow, and CSF from N = 10 children with B-ALL using liquid chromatography-mass spectrometry. We estimated correlations between plasma and marrow/CSF metabolite abundances detected in ≥ 3 patients using Spearman rank correlation coefficients (rs). Most marrow metabolites were detected in plasma (N = 661; 81%), and we observed moderate-to-strong correlations (median rs 0.62, interquartile range [IQR] 0.29–0.83). We detected 328 CSF metabolites in plasma (90%); plasma-CSF correlations were weaker (median rs 0.37, IQR 0.07–0.70). We observed plasma-marrow correlations for metabolites in pathways associated with end-induction residual disease (pyruvate, asparagine) and plasma-CSF correlations for a biomarker of fatigue (gamma-glutamylglutamine). There is considerable overlap between the plasma, marrow, and CSF metabolomes, and we observed strong correlations for biomarkers of clinically relevant phenotypes. Plasma may be suitable for biomarker studies in B-ALL.

The effect of pre-analytical handling on the stability of fractalkine, monocyte chemoattractant protein 1 (MCP1), interleukin 6 and interleukin 8 in samples of human cerebrospinal fluid

Cytokine networks in cerebrospinal fluid (CSF) are important to our understanding of several neuroinflammatory diseases. Knowledge about optimal handling of samples is limited but important to minimize bias and reduce costs in CSF biomarker studies. The aim of this study was to examine the effect of storage temperature and time delay from CSF sample collection until freezing on the concentration of 11 different cytokines thought to be associated with chronic pain. CSF samples from 21 individuals undergoing hip or knee arthroplasty under spinal anesthesia were divided between two tubes. One tube was stored and centrifuged (within 30 min) at room temperature, and one tube was stored in ice water and centrifuged (within 30 min) at 4 °C. Each tube was split into six vials that were frozen at −80 °C, 0.5, 1, 2, 3, 4, or 5 h after collection. Cytokines were analyzed using a multiplex panel. A random effect panel data regression was conducted for each biomarker including the variables of storage temperature until freezing and time delay. Four cytokines had detectable levels: Fractalkine, monocyte chemoattractant protein 1(MCP-1), interleukine 6 (IL-6), and interleukine 8 (IL-8). There was no significant effect of storage temperature and time delay on MCP-1, IL-6, or IL-8 concentrations. Fractalkine concentration showed no clear trend. No concentration differences were observed between samples kept in ice water and those at room temperature except at the 3-h time point, and there was no overall significant effect of time delay on fractalkine concentration. We found no clear effect of storage temperature and time delay up to five hours from sample collection until freezing on the CSF concentrations of fractalkine, MCP-1, IL-6, or IL-8.

The Anaesthetic Biobank of Cerebrospinal fluid: a unique repository for neuroscientific biomarker research.

BackgroundThe pathophysiology of numerous central nervous system disorders remains poorly understood. Biomarker research using cerebrospinal fluid (CSF) is a promising way to illuminate the neurobiology of neuropsychiatric disorders. CSF biomarker studies performed so far generally included patients with neurodegenerative diseases without an adequate control group. The Anaesthetic Biobank of Cerebrospinal fluid (ABC) was established to address this. The aims are to (I) provide healthy-control reference values for CSF-based biomarkers, and (II) to investigate associations between CSF-based candidate biomarkers and neuropsychiatric symptoms.MethodsIn this cross-sectional study, we collect and store CSF and blood from adult patients undergoing spinal anaesthesia for elective surgery. Blood (20.5 mL) is collected during intravenous cannulation and CSF (10 mL) is aspirated prior to intrathecal local anaesthetic injection. A portion of the blood and CSF is sent for routine laboratory analyses, the remaining material is stored at −80 °C. Relevant clinical, surgical and anaesthetic data are registered. A neurological examination and Montreal Cognitive Assessment (MoCA) are performed pre-operatively and a subset of patients fill in questionnaires on somatic and mental health (depression, anxiety and stress).ResultsFour-hundred-fifty patients (58% male; median age: 56 years) have been enrolled in the ABC. The planned spinal anaesthetic procedure was not attempted for various reasons in eleven patients, in fourteen patients the spinal puncture failed and in twelve patients CSF aspiration was unsuccessful. A mean of 9.3 mL CSF was obtained in the remaining 413 of patients. Most patients had a minor medical history and 60% scored in the normal range on the MoCA (median score: 26).ConclusionsThe ABC is an ongoing biobanking project that can contribute to CSF-based biomarker research. The large sample size with constant sampling methods and extensive patient phenotyping provide excellent conditions for future neuroscientific research.

Impact of Pre-Analytical Differences on Biomarkers in the ADNI and PPMI Studies: Implications in the Era of Classifying Disease Based on Biomarkers.

Neurodegenerative diseases require characterization based on underlying biology using biochemical biomarkers. Mixed pathology complicates discovery of biomarkers and characterization of cohorts, but inclusion of greater numbers of patients with different, related diseases with frequently co-occurring pathology could allow better accuracy. Combining cohorts collected from different studies would be a more efficient use of resources than recruiting subjects from each population of interest for each study. To explore the possibility of combining existing datasets by controlling pre-analytic variables in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Parkinson's Progression Markers Initiative (PPMI) studies. Cerebrospinal fluid (CSF) was collected and processed from 30 subjects according to both the ADNI and PPMI protocols. Relationships between reported levels of Alzheimer's disease (AD) and Parkinson's disease (PD) biomarkers in the same subject under each protocol were examined. Protocol-related differences were observed for Aβ, but not t-tau or α-syn, and trended different for p-tau and pS129. Values of α-syn differed by platform. Conversion of α-syn values between ADNI and PPMI platforms did not completely eliminate differences in distribution. Factors not captured in the pre-analytical sample handling influence reported biomarker values. Assay standardization and better harmonized characterization of cohorts should be included in future studies of CSF biomarkers.

Cerebrospinal fluid biomarkers in idiopathic normal pressure hydrocephalus

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) presents difficulties because of the same symptomatology in neurodegenerative diseases. The data of brain magnetic resonance imaging (MRI) and invasive techniques (tap test, external lumbar drainage, and infusion test) not always allow an accurate diagnosis of iNPH, especially when patients have comorbidity. This increases the role of cerebrospinal fluid (CSF) biomarkers in the differential diagnosis of iNPH and comorbidities at early stages. Objective : to analyze the data available in the literature on current ideas about CSF biomarkers and their role in the differential diagnosis of iNPH and neurodegenerative diseases in the brain. Material and methods . The literature data were sought in the internet resource PubMed by the keywords: normal pressure hydrocephalus, CSF biomarkers, neurodegeneration, Alzheimer's disease (AD), beta-amyloid protein, and tau protein. Fifty-three communications published in 1965 to 2018 were reviewed. Results and discussion . In accordance with the data available in the literature, the most informative CSF biomarkers for the differential diagnosis of iNPH are beta-amyloid (Aβ) proteins β42, Aβ-40, Aβ -38, sAPPβ, sAPPβ, and t-tau and p-tau. The study of CSF biomarkers opens up prospects not only for the detection of iNPH, but also for its differential diagnosis with neurodegenerative diseases, primarily with AD. The detection of biomarkers can be used in addition to brain MRI and invasive techniques to improve the accuracy of diagnosis, as well as to predict the efficiency of bypass surgery, but provided that they are comprehensively assessed. Conclusion . The analysis of the levels of specific CSF proteins holds promise for the differential diagnosis of iNPH.

Affinity depletion versus relative protein enrichment: a side-by-side comparison of two major strategies for increasing human cerebrospinal fluid proteome coverage

Cerebrospinal fluid (CSF) is in direct contact with the central nervous system. This makes human CSF an attractive source of potential biomarkers for neurologic diseases. Similarly to blood plasma, proteomic analysis of CSF is complicated by a high dynamic range of individual protein concentrations and by the presence of several highly abundant proteins. To deal with the abundant human CSF proteins, methods developed for blood plasma/serum are routinely used. Multiple affinity removal systems and protein enrichment of less abundant proteins using a combinatorial peptide ligand library are among the most frequent approaches. However, their relative impact on CSF proteome coverage has never been evaluated side-by-side in a single study. Therefore, we explored the effect of CSF depletion using MARS 14 cartridge and ProteoMiner ligand library on the number of CSF proteins identified in subsequent LC–MS/MS analysis. LC–MS/MS analysis of crude (non-treated) CSF provided roughly 500 identified proteins. Depletion of CSF by MARS 14 cartridge increased the number of identifications to nearly 800, while treatment of CSF using ProteoMiner enabled identification of 600 proteins. To explore the potential losses of CSF proteins during the depletion process, we also analyzed the “waste” fractions generated by both methods, i.e., proteins retained by the MARS 14 cartridge, and the molecules present in the flow-through fraction from ProteoMiner. More than 250 proteins were bound to MARS 14 cartridge, 100 of those were not identified in the corresponding depleted CSF. Similarly, analysis of the waste fraction in ProteoMiner workflow provided almost 70 unique proteins not found in the CSF depleted by the ligand library. Both depletion strategies significantly increased the number of identified CSF proteins compared to crude CSF. However, MARS 14 depletion provided a markedly higher number of identified proteins (773) compared to ProteoMiner (611). Further, we showed that CSF proteins are lost due to co-depletion (MARS 14) or exclusion (ProteoMiner) during the depletion process. This suggests that the routinely discarded “waste” fractions contain proteins of potential interest and should be included in CSF biomarker studies.

Cerebrospinal Fluid Biomarkers of Cognitive Decline in Parkinson's Disease.

Among the nonmotor symptoms in Parkinson's disease (PD), cognitive impairment is one of the most common and devastating. Over recent years, mild cognitive impairment (MCI) has become a recognized feature of PD (PD-MCI). The underlying mechanisms which influence onset, rate of decline, and conversion to dementia (PDD) are largely unknown. Adding to this uncertainty is the heterogeneity of cognitive domains affected. Currently there are no disease-modifying treatments that can slow or reverse this process. Identification of biomarkers that can predict rate and risk of cognitive decline is therefore an unmet need. Cerebrospinal fluid (CSF) is an ideal biomarker candidate as its constituents reflect the metabolic processes underlying the functioning of brain parenchyma. The pathological hallmark of PD is the presence of aggregated α-synuclein (α-Syn) in intracellular Lewy inclusions. In addition, there is concomitant Alzheimer's disease (AD) pathology. In AD, decreased CSF β-amyloid 1-42 (Aβ42) and increased CSF tau levels are predictive of future cognitive decline, setting a precedent for such studies to be carried out in PD. CSF studies in PD have focused on the classical AD biomarkers and α-Syn. Longitudinal studies indicate that low levels of CSF Aβ42 are predictive of cognitive decline; however, results for tau and α-Syn were not consistent. This chapter summarizes recent findings of CSF biomarker studies and cognitive dysfunction in PD.

Feasibility of Lumbar Puncture in the Study of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease in Subjects with Down Syndrome.

Alzheimer's disease (AD) is the main medical problem in older adults with Down syndrome (DS). Studies of cerebrospinal fluid (CSF) AD biomarkers are limited and the feasibility of lumbar puncture (LP) is controversial in this population. To analyze the frequency of complications after a LP in DS. We collected data from 80 adults with DS that underwent a LP within the Down Alzheimer Barcelona Neuroimaging Initiative. Demographics, cognitive status, headache history, and presence of complications after the LP were recorded in every subject. In 53 of them (active group), this information was collected following a semi-structured and validated protocol that actively looks for complications. Other variables related to the LP procedure were also recorded. A telephone interview to the caregiver was performed 5-7 days after the procedure to ask about complications. Data from 27 subjects (clinical practice group), from whom the presence of complications was obtained in a medical follow-up visit within the three months after the LP, were also included. There were no adverse events in 90% of our participants. The most frequent complication was headache (6.25%); only one subject reported a typical post-lumbar puncture headache with moderate severity that required analgesic treatment. Dizziness (3.75%) and back pain (1.25%) were also reported. All the participants that reported complications belonged to the active group. LP can be safely performed to study CSF biomarkers in DS. The reported complications are qualitatively similar to the general population, but are less frequently reported, even when actively searched for.

Late life bipolar disorder evolving into frontotemporal dementia mimic.

ObjectivesAlthough bipolar disorder has been understood classically as a cyclic disease with full recovery between mood episodes, in the last decade, evidence has accumulated supporting progressive features. The clinical picture of advanced or end-stage bipolar disorder is heterogeneous with possible deficits in cognition and behavior, as illustrated by our case series.CasesFrom our neuropsychiatric outpatient clinic, we describe four cases with bipolar disorder gradually developing a clinical syndrome, including apathy, disinhibition, loss of empathy, stereotypical behavior, and compulsiveness, fulfilling the criteria for possible behavioral variant frontotemporal dementia. All cases were diagnosed with bipolar 1 disorder at least 10 years before the onset of the current symptoms, which were not due to recent mood episodes or switches of medication. In all cases, 3–7 years of follow-up yielded no progression. Repeated neuroimaging was within normal limits. Cerebrospinal fluid biomarker studies were not supportive of underlying neurodegenerative pathology. C9orf72 mutation status was negative in all cases.ConclusionSymptoms fitting the criteria for possible behavioral variant frontotemporal dementia may be present in end-stage of bipolar disorder. An alternative neurodegenerative nature seems unlikely based on repeated normal neuroimaging and the absence of clinical progression. Functional involvement of the frontal-subcortical networks might play a role.

Improving CSF Biomarkers' Performance for Predicting Progression from Mild Cognitive Impairment to Alzheimer's Disease by Considering Different Confounding Factors: A Meta-Analysis.

Background: Cerebrospinal fluid (CSF) biomarkers’ performance for predicting conversion from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) is still suboptimal.Objective: By considering several confounding factors we aimed to identify in which situations these CSF biomarkers can be useful.Data Sources: A systematic review was conducted on MEDLINE, PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane, and CRD (1990–2013).Eligibility Criteria: (1) Prospective studies of CSF biomarkers’ performance for predicting conversion from MCI to AD/dementia; (2) inclusion of Aβ42 and T-tau and/or p-tau. Several meta-analyses were performed.Results: Aβ42/p-tau ratio had high capacity to predict conversion to AD in MCI patients younger than 70 years. The p-tau had high capacity to identify MCI cases converting to AD in ≤24 months.Conclusions: Explaining how different confounding factors influence CSF biomarkers’ predictive performance is mandatory to elaborate a definitive map of situations, where these CSF biomarkers are useful both in clinics and research.

Feasibility of Lumbar Puncture in the Study of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease: A Multicenter Study in Spain

Lumbar puncture (LP) is increasingly performed in memory units due to the usefulness of cerebrospinal fluid (CSF) biomarkers in the diagnosis of Alzheimer's disease. The feasibility of this procedure in this context, however, is controversial. Our aim was to analyze the incidence of complications and their associated factors so as to determine the impact of LP in the study of CSF biomarkers of Alzheimer's disease. In the context of a larger international initiative, we prospectively collected data from 689 participants who underwent LP in three memory units in Spain. Data included demographic factors, headache history, subjective attitude toward the procedure, patient positioning, needle characteristics, volume of CSF extracted, attempts needed, and resting time after CSF acquisition. Five to seven days after the procedure, we asked participants about complications through a semi-structured telephone interview. No adverse events were reported in 441 (64.0%) participants. The most frequent complication was headache, reported by 171 (24.8%) subjects. It was severe in only 17 (2.5%). Headache was more frequent in younger participants and when a cutting-edge needle was used. Back pain was present in 111 (16.1%) cases, and it was associated with female gender, cutting-edge needles, increased number of attempts, and longer resting time after LP. No major complications were reported. The use of pen-point needles showed a trend toward a higher frequency of hematic CSF. LP can be safely performed to study CSF biomarkers. The main complication is headache, associated with younger age and use of cutting-edge needles.

Approach to Cerebrospinal Fluid (CSF) Biomarker Discovery and Evaluation in HIV Infection

Central nervous system (CNS) infection is a nearly universal facet of systemic HIV infection that varies in character and neurological consequences. While clinical staging and neuropsychological test performance have been helpful in evaluating patients, cerebrospinal fluid (CSF) biomarkers present a valuable and objective approach to more accurate diagnosis, assessment of treatment effects and understanding of evolving pathobiology. We review some lessons from our recent experience with CSF biomarker studies. We have used two approaches to biomarker analysis: targeted, hypothesis-driven and non-targeted exploratory discovery methods. We illustrate the first with data from a cross-sectional study of defined subject groups across the spectrum of systemic and CNS disease progression and the second with a longitudinal study of the CSF proteome in subjects initiating antiretroviral treatment. Both approaches can be useful and, indeed, complementary. The first is helpful in assessing known or hypothesized biomarkers while the second can identify novel biomarkers and point to broad interactions in pathogenesis. Common to both is the need for well-defined samples and subjects that span a spectrum of biological activity and biomarker concentrations. Previously-defined guide biomarkers of CNS infection, inflammation and neural injury are useful in categorizing samples for analysis and providing critical biological context for biomarker discovery studies. CSF biomarkers represent an underutilized but valuable approach to understanding the interactions of HIV and the CNS and to more objective diagnosis and assessment of disease activity. Both hypothesis-based and discovery methods can be useful in advancing the definition and use of these biomarkers.

Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis

The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.

Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment

Objectives To longitudinally evaluate five cerebrospinal fluid (CSF) biomarkers in the transition from mild cognitive impairment (MCI) to Alzheimer's disease (AD). Methods A baseline and 2-year follow-up clinical and CSF study of 86 subjects, including 22 MCI patients that declined to AD (MCI-AD), 43 MCI that did not deteriorate (MCI-MCI) and 21 controls (NL-NL). All subjects were studied for total and phosphorylated tau (T-tau, P-tau 231), amyloid beta (Aβ) Aβ 42/Aβ 40 ratio, isoprostane (IP) as well as P-tau 231/Aβ 42/40 and T-tau/Aβ 42/40 ratios. Results At baseline and at follow-up MCI-AD showed higher levels P-tau 231, T-tau, IP, P-tau 231/Aβ 42/40 and T-tau/Aβ 42/40 ratios and lower Aβ 42/Aβ 40 than MCI-MCI or NL-NL. Baseline P-tau 231 best predicted MCI-AD (80%, p < 0.001) followed in accuracy by P-tau 231/Aβ 42/40 and T-tau/Aβ 42/40 ratios (both 75%, p's < 0.001), T-tau (74%, p < 0.001), Aβ 42/Aβ 40 (69%, p < 0.01), and IP (68%, p < 0.01). Only IP showed longitudinal effects ( p < 0.05). Conclusions P-tau 231 is the strongest predictor of the decline from MCI to AD. IP levels uniquely show longitudinal progression effects. These results suggest the use of CSF biomarkers in secondary prevention trials.

Comparative Proteomic Analysis of Intra- and Interindividual Variation in Human Cerebrospinal Fluid

Cerebrospinal fluid (CSF) is a potential source of biomarkers for many disorders of the central nervous system, including Alzheimer disease (AD). Prior to comparing CSF samples between individuals to identify patterns of disease-associated proteins, it is important to examine variation within individuals over a short period of time so that one can better interpret potential changes in CSF between individuals as well as changes within a given individual over a longer time span. In this study, we analyzed 12 CSF samples, composed of pairs of samples from six individuals, obtained 2 weeks apart. Multiaffinity depletion, two-dimensional DIGE, and tandem mass spectrometry were used. A number of proteins whose abundance varied between the two time points was identified for each individual. Some of these proteins were commonly identified in multiple individuals. More importantly, despite the intraindividual variations, hierarchical clustering and multidimensional scaling analysis of the proteomic profiles revealed that two CSF samples from the same individual cluster the closest together and that the between-subject variability is much larger than the within-subject variability. Among the six subjects, comparison between the four cognitively normal and the two very mildly demented subjects also yielded some proteins that have been identified in previous AD biomarker studies. These results validate our method of identifying differences in proteomic profiles of CSF samples and have important implications for the design of CSF biomarker studies for AD and other central nervous system disorders.

Taps to Alzheimer's patients: A continuous Japanese study of cerebrospinal fluid biomarkers

Annals of NeurologyVolume 48, Issue 3 p. 402-402 Letter Taps to Alzheimer's patients: A continuous Japanese study of cerebrospinal fluid biomarkers Mikio Shoji MD, PhD, Mikio Shoji MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorMitsuyasu Kanai MD, PhD, Mitsuyasu Kanai MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorEtsuro Matsubara MD, PhD, Etsuro Matsubara MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorMasaki Ikeda MD, PhD, Masaki Ikeda MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorYasuo Harigaya MD, PhD, Yasuo Harigaya MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorKoichi Okamoto MD, PhD, Koichi Okamoto MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorShunsaku Hirai MD, PhD, Shunsaku Hirai MD, PhD Tokyo Metropolitan Neurological Hospital, Tokyo, JapanSearch for more papers by this author Mikio Shoji MD, PhD, Mikio Shoji MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorMitsuyasu Kanai MD, PhD, Mitsuyasu Kanai MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorEtsuro Matsubara MD, PhD, Etsuro Matsubara MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorMasaki Ikeda MD, PhD, Masaki Ikeda MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorYasuo Harigaya MD, PhD, Yasuo Harigaya MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorKoichi Okamoto MD, PhD, Koichi Okamoto MD, PhD Department of Neurology, Gunma University School of Medicine, Gunma, JapanSearch for more papers by this authorShunsaku Hirai MD, PhD, Shunsaku Hirai MD, PhD Tokyo Metropolitan Neurological Hospital, Tokyo, JapanSearch for more papers by this author First published: 15 March 2001 https://doi.org/10.1002/1531-8249(200009)48:3<402::AID-ANA23>3.0.CO;2-GCitations: 8AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume48, Issue3September 2000Pages 402-402 RelatedInformation

Taps to Alzheimer's patients: A continuous Japanese study of cerebrospinal fluid biomarkers

Taps to Alzheimer's patients: A continuous Japanese study of cerebrospinal fluid biomarkers