Use Of Cerebrospinal Fluid Biomarkers Research Articles

Use of cerebrospinal fluid biomarkers for accurate diagnosis of Alzheimer’s disease in a tertiary care memory center

AbstractBackgroundAccurate clinical‐biological diagnosis of dementia and of Alzheimer’s disease (AD) is important for exclusion of treatable modifiable conditions, to differentiate AD from conditions with similar clinical manifestations, and for consideration of novel disease‐modifying therapeutic agents. Recently, it has become possible to measure protein biomarkers that reflect the pathology of AD. Our aim was to examine our initial experience of running a “cognitive” CSF biomarker service and bank at our institute.MethodThe service operates since June 2020. All subjects underwent physical, neurological and cognitive evaluation, imaging and laboratory work‐up. Consenting patients presenting at young age or with atypical or unclear manifestations of cognitive and/or behavioral deterioration underwent lumbar puncture for CSF examination, tailored according to the clinical differential diagnosis [cells, protein, glucose, chloride, cytology, AD biomarkers‐ total tau (tTau), 181‐phosphorylated tau (pTau181), amyloid‐β42 (Aβ42)]. When appropriate, antibody analysis and microbiological studies were added.ResultAD biomarkers results were available for 63 subjects presenting with cognitive/behavioral impairment, mean age 59 (range 31‐78) years, 34 (54%) were men. Mean MMSE score was 21/30 (range 6‐30), mean MoCA score was 18/30 (range 6‐28). Pre CSF analysis, 27 (43%) subjects were clinically diagnosed with possible AD (CDAD) and 36 (57%) with clinically diagnosed possible non‐AD (CDNAD) (FTD, LBD, CBD, vascular disease, autoimmune encephalopathy, unclear etiology). In our sample 28 (44%) were biomarkers positive for AD. Among 27 subjects with CDAD in 5 AD was excluded and among 36 with CDNAD 6 were biomarker positive AD (clinical sensitivity 78%, false positive 18.5%, false negative 16.6%).ConclusionOur study emphasizes the added value of biomarker supported diagnosis in subjects with cognitive/behavioral impairment, to avoid incorrectly labeling AD or misdiagnosis and for disclosure recommendation in the era of disease‐modifying therapies.

Exploring the Role of Cerebrospinal Fluid As Analyte in Neurologic Disorders

The cerebrospinal fluid (CSF) is a clear ultrafiltrate of blood that envelopes and protects the central nervous system while regulating neuronal function through the maintenance of interstitial fluid homeostasis in the brain. Due to its anatomic location and physiological functions, the CSF can provide a reliable source of biomarkers for the diagnosis and treatment monitoring of different neurological diseases, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and primary and secondary brain malignancies. The incorporation of CSF biomarkers into the drug discovery and development can improve the efficiency of drug development and increase the chances of success. This review aims to consolidate the current use of CSF biomarkers in clinical practice and explore future perspectives for the field.

Cerebrospinal Fluid Biomarkers for Cerebral Amyloid Angiopathy Diagnosis.

An accurate diagnosis of sporadic cerebral amyloid angiopathy (CAA) is critical for patient management and research (including clinical trials) for this common small vessel pathology of the brain. While the "big bang" of the CAA field has been the device and wide adoption of the clinico-radiological Boston criteria which allowed for CAA diagnosis during life, these criteria are not without major shortcoming. As it is now becoming evident that CAA is probably not a single disease, but rather represents divergent pathophysiological phenotypes and clinical trajectories, new biomarker-driven diagnostic approaches should be sought. One such complimentary approach for CAA diagnosis is the use of cerebrospinal fluid biomarkers (CSF), which could provide dynamic measures of the underlying disease process and is discussed in this commentary given exciting new advances. A hint on how the practicing clinician could apply the current CSF data for CAA diagnosis is also provided.

Lights and Shadows of Cerebrospinal Fluid Biomarkers in the Current Alzheimer's Disease Framework.

Background: The most significant biomarkers that are included in the Alzheimer’s disease (AD) research framework are amyloid-β plaques deposition, p-tau, t-tau, and neurodegeneration.Although cerebrospinal fluid (CSF) biomarkers are included in the most recent AD research criteria, their use is increasing in the routine clinical practice and is applied also to the preclinical phases of AD, including mild cognitive impairment. The role of these biomarkers is still unclear concerning the preclinical stage of AD diagnosis, the CSF methodology, and the costs-benefits of the biomarkers’ tests. The controversies regarding the use of biomarkers in the clinical practice are related to the concepts of analytical validity, clinical validity, and clinical utility and to the question of whether they are able to diagnose AD without the support of AD clinical phenotypes.Objective: The objective of the present work is to expose the strengths and weaknesses of the use of CSF biomarkers in the diagnosis of AD in a clinical context.Methods: We used PubMed as main source for articles published and the final reference list was generated on the basis of relevance to the topics covered in this work.Results: The use of CSF biomarkers for AD diagnosis is certainly important but its indication in routine clinical practice, especially for prodromal conditions, needs to be regulated and also contextualized considering the variety of possible clinical AD phenotypes.Conclusion: We suggest that the diagnosis of AD should be understood both as clinical and pathological.

Biomarkers in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. AD is the main cause of dementia worldwide and aging is the main risk factor for developing the illness. AD classical diagnostic criteria rely on clinical data. However, the development of a biological definition of AD using biomarkers that reflect the underling neuropathology is needed. The aim of this review is to describe the main outcomes when measuring classical and novel biomarkers in biological fluids or neuroimaging. Nowadays, there are three classical biomarkers for the diagnosis of AD: Aβ42, t-Tau and p-Tau. The diagnostic use of cerebrospinal fluid biomarkers is limited due to invasive collection by lumbar puncture with potential side effects. Plasma/serum measurements are the gold standard in clinics, because they are minimally invasive and, in consequence, easily collected and processed. The two main proteins implicated in the pathological process, Aβ and Tau, can be visualized using neuroimaging techniques, such as positron emission tomography. As it is currently accepted that AD starts decades before clinical symptoms could be diagnosed, the opportunity to detect biological alterations prior to clinical symptoms would allow early diagnosis or even perhaps change treatment possibilities.

Diagnostic accuracy of cerebrospinal fluid biomarkers measured by chemiluminescent enzyme immunoassay for Alzheimer disease diagnosis

In the last decades, an important role of cerebrospinal fluid (CSF) biomarkers for Alzheimer disease (AD) diagnosis has emerged. The evaluation of the triad consisting of 42 aminoacid-long amyloid-beta peptide (Aβ42), total Tau (tTau) and Tau phosphorylated at threonine 181 (pTau) have been recently integrated into the research diagnostic criteria of AD. For a long time, the enzyme-linked immunosorbent assay (ELISA) has represented the most commonly used method for the measurement of CSF biomarkers levels. This study aimed to assess the diagnostic accuracy of CSF biomarkers, namely Aβ42, tTau and pTau and their ratio, measured by fully automated CLEIA assay (Lumipulse). We included 96 patients clinically diagnosed as AD (48) and non-AD (48). All CSF biomarkers levels were measured on Lumipulse G1200 fully automated platform (Fujirebio Inc. Europe, Gent, Belgium). Aβ42 levels, 42/40 ratio, 42/tTau ratio, 42/PTau ratio were significantly reduced, and tTau and PTau levels were significantly increased in AD patients in comparison with non-AD patients. The receiving operator curve (ROC) analysis showed good diagnostic accuracy of all CSF biomarkers and their ratios for discriminating AD patients from non-AD patients, with 42/40 ratio having the best AUC (0.724, 95%CI 0.619–0.828; p < 0.001). Our findings support the use of CSF biomarkers measured by CLEIA method on a fully automated platform for AD diagnosis.

Diagnostic Impact of CSF Biomarkers in a Local Hospital Memory Clinic Revisited

Background/Aims: Research guidelines on predicting and diagnosing Alzheimer’s disease (AD) acknowledge cerebrospinal fluid (CSF) levels as pivotal biomarkers. We studied the usefulness of CSF biomarkers in the diagnostic workup of patients in a geriatric outpatient memory clinic of a community-based hospital, attempted to determine a cutoff age for the use of CSF biomarkers in this group of patients, and compared the total τ/Aβ ratio as an alternative CSF diagnostic rule with the usual rules for interpreting CSF levels. Methods: This was a prospective study of consecutively referred patients. Inclusion criteria were described on the basis of previous study results in the same setting. The CSF tool was applied either to differentiate between AD and no AD or to increase certainty having made the diagnosis of AD. Clinicians were asked to judge whether the CSF results were helpful to them or not. Results: The reasons to use the CSF tool in the diagnostic workup were in 78/106 patients to decide between the diagnosis “AD” and “no AD” and in 28/106 patients to increase the certainty regarding the diagnosis. In 75% of cases the CSF levels were considered diagnostically helpful to the clinicians. Results in the present setting suggest 65 years as the cutoff age to use CSF as a diagnostic tool. The sensitivity and specificity of the total τ/Aβ ratio using the clinical diagnosis as the gold standard were at least as good as the usual categorization rule. Conclusions: Our study results corroborate earlier findings that the CSF tool is of added value to the diagnostic workup in daily clinical practice outside tertiary referral centers. CSF levels can best be used in patients under 66 years of age. Given the limited use of this tool in settings outside research facilities, we recommend that the usefulness of CSF biomarkers is studied in a multicenter study. When in the future CSF levels can be reliably measured in plasma, this may become even more relevant.

Use of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Risk in Mild Cognitive Impairment and Subjective Cognitive Decline in Routine Clinical Care in Germany.

The National Institute of Aging and Alzheimer's Association's diagnostic recommendations for preclinical Alzheimer's disease (AD) and mild cognitive impairment (MCI) define AD by pathological processes which can be detected by biomarkers. These criteria were established as part of a research framework intended for research purposes but progressively enter the clinical practice. We investigated the availability, frequency of use, interpretation, and therapeutic implications of biomarkers for the etiologic diagnosis and prognosis in MCI and subjective cognitive decline (SCD) in routine clinical care. We conducted a cross-sectional questionnaire survey among 215 expert dementia centers (hospitals and memory clinics) in Germany. From the 98 centers (45.6% of contacted centers) included, two-thirds reported use of the cerebrospinal fluid (CSF) biomarkers Aβ42, tau, and phospho-tau in the diagnostic workup of MCI and one third in SCD. CSF biomarker analysis was more often employed by neurological (MCI 84%; SCD 42%) compared to psychiatric institutions (MCI 61%; SCD 33%; p≤0.001). Although dementia experts disagreed on the risk of progression associated with different CSF biomarker constellations, CSF biomarker results guided therapeutic decisions: ∼40% of responders reported to initiate cholinesterase inhibitor therapy in MCI and 18% in SCD (p = 0.006), given that all CSF biomarkers were in the pathological range. Considering the vast heterogeneity among dementia expert centers in use of CSF biomarker analysis, interpretation of results, and therapeutic consequences, a standardization of biomarker-based diagnosis practice in pre-dementia stages is needed.

Decision tree supports the interpretation of CSF biomarkers in Alzheimer's disease

IntroductionWe developed and validated a clinically applicable decision tree for the use of cerebrospinal fluid biomarkers in the diagnosis of Alzheimer's disease (AD). MethodsSubjects with probable AD (n = 1004) and controls (n = 442) were included. A decision tree was modeled using Classification And Regression Tree analysis in a training cohort (AD n = 221; controls n = 221) and validated in an independent cohort (AD n = 783; controls n = 221). Diagnostic performance was compared to previously defined cutoffs (amyloid β 1-42 < 813 pg/ml; tau>375 pg/ml). ResultsTwo cerebrospinal fluid AD biomarker profiles were revealed: the “classical” AD biomarker profile (amyloid β 1-42: 647-803 pg/ml; tau >374 pg/ml) and an “atypical” AD biomarker profile with strongly decreased amyloid β 1-42 (<647 pg/ml) and normal tau concentrations (<374 pg/ml). Compared to previous cutoffs, the decision tree performed better on diagnostic accuracy (86% [84-88] vs 80% [78-83]). DiscussionTwo cerebrospinal fluid AD biomarker profiles were identified and incorporated in a readily applicable decision tree, which improved diagnostic accuracy.

Cerebrospinal Fluid Biomarkers in Alzheimer's Disease: An Invaluable Tool for Clinical Diagnosis and Trial Enrichment.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting around 35 million people worldwide. Cerebrospinal fluid (CSF) biomarkers entered the diagnostic criteria as support for early diagnosis. The classical biochemical signature of AD includes total tau (T-tau), phosphorylated tau (P-tau), and the 42 amino acid peptide (Aβ42) of amyloid-β. Recent observations suggest that the use of CSF Aβ42:Aβ40 ratio rather than CSF Aβ42 alone could contribute to reduce inter-laboratory variation in Aβ values and increasing diagnostic performance of the CSF AD biomarkers in routine practice. However, research efforts aimed at enriching the CSF biomarker panel are ongoing. The CSF AD signature is also crucial for the design of clinical trials for AD, since it best guarantees AD pathology as the cause of cognitive impairment. Accordingly, CSF biomarkers have been now reported in the inclusion criteria of Phase I, Phase II, and Phase III clinical trials as enrichment strategy. So far, one of the most important reasons for the failure of AD clinical trials was the inclusion of participants with unlikely AD pathology. In order to implement the use of CSF biomarkers in AD routine diagnostic work-up and as accepted strategy for enriching trial populations, inter-laboratory variability should be minimized. Increasing efforts should also be devoted to promote data sharing practices, encouraging individual participant data meta-analyses.

Intensive Combination Immunotherapy and Neuroinflammation Resolution in a Child With Anti-PCA-1 (Yo) Paraneoplastic Syndrome and 2 Malignancies

Paraneoplastic cerebellar degeneration is rare and noteworthy in children. In this 7-year-old, it was documented to have occurred within a year of ataxia presentation. The instigating cancer was stage III adrenal adenocarcinoma, remitted after surgical resection at age 2. When her severe ataxia progressed, neuroinflammation was characterized by high cerebrospinal fluid Purkinje cell cytoplasmic antibody type 1 titers, oligoclonal bands, and neurofilament light chain. The immunotherapy strategy was to replace IV methylprednisolone, which lowered Purkinje cell cytoplasmic antibody type 1 titers without clinical improvement, with induction of adrenocorticotropic hormone/intravenous immunoglobulin/rituximab (ACTH/IVIG/rituximab) combination immunotherapy, ACTH/dexamethasone transition, and intravenous immunoglobulin maintenance. She became self-ambulatory and cerebrospinal fluid inflammatory markers regressed. Down syndrome predisposed her to a second cancer, pre-B acute lymphoblastic leukemia, 4 years later. Despite reversible cytosine arabinoside-provoked cerebellar toxicity, the ataxia is stable on monthly intravenous immunoglobulin without relapse, now 5 years after initial diagnosis. This report illustrates the use of cerebrospinal fluid biomarkers to detect, target, and monitor neuroinflammation, and successful combinations of immunotherapy to better the quality of life.

Concordance Between Different Amyloid Immunoassays and Visual Amyloid Positron Emission Tomographic Assessment

Visual assessment of amyloid positron emission tomographic (PET) images has been approved by regulatory authorities for clinical use. Several immunoassays have been developed to measure β-amyloid (Aβ) 42 in cerebrospinal fluid (CSF). The agreement between CSF Aβ42 measures from different immunoassays and visual PET readings may influence the use of CSF biomarkers and/or amyloid PET assessment in clinical practice and trials. To determine the concordance between CSF Aβ42 levels measured using 5 different immunoassays and visual amyloid PET analysis. The study included 262 patients with mild cognitive impairment or subjective cognitive decline from the Swedish BioFINDER (Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably) cohort (recruited from September 1, 2010, through December 31, 2014) who had undergone flutemetamol F 18 ([18F]flutemetamol)-labeled PET. Levels of CSF Aβ42 were analyzed using the classic INNOTEST and the newer modified INNOTEST, fully automated Lumipulse (FL), EUROIMMUN (EI), and Meso Scale Discovery (MSD) assays. Concentrations of CSF Aβ were assessed using an antibody-independent mass spectrometry-based reference measurement procedure. The concordance of CSF Aβ42 levels and Aβ42:Aβ40 and Aβ42:tau ratios with visual [18F]flutemetamol PET status. Of 262 participants (mean [SD] age, 70.9 [5.5] years), 108 were women (41.2%) and 154 were men (58.8%). The mass spectrometry-derived Aβ42 values showed higher correlations with the modified Aβ42-INNOTEST (r = 0.97), Aβ42-FL (r = 0.93), Aβ42-EI (r = 0.93), and Aβ42-MSD (r = 0.95) assays compared with the classic Aβ42-INNOTEST assay (r = 0.88; P ≤ .01). The signal in the classic Aβ42-INNOTEST assay was partly quenched by recombinant Aβ1-40 peptide. However, the classic Aβ42-INNOTEST assay showed better concordance with visual [18F]flutemetamol PET status (area under the receiver operating characteristic curve [AUC], 0.92) compared with the newer assays (AUCs, 0.87-0.89; P ≤ .01). The accuracies of the newer assays improved significantly when Aβ42:Aβ40 (AUCs, 0.93-0.95; P ≤ .01), Aβ42 to total tau (T-tau) (AUCs, 0.94; P ≤ .05), or Aβ42 to phosphorylated tau (P-tau) (AUCs, 0.94-0.95; P ≤ .001) ratios were used. A combination of the Aβ42:Aβ40 ratio and T-tau or P-tau level did not improve the accuracy compared with the ratio alone. Concentrations of CSF Aβ42 derived from the new immunoassays (modified INNOTEST, FL, EI, and MSD) may correlate better with the antibody-independent mass spectrometry-based reference measurement procedure and may show improved agreement with visual [18F]flutemetamol PET assessment when using the Aβ42:Aβ40 or Aβ42:tau ratios. These findings suggest the benefit of implementing the CSF Aβ42:Aβ40 or Aβ42:tau ratios as a biomarker of amyloid deposition in clinical practice and trials.

Current Approaches and Clinician Attitudes to the Use of Cerebrospinal Fluid Biomarkers in Diagnostic Evaluation of Dementia in Europe.

BIOMARKAPD seeks to diminish the barriers associated with the clinical use of cerebrospinal fluid (CSF) biomarker analysis by reducing variation in CSF laboratory methodologies and generating consensus recommendations on their clinical interpretation and application for dementia diagnosis. To examine the disparity in practitioner attitudes and clinical practice relating to the use of CSF biomarkers for dementia diagnosis across Europe. Clinical dementia experts were surveyed on the prevalence of national consensus guidelines and analytical reimbursement across Europe, their biomarker platform preferences, lumbar puncture methodologies and application of reference values and cut-offs for CSF analysis. 74% of respondents (total n = 51) use CSF biomarkers in clinical practice and 69% perform lumbar punctures on an outpatient basis. Most use CSF biomarkers to diagnose atypical (84%) and early-onset cases of cognitive impairment (71%) and for the differential diagnosis of other dementias (69%). 82% state they are sufficiently informed about CSF biomarkers yet 61% report a lack of national consensus guidelines on their use for dementia diagnosis. 48% of countries represented do not reimburse clinical CSF analysis costs. 43% report using normal reference ranges derived from publications. Variations in attitude and practice relating to CSF biomarkers, widely recognised as barriers to their clinical acceptance, remain evident within and between countries across Europe, even in expert centres. These shortcomings must be addressed by developing consensus guidelines on CSF-related methodologies and their clinical application, to further their use for the diagnostic evaluation of dementia.

The Clinical Use of Cerebrospinal Fluid Biomarkers for Alzheimer's Disease Diagnosis: The Italian Selfie.

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

Blood Biomarkers for Alzheimer's Disease: Much Promise, Cautious Progress.

Biomarkers in Alzheimer's disease (AD) have the potential to allow early and more accurate diagnosis, predict disease progression, stratify individuals and track response to candidate therapies in drug trials. The first fluid biomarkers reflecting aspects of AD neuropathology were identified in cerebrospinal fluid (CSF) in the 1990s. Three CSF biomarkers (amyloid-β 1-42, total tau and phospho-tau) have consistently been shown to have diagnostic utility and are incorporated into the new diagnostic criteria for AD. These markers have also been shown in longitudinal studies to predict conversion of mild cognitive impairment to AD. However, a key issue with the use of CSF biomarkers as a screening test is the invasiveness of lumbar puncture. Over the last 20years there has been an active quest for blood biomarkers, which could be easily acquired and tested repeatedly throughout the disease course. One approach to identifying such markers is to attempt to measure candidates that have already been identified in CSF. Until recently, this approach has been limited by assay sensitivity, but newer platforms now allow single molecule-level detection. Another approach is identification of candidates in large multiplex panels that allow for multiple analytes to be quantified in parallel. While both approaches show promise, to date no blood-based biomarker or combination of biomarkers has sufficient predictive value to have utility in clinical practice. In this review, an overview of promising blood protein candidates is provided, and the challenges of validating and converting these into practicable tests are discussed.

Cerebrospinal fluid tau and amyloid-β1-42 in patients with dementia.

Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-β1-42 and high levels of total tau and phosphorylated tau is typical of Alzheimer's disease. However, several neurodegenerative disorders may overlap with Alzheimer's disease both in regards to clinical symptoms and neuropathology. In a uniquely large cohort of dementia patients, we examined the associations of cerebrospinal fluid biomarkers for Alzheimer's disease molecular pathology with clinical dementia diagnoses and disease severity. We cross-referenced the Swedish Dementia Registry with the clinical laboratory database at the Sahlgrenska University Hospital. The final data set consisted of 5676 unique subjects with a clinical dementia diagnosis and a complete set of measurements for cerebrospinal fluid amyloid-β1-42, total tau and phosphorylated tau. In cluster analysis, disregarding clinical diagnosis, the optimal natural separation of this data set was into two clusters, with the majority of patients with early onset Alzheimer's disease (75%) and late onset Alzheimer's disease (73%) assigned to one cluster and the patients with vascular dementia (91%), frontotemporal dementia (94%), Parkinson's disease dementia (94%) and dementia with Lewy bodies (87%) to the other cluster. Frontotemporal dementia had the highest cerebrospinal fluid levels of amyloid-β1-42 and the lowest levels of total tau and phosphorylated tau. The highest levels of total tau and phosphorylated tau and the lowest levels of amyloid-β1-42 and amyloid-β1-42:phosphorylated tau ratios were found in Alzheimer's disease. Low amyloid-β1-42, high total tau and high phosphorylated tau correlated with low Mini-Mental State Examination scores in Alzheimer's disease. In Parkinson's disease dementia and vascular dementia low cerebrospinal fluid amyloid-β1-42 was associated with low Mini-Mental State Examination score. In the vascular dementia, frontotemporal dementia, dementia with Lewy bodies and Parkinson's disease dementia groups 53%, 34%, 67% and 53% of the subjects, respectively had abnormal amyloid-β1-42 levels, 41%, 41%, 28% and 28% had abnormal total tau levels, and 29%, 28%, 25% and 19% had abnormal phosphorylated tau levels. Cerebrospinal fluid biomarkers were strongly associated with specific clinical dementia diagnoses with Alzheimer's disease and frontotemporal dementia showing the greatest difference in biomarker levels. In addition, cerebrospinal fluid amyloid-β1-42, total tau, phosphorylated tau and the amyloid-β1-42:phosphorylated tau ratio all correlated with poor cognitive performance in Alzheimer's disease, as did cerebrospinal fluid amyloid-β1-42 in Parkinson's disease dementia and vascular dementia. The results support the use of cerebrospinal fluid biomarkers to differentiate between dementias in clinical practice, and to estimate disease severity.

Cerebrospinal Fluid Biomarkers in Spinocerebellar Ataxia: A Pilot Study.

Neurodegenerative diseases, including the spinocerebellar ataxias (SCA), would benefit from the identification of reliable biomarkers that could serve as disease subtype-specific and stage-specific indicators for the development and monitoring of treatments. We analyzed the cerebrospinal fluid (CSF) level of tau, α-synuclein, DJ-1, and glial fibrillary acidic protein (GFAP), proteins previously associated with neurodegenerative processes, in patients with the autosomal dominant SCA1, SCA2, and SCA6, and the sporadic disease multiple system atrophy, cerebellar type (MSA-C), compared with age-matched controls. We estimated disease severity using the Scale for the Assessment and Rating of Ataxia (SARA). Most proteins measured trended higher in disease versus control group yet did not reach statistical significance. We found the levels of tau in both SCA2 and MSA-C patients were significantly higher than control. We found that α-synuclein levels were lower with higher SARA scores in SCA1 and tau levels were higher with greater SARA in MSA-C, although this final correlation did not reach statistical significance after post hoc correction. Additional studies with larger sample sizes are needed to improve the power of these studies and validate the use of CSF biomarkers in SCA and MSA-C.

Biomarcadores en la enfermedad de Alzheimer

The new diagnostic criteria for Alzheimer's disease (AD) include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. Three CSF biomarkers, Aß42, total tau, and phosphorylated tau, reflect the core pathological features of AD. It is already known that these pathological processes of AD starts decades before the first symptoms, so these biomarkers may provide means of early disease detection. At least three stages of AD could be identified: preclinical AD, mild cognitive impairment due to AD, and dementia due to AD. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review the actual research on blood-based biomarkers. Recent studies on healthy elderly subjects and on carriers of dominantly inherited AD mutations have also found biomarker changes that allow separate groups in these preclinical stages. These studies may aid for segregate populations in clinical trials and objectively evaluate if there are changes over the pathological processes of AD. Limits to widespread use of CSF biomarkers, apart from the invasive nature of the process itself, is the higher coefficient of variation for the analyses between centres. It requires strict pre-analytical and analytical procedures that may make feasible multi-centre studies and global cut-off points for the different stages of AD.

Latin American Experience with Alzheimer's Disease Cerebrospinal Fluid Biomarkers

Fil: Surace, Ezequiel Ignacio. Fundacion para la Lucha Contra las Enfermedades Neurologicas de la Infancia. Instituto de Investigaciones Neurologicas "Raul Carrea"; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas; Argentina

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

Background: The mechanism underlying disease progression in progressive multiple sclerosis (MS) is uncertain. Pathological studies found widespread inflammation in progressive MS brains correlating with disease progression and axonal damage. Objectives: To study cerebrospinal fluid (CSF) biomarkers and clarify whether inflammation and axonal damage are associated in progressive MS. Methods: Using enzyme-linked immunosorbent assay (ELISA), we analysed CSF from 40 secondary progressive (SPMS), 21 primary progressive (PPMS), and 36 relapsing–remitting (RRMS) and 20 non-inflammatory neurological disease (NIND) patients. Twenty-two of the SPMS patients participated in an MBP8298 peptide clinical trial and had CSF follow-up after one year. Results: Compared to NIND patients, inflammatory biomarkers osteopontin and matrix metalloproteinase-9 (MMP9) were increased in all MS patients while CXCL13 was increased in RRMS and SPMS patients. Biomarkers of axonal damage (NFL) and demyelination (MBP) were increased in all MS patients. In progressive MS patients CSF levels of osteopontin and CXCL13 correlated with NFL while osteopontin and MMP9 correlated with MBP. MBP8298 treatment did not affect the levels of the biomarkers after one year of treatment. All biomarkers were continuously increased after one year of follow-up except MBP, which decreased. Conclusion: CSF biomarkers of inflammation, axonal damage and demyelination are continuously increased in progressive MS patients and correlate. These findings parallel pathology studies, emphasise a relationship between inflammation, axonal damage and demyelination and support the use of CSF biomarkers in progressive MS clinical trials.