High levels of neurofilament light and YKL-40 in cerebrospinal fluid are related to poor outcome in ALS.

Amyotrophic lateral sclerosis (ALS) is a neurological disease without effective treatment. No pathognomonic test can diagnose ALS in sporadic cases. Routine investigation in suspected cases includes neurological examination, imaging of the brain and spine and electromyography supported by blood and cerebrospinal fluid (CSF) analyses. The ALS diagnosis is made by clinical judgement and results from examinations. We aimed to study if the CSF biomarkers neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), YKL-40, soluble amyloid precursor protein (sAPP) α and ß, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) were associated with ALS diagnosis and could predict disease progression. Eighty-one patients with suspected ALS were included after referral to the neurological clinic at Sahlgrenska University Hospital. Fifty-nine patients were diagnosed having ALS, while 22 patients were given alternative diagnoses and labeled ALS mimics. Finally, 25 age-matched neurologically intact individuals were used as controls. ALS patients had significantly higher CSF levels of NFL than controls and mimics. Levels of YKL-40 and GFAP were significantly higher in ALS patients compared with controls. No difference was found between study groups when comparing levels of sAPPα, sAPPß and sTREM2. Further, elevated levels of NFL and YKL-40 were associated with an increased hazard of death and the annual decline in ALSFRS-R. We also found that patients with elevated levels of both NFL and YKL-40 had a particularly poor prognosis. The results demonstrate the usefulness of CSF biomarkers in the diagnosis and prognostication of ALS.

CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis.

BACKGROUND: Alzheimer's disease biomarkers are important for early diagnosis in routine clinical practice and research. Three core CSF biomarkers for the diagnosis of Alzheimer's disease (Aß42, T-tau, and P-tau) have been assessed in numerous studies, and several other Alzheimer's disease markers are emerging in the literature. However, there have been no comprehensive meta-analyses of their diagnostic performance. We systematically reviewed the literature for 15 biomarkers in both CSF and blood to assess which of these were most altered in Alzheimer's disease. METHODS: In this systematic review and meta-analysis, we screened PubMed and Web of Science for articles published between July 1, 1984, and June 30, 2014, about CSF and blood biomarkers reflecting neurodegeneration (T-tau, NFL, NSE, VLP-1, and HFABP), APP metabolism (Aß42, Aß40, Aß38, sAPPα, and sAPPß), tangle pathology (P-tau), blood-brain-barrier function (albumin ratio), and glial activation (YKL-40, MCP-1, and GFAP). Data were taken from cross-sectional cohort studies as well as from baseline measurements in longitudinal studies with clinical follow-up. Articles were excluded if they did not contain a cohort with Alzheimer's disease and a control cohort, or a cohort with mild cognitive impairment due to Alzheimer's disease and a stable mild cognitive impairment cohort. Data were extracted by ten authors and checked by two for accuracy. For quality assessment, modified QUADAS criteria were used. Biomarker performance was rated by random-effects meta-analysis based on the ratio between biomarker concentration in patients with Alzheimer's disease and controls (fold change) or the ratio between biomarker concentration in those with mild cognitive impariment due to Alzheimer's disease and those with stable mild cognitive impairment who had a follow-up time of at least 2 years and no further cognitive decline. FINDINGS: Of 4521 records identified from PubMed and 624 from Web of Science, 231 articles comprising 15 699 patients with Alzheimer's disease and 13 018 controls were included in this analysis. The core biomarkers differentiated Alzheimer's disease from controls with good performance: CSF T-tau (average ratio 2·54, 95% CI 2·44-2·64, p<0·0001), P-tau (1·88, 1·79-1·97, p<0·0001), and Aß42 (0·56, 0·55-0·58, p<0·0001). Differentiation between cohorts with mild cognitive impairment due to Alzheimer's disease and those with stable mild cognitive impairment was also strong (average ratio 0·67 for CSF Aß42, 1·72 for P-tau, and 1·76 for T-tau). Furthermore, CSF NFL (2·35, 1·90-2·91, p<0·0001) and plasma T-tau (1·95, 1·12-3·38, p=0·02) had large effect sizes when differentiating between controls and patients with Alzheimer's disease, whereas those of CSF NSE, VLP-1, HFABP, and YKL-40 were moderate (average ratios 1·28-1·47). Other assessed biomarkers had only marginal effect sizes or did not differentiate between control and patient samples. INTERPRETATION: The core CSF biomarkers of neurodegeneration (T-tau, P-tau, and Aß42), CSF NFL, and plasma T-tau were strongly associated with Alzheimer's disease and the core biomarkers were strongly associated with mild cognitive impairment due to Alzheimer's disease. Emerging CSF biomarkers NSE, VLP-1, HFABP, and YKL-40 were moderately associated with Alzheimer's disease, whereas plasma Aß42 and Aß40 were not. Due to their consistency, T-tau, P-tau, Aß42, and NFL in CSF should be used in clinical practice and clinical research. FUNDING: Swedish Research Council, Swedish State Support for Clinical Research, Alzheimer's Association, Knut and Alice Wallenberg Foundation, Torsten Söderberg Foundation, Alzheimer Foundation (Sweden), European Research Council, and Biomedical Research Forum.

Cerebrospinal fluid tau and amyloid-ß1-42 in patients with dementia.

Progressive cognitive decline in combination with a cerebrospinal fluid biomarker pattern of low levels of amyloid-ß1-42 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-ß1-42, 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-ß1-42 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-ß1-42 and amyloid-ß1-42:phosphorylated tau ratios were found in Alzheimer's disease. Low amyloid-ß1-42, 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-ß1-42 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-ß1-42 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-ß1-42, total tau, phosphorylated tau and the amyloid-ß1-42:phosphorylated tau ratio all correlated with poor cognitive performance in Alzheimer's disease, as did cerebrospinal fluid amyloid-ß1-42 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.

Benchmarking biomarker-based criteria for Alzheimer's disease: Data from the Swedish Dementia Registry, SveDem.

INTRODUCTION: New research guidelines for the diagnosis of Alzheimer's disease (AD) include biomarker evidence of amyloid-ß (Aß) and tau pathology. The aim of this study was to investigate what proportion of AD patients diagnosed in clinical routine in Sweden that had an AD-indicative cerebrospinal fluid (CSF) biomarker profile. METHODS: By cross-referencing a laboratory database with the Swedish Dementia Registry (SveDem), 2357 patients with data on CSF Aß and tau biomarkers and a clinical diagnosis of AD with dementia were acquired. RESULTS: Altogether, 77.2% had pathologic Aß42 and total tau or phosphorylated tau in CSF. These results were stable across age groups. Female sex and low mini-mental state examination score increased the likelihood of pathologic biomarkers. DISCUSSION: About a quarter of clinically diagnosed AD patients did not have an AD-indicative CSF biomarker profile. This discrepancy may partly reflect incorrect (false positive) clinical diagnosis or a lack in sensitivity of the biomarker assays.

CSF neurofilament light differs in neurodegenerative diseases and predicts severity and survival.

OBJECTIVES: We hypothesized that CSF neurofilament light (NFL) levels would be elevated in dementias with subcortical involvement, including vascular dementia (VaD), but less elevated in dementias primarily affecting gray matter structures, such as Alzheimer disease (AD), and that elevated CSF NFL would correlate with disease severity and shorter survival time irrespective of clinical diagnosis. METHODS: We included 3,356 individuals with dementia who had CSF NFL analyzed in our laboratory between 2005 and 2012. Clinical diagnoses and Mini-Mental State Examination (MMSE) scores were obtained from the Swedish Dementia Registry, and in selected cases (n = 478), date of death from the Swedish Mortality Registry. RESULTS: CSF NFL differed among clinical diagnoses, with the highest levels seen in frontotemporal dementia, VaD, and mixed AD and VaD. Early-onset AD (younger than 65 years) had the lowest levels. High CSF NFL correlated with low MMSE score and short survival time irrespective of diagnosis, and was also particularly evident in AD. CONCLUSIONS: CSF NFL differs among different neurodegenerative diseases and is especially high in dementias engaging subcortical brain regions, such as VaD and mixed AD and VaD, but also in frontotemporal dementia. The association of high CSF NFL levels with disease severity and short survival supports the notion that high CSF NFL levels indicate more aggressive disease processes.

Increased Levels of Chitotriosidase and YKL-40 in Cerebrospinal Fluid from Patients with Alzheimer's Disease.

BACKGROUND: The cerebrospinal fluid (CSF) biomarkers total tau, abnormally phosphorylated tau and amyloid ß 1-42 are strongly associated with Alzheimer's disease (AD). Apart from the pathologic hallmarks that these biomarkers represent, other processes such as inflammation and microglial activation are present in the brains of patients with AD. New biomarkers related to these processes could be valuable for the diagnosis and follow-up of AD patients and for the evaluation of inflammation-related pathologies. AIM: The aim of this study was to evaluate the association of inflammatory CSF biomarkers with AD. METHODS: Twenty-five AD patients and 25 controls who had a pathological and normal CSF profile of the core AD biomarkers, respectively, were included in this study. CSF levels of chitotriosidase, YKL-40 (also known as chitinase-3-like protein 1) and monocyte chemoattractant protein-1 (MCP-1) were quantified and the levels compared between the groups. RESULTS: AD patients had increased CSF levels of chitotriosidase and YKL-40 (both approximately twice higher than in controls), while the levels of MCP-1 were similar in the AD and control groups. CONCLUSION: The results indicate that chitotriosidase and YKL-40 may be helpful for the evaluation of cerebral inflammatory activity in AD patients.

CSF in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive brain amyloidosis that injures brain regions involved in memory consolidation and other cognitive functions. Neuropathologically, the disease is characterized by accumulation of a 42-amino acid protein called amyloid beta, and N-terminally truncated fragments thereof, in extracellular senile plaques together with intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles, and neuronal and axonal degeneration and loss. Clinical chemistry tests for these pathologies have been developed for use on cerebrospinal fluid samples. Here, we review what these markers have taught us on the disease process in AD and how they can be implemented in routine clinical chemistry. We also provide an update on new marker development and ongoing analytical standardization effort.

Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish Mortality Registry.

IMPORTANCE: Identifying a clinical distinction between the invariably lethal prion disease Creutzfeldt-Jakob disease (CJD) and nonprion rapidly progressive dementias is important and sometimes difficult; thus, reliable tools for diagnosis are in great demand. OBJECTIVE: To test the diagnostic performance of dementia cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phosphorylated tau (P-tau), and the T-tau to P-tau ratio for CJD by analyzing the results from a large database of routine clinical samples in combination with diagnosis information from the Swedish Mortality Registry. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study. We cross-referenced the Swedish Mortality Registry with a data set of CSF measurements of T-tau and P-tau performed in routine clinical testing at the Clinical Neurochemistry Laboratory of the Sahlgrenska University Hospital, which serves most of Sweden. The data set consisted of 9765 deceased individuals with CSF measures, including 93 with CJD, with 52 autopsy-verified samples (56%). MAIN OUTCOMES AND MEASURES: For each patient, T-tau and P-tau levels in CSF were measured and the T-tau to P-tau ratio was calculated. Biomarker levels (adjusted for age and sex) were analyzed in relation to the recorded cause of death and time of death. We specifically tested a previously defined CJD biomarker profile (T-tau >1400 ng/L and T-tau to P-tau-ratio >25). RESULTS: Patients who died of CJD had elevated CSF T-tau levels and T-tau to P-tau ratio, but not elevated CSF P-tau levels, compared with patients who died of Alzheimer disease (AD) and other dementias. The previously defined biomarker profile had a specificity of 99.0%, a sensitivity of 78.5%, and a positive likelihood ratio of 79.9. When tested against common differential diagnoses, the sensitivity, specificity, and positive likelihood ratio of this profile was 78.5%, 99.6%, and 196.6, respectively, in relation to AD and 78.5%, 99.3%, and 109.3, respectively, in relation to other dementias. In CJD individuals (n = 30) with repeated measurements, but not in those with AD (n = 242) or other dementias (n = 258), T-tau levels and T-tau to P-tau ratios increased over time. CONCLUSIONS AND RELEVANCE: In this routine clinical setting, the combination of increased T-tau levels and increased T-tau to P-tau ratios in CJD patients has a very high specificity against important differential diagnoses to CJD and may serve as a clinically useful diagnostic test.

Cerebrospinal fluid biomarkers in cardiac arrest survivors.

AIM: The aim of this study was to investigate the levels of various cerebrospinal fluid (CSF) biomarkers related to neuronal damage, inflammation and amyloid ß (Aß) metabolism in patients resuscitated after an out-of-hospital cardiac arrest (CA). METHODS: CSF levels of neurofilament light protein (NFL), total tau (T-tau), hyperphosphorylated tau (P-tau), YKL-40, Aß38, Aß40, Aß42, soluble amyloid precursor protein α and ß (sAPPα and sAPPß) were measured in 21 patients approximately two weeks after CA and in 21 age-matched neurologically healthy controls. The biomarker levels were also compared between patients with good and poor long-term clinical outcome according to Glasgow Outcome Scale (GOS), activities of daily living (ADL) and mini-mental state examination (MMSE), measuring neurologic function, daily functioning and cognitive function, respectively. RESULTS: Patients with CA had a very marked increase in the CSF levels of NFL, T-tau and YKL-40 as compared with controls. The levels were increased at about 1200, 700 and 100%, respectively. NFL and T-tau were significantly higher in patients with poor outcome according to all three outcome measures. Patients with poor outcome according to GOS and ADL had higher levels of YKL-40. Levels of Aß38, Aß40, Aß42, sAPPα and sAPPß were lower in patients with a low MMSE score. P-tau was not significantly altered. CONCLUSIONS: Biomarkers reflecting neuronal damage and inflammation, but not so much Aß metabolism, were significantly altered in patients after a CA, and the changes were more pronounced in the groups with poor outcome. This calls for future larger studies to determine the prognostic potential of these biomarkers.

Fluid biomarkers in Alzheimer's disease - current concepts.

The diagnostic guidelines of Alzheimer's disease (AD) have recently been updated to 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. The CSF biomarkers total tau (T-tau), hyperphosphorylated tau (P-tau) and the 42 amino acid isoform of amyloid ß (Aß42) reflect the core pathologic features of AD, which are neuronal loss, intracellular neurofibrillary tangles and extracellular senile plaques. Since the pathologic processes of AD start decades before the first symptoms, these biomarkers may provide means of early disease detection. The updated guidelines identify three different stages of AD: preclinical AD, mild cognitive impairment (MCI) due to AD and AD with dementia. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review results from blood biomarker studies. In summary, the core AD CSF biomarkers have high diagnostic accuracy both for AD with dementia and to predict incipient AD (MCI due to AD). Longitudinal studies on healthy elderly and recent cross-sectional studies on patients with dominantly inherited AD mutations have also found biomarker changes in cognitively normal at-risk individuals. This will be important if disease-modifying treatment becomes available, given that treatment will probably be most effective early in the disease. An important prerequisite for this is trustworthy analyses. Since measurements vary between studies and laboratories, standardization of analytical as well as pre-analytical procedures will be essential. This process is already initiated. Apart from filling diagnostic roles, biomarkers may also be utilized for prognosis, disease progression, development of new treatments, monitoring treatment effects and for increasing the knowledge about pathologic processes coupled to the disease. Hence, the search for new biomarkers continues. Several candidate biomarkers have been found in CSF, and although biomarkers in blood have been harder to find, some recent studies have presented encouraging results. But before drawing any major conclusions, these results need to be verified in independent studies.

Cerebrospinal fluid biomarkers for pathological processes in Alzheimer's disease.

PURPOSE OF REVIEW: To review the rationale behind and the use of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD). Established as well as new candidate biomarkers will be covered. RECENT FINDINGS: AD is a complex disorder and the AD brain is characterized by multiple pathological processes, in addition to well-described plaque and tangle diseases. Recent studies have tried to address this by evaluating biomarkers related to features such as neuroinflammation, oxidative stress, microglial activation and synaptic degeneration, with some positive results. SUMMARY: The CSF biomarkers total tau, phosphorylated-tau and the 42 amino acid isoform of amyloid beta reflect core elements of AD, that is, axonal degeneration, tangle disease and senile plaques, have been thoroughly tested and provide high diagnostic accuracy in the discrimination of patients with AD as compared with cognitively normal controls. They are also highly predictive of AD with dementia in patients with mild cognitive impairment, and have been included in new diagnostic criteria. New biomarkers may add to their diagnostic performance. Other potential fields of use include the monitoring of disease progression or pharmacodynamic drug effects. A common denominator for the candidate biomarkers is the need for validation in further studies to clarify their potential.

Cerebrospinal fluid profiles of amyloid ß-related biomarkers in Alzheimer's disease.

The amyloid cascade hypothesis on the pathogenesis of Alzheimer's disease (AD) states that amyloid ß (Aß) accumulation in the brain is a key factor that initiates the neurodegenerative process. Aß is generated from amyloid precursor protein (APP) through sequential cleavages by BACE1 (the major ß-secretase in the brain) and γ-secretase. The purpose of this study was to characterize APP metabolism in vivo in AD patients versus cognitively healthy subjects by examining alterations in cerebrospinal fluid (CSF) biomarkers. We measured BACE1 activity and concentrations of α- and ß-cleaved soluble APP (sAPPα and sAPPß, respectively) and Aß40 in CSF, biomarkers that all reflect the metabolism of APP, in 75 AD patients and 65 cognitively healthy controls. These analytes were also applied in a multivariate model to determine whether they provided any added diagnostic value to the core CSF AD biomarkers Aß42, T-tau, and P-tau. We found no significant differences in BACE1 activity or sAPPα, sAPPß, and Aß40 concentrations between AD patients and controls. A multivariate model created with all analytes did not improve the separation of AD patients from controls compared with using the core AD biomarkers alone, highlighting the strong diagnostic performance of Aß42, T-tau, and P-tau for AD. However, AD patients in advanced clinical stage, as determined by low MMSE score (≤20), had lower BACE1 activity and sAPPα, sAPPß, and Aß40 concentrations than patients with higher MMSE score, suggesting that these markers may be related to the severity of the disease.

Discriminatory Analysis of Biochip-Derived Protein Patterns in CSF and Plasma in Neurodegenerative Diseases.

The role of biomarkers in neurodegenerative diseases has been emphasized by recent research. Future clinical demands for identifying diseases at an early stage may render them essential. The aim of this pilot study was to test the analytical performance of two multiplex assays of cerebral markers on a well-defined clinical material consisting of patients with various neurodegenerative diseases. We measured 10 analytes in plasma and cerebrospinal fluid (CSF) from 60 patients suffering from Alzheimer's disease (AD), vascular dementia, frontotemporal dementia, dementia with Lewy bodies, or mild cognitive impairment, as well as 20 cognitively healthy controls. We used the Randox biochip-based Evidence Investigator™ system to measure the analytes. We found it possible to measure most analytes in both plasma and CSF, and there were some interesting differences between the diagnostic groups, although with large overlaps. CSF heart-type fatty acid-binding protein was increased in AD. Glial fibrillary acidic protein and neutrophil gelatinase-associated lipocalin in CSF and D-dimer in plasma were elevated in patients with cerebrovascular disease. A multivariate statistical analysis revealed that the pattern of analytes could help to differentiate the conditions, although more studies are required to verify this.