Dynamics of Selected Biomarkers in Cerebrospinal Fluid During Complex Endovascular Aortic Repair - A Pilot Study.

INTRODUCTION: Ischemic spinal cord injury (SCI) is a serious complication of complex aortic repair. Prophylactic cerebrospinal fluid (CSF) drainage, used to decrease lumbar cerebrospinal fluid (CSF) pressure, enables monitoring of CSF biomarkers that may aid in detecting impending SCI. We hypothesized that biomarkers, previously evaluated in traumatic SCI and brain injury, would be altered in CSF over time following complex endovascular aortic repair (cEVAR). OBJECTIVES: To examine if a chosen cohort of CSF biomarker correlates to SCI and warrants further research. METHODS: A prospective observational study on patients undergoing cEVAR with extensive aortic coverage. Vital parameters and CSF samples were collected on ten occasions during 72 hours post-surgery. A panel of ten biomarkers were analyzed (Neurofilament Light Polypeptide (NFL), Tau, Glial Fibrillary Acidic Protein (GFAP), Soluble Amyloid Precursos Protein (APP) α and ß, Amyloid ß 38, 40 and 42 (Aß38, 40 and 42), Chitinase-3-like protein 1 (CHI3LI or YKL-40), Heart-type fatty acid binding protein (H-FABP).). RESULTS: Nine patients (mean age 69, 7 males) were included. Median total aortic coverage was 68% [33, 98]. One patient died during the 30-day post-operative period. After an initial stable phase for the first few postoperative hours, most biomarkers showed an upward trend compared with baseline in all patients with >50% increase in value for NFL in 5/9 patients, in 7/9 patients for Tau and in 5/9 patients for GFAP. One patient developed spinal cord and supratentorial brain ischemia, confirmed with MRI. In this case, NF-L, GFAP and tau were markedly elevated compared with non-SCI patients (maximum increase compared with baseline in the SCI patient versus mean value of the maximal increase for all other patients: NF-L 367% vs 79%%, GFAP 95608% versus 3433%, tau 1020% vs 192%). CONCLUSION: This study suggests an increase in all ten studied CSF biomarkers after coverage of spinal arteries during endovascular aortic repair. However, the pilot study was not able to establish a specific correlation between spinal fluid biomarker elevation and clinical symptoms of SCI due to small sample size and event rate.

Applying fluid biomarkers to Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disease that starts with a clinically silent phase of a decade or more during which brain pathologies accumulate predominantly in the medial temporal lobe but also elsewhere in the brain. Network dysfunction and clinical symptoms typically appear when senile plaque (amyloid-ß) and neurofibrillary tangle (tau) pathologies meet in the brain parenchyma, producing synapse and neuronal loss. For plaque and tangle pathologies, reliable fluid biomarkers have been developed. These require sampling of cerebrospinal fluid. Reliable blood tests for plaque and tangle pathologies are currently lacking, but blood tests for general neurodegeneration have recently been developed. In AD, plaques and tangles often coexist with other pathologies, including Lewy bodies, and to what extent these contribute to symptoms is currently unknown. There are also important differential diagnoses that may be possible to distinguish from AD with the aid of biomarkers. The scope of this review is fluid biomarkers for AD and related pathologies. The purpose is to provide the reader with an updated account of currently available fluid biomarkers for AD and clinically relevant differential diagnoses.

Cerebrospinal Fluid Fatty Acid-Binding Protein 3 is Related to Dementia Development in a Population-Based Sample of Older Adult Women Followed for 8 Years.

BACKGROUND: Increased fatty acid-binding protein 3 (FABP-3) levels have been reported in neurodegenerative diseases, including Alzheimer's disease (AD). Cerebrospinal fluid (CSF) FABP-3 has therefore been proposed as a putative marker for dementia. Population-based studies examining whether CSF FABP-3 predicts later development of dementia are lacking. OBJECTIVE: The aim of this study was to examine CSF levels of FABP-3 in relation to later development of dementia in elderly women and in relation to Aß42, T-tau, P-tau181, and CSF: serum albumin ratio. METHODS: 86 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-93. CSF-FABP-3, Aß42, T-tau, P-tau181, and the CSF: serum albumin ratio were measured at baseline. Participants were examined with a neuropsychiatric exam at baseline and at follow-up in 2000. Dementia was diagnosed in accordance with DSM-III-R criteria. RESULTS: Between 1992 and 2000, 8 women developed dementia (4 AD, 3 vascular dementia, 1 mixed vascular dementia and AD). Higher levels of CSF-FABP-3 at baseline were related to development of dementia (OR 1.36 CI [1.05-1.76] p = 0.022) and the subtype AD (OR 1.38 CI [1.06-1.82), p = 0.019) during follow-up. FABP-3 correlated with CSF T-tau (r = 0.88, p <  0.001), P-tau181 (r = 0.619, p <  0.001), and CSF:serum albumin ratio (r = 0.233, p = 0.031), but not with Aß42 (r = -0.08, p = 0.444)CONCLUSION:CSF FABP-3 may be an early marker for later development of dementia, probably related to neuronal degeneration, but independent of Aß metabolism.

Elevated concentrations of neurofilament light chain in the cerebrospinal fluid of bipolar disorder patients.

Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.

Phosphorylated tau-Aß42 ratio as a continuous trait for biomarker discovery for early-stage Alzheimer's disease in multiplex immunoassay panels of cerebrospinal fluid.

BACKGROUND: Identification of the physiologic changes that occur during the early stages of Alzheimer's disease (AD) may provide critical insights for the diagnosis, prognosis, and treatment of disease. Cerebrospinal fluid (CSF) biomarkers are a rich source of information that reflect the brain proteome. METHODS: A novel approach was applied to screen a panel of ~190 CSF analytes quantified by multiplex immunoassay, and common associations were detected in the Knight Alzheimer's Disease Research Center (N = 311) and the Alzheimer's Disease Neuroimaging Initiative (N = 293) cohorts. Rather than case-control status, the ratio of CSF levels of tau phosphorylated at threonine 181 (ptau181) and Aß42 was used as a continuous trait in these analyses. RESULTS: The ptau181-Aß42 ratio has more statistical power than traditional modeling approaches, and the levels of CSF heart-type fatty acid binding protein (FABP) and 12 other correlated analytes increase as AD progresses. These results were validated using the traditional case-control status model. Stratification of the dataset demonstrated that increases in these analytes occur very early in the disease course and were apparent even in nondemented individuals with AD pathology (low ptau181, low Aß42) compared with elderly control subjects with no pathology (low ptau181, high Aß42). The FABP-Aß42 ratio demonstrates a similar hazard ratio for disease conversion to ptau181-Aß42 even though the overlap in classification is incomplete suggesting that FABP contributes independent information as a predictor of AD. CONCLUSIONS: Our results indicate that the approach presented here can be used to identify novel biomarkers for AD correctly and that CSF heart FABP levels start to increase at very early stages of AD.

Heart fatty acid binding protein and Aß-associated Alzheimer's neurodegeneration.

BACKGROUND: Epidemiological and molecular findings suggest a relationship between Alzheimer's disease (AD) and dyslipidemia, although the nature of this association is not well understood. RESULTS: Using linear mixed effects models, we investigated the relationship between CSF levels of heart fatty acid binding protein (HFABP), a lipid binding protein involved with fatty acid metabolism and lipid transport, amyloid-ß (Aß), phospho-tau, and longitudinal MRI-based measures of brain atrophy among 295 non-demented and demented older individuals. Across all participants, we found a significant association of CSF HFABP with longitudinal atrophy of the entorhinal cortex and other AD-vulnerable neuroanatomic regions. However, we found that the relationship between CSF HABP and brain atrophy was significant only among those with low CSF Aß1-42 and occurred irrespective of phospho-tau181p status. CONCLUSIONS: Our findings indicate that Aß-associated volume loss occurs in the presence of elevated HFABP irrespective of phospho-tau. This implicates a potentially important role for fatty acid binding proteins in Alzheimer's disease neurodegeneration.

Heart-fatty acid-binding and tau proteins relate to brain injury severity and long-term outcome in subarachnoid haemorrhage patients.

BACKGROUND: Vasospasm and other secondary neurological insults may follow subarachnoid haemorrhage (SAH). Biomarkers have the potential to stratify patient risk and perhaps serve as an early warning sign of delayed ischaemic injury. METHODS: Serial cerebrospinal fluid (CSF) samples were collected from 38 consecutive patients with aneurysmal SAH admitted to the neurosurgical intensive care unit. We measured heart-fatty acid-binding protein (H-FABP) and tau protein (τ) levels in the CSF to evaluate their association with brain damage, and their potential as predictors of the long-term outcome. H-FABP and τ were analysed in relation to acute clinical status, assessed by the World Federation of Neurological Surgeons (WFNS) scale, radiological findings, clinical vasospasm, and 6-month outcome. RESULTS: H-FABP and τ increased after SAH. H-FABP and τ were higher in patients in poor clinical status on admission (WFNS 4-5) compared with milder patients (WFNS 1-3). Elevated H-FABP and τ levels were also observed in patients with early cerebral ischaemia, defined as a CT scan hypodense lesion visible within the first 3 days after SAH. After the acute phase, H-FABP, and τ showed a delayed increase with the occurrence of clinical vasospasm. Finally, patients with the unfavourable outcome (death, vegetative state, or severe disability) had higher peak levels of both proteins compared with patients with good recovery or moderate disability. CONCLUSIONS: H-FABP and τ show promise as biomarkers of brain injury after SAH. They may help to identify the occurrence of vasospasm and predict the long-term outcome.

Heart-type fatty acid binding protein and vascular endothelial growth factor: cerebrospinal fluid biomarker candidates for Alzheimer's disease.

The main objective of the study was to validate the findings of previous cerebrospinal fluid (CSF) proteomic studies for the differentiation between Alzheimer's disease (AD) dementia and physiological ageing. The most consistently significant proteins in the separation between AD dementia versus normal controls using CSF proteomics were identified in the literature. The classification performance of the four pre-selected proteins was explored in 92 controls, 149 patients with mild cognitive impairment (MCI), and 69 patients with AD dementia. Heart-type fatty acid binding protein (hFABP) and vascular endothelial growth factor (VEGF) CSF concentrations distinguished between healthy controls and patients with AD dementia with a sensitivity and specificity of 57 and 35%, and 76 and 84%, respectively. The optimal classification was achieved by a combination of the two additional CSF biomarker candidates in conjunction with the three established markers Amyloid-ß (Aß)1-42, total-Tau (tTau), and phosphorylated-Tau (pTau)181, which resulted in a sensitivity of 83% and a specificity of 86%. hFABP also predicted the progression from MCI to AD dementia. The present study provides evidence in support of hFABP and VEGF in CSF as AD biomarker candidates to be used in combination with the established markers Aß1-42, tTau, and pTau181.

Cerebrospinal fluid levels of heart fatty acid binding protein are elevated prodromally in Alzheimer's disease and vascular dementia.

Heart fatty acid binding protein (HFABP) is expressed in the brain and is elevated in cerebrospinal fluid (CSF) from patients with several forms of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease with dementia, Lewy body dementia, vascular dementia (VaD), and Creutzfeldt-Jakob disease. However, whether HFABP in CSF is a stable biomarker or if it can help predict conversion from mild cognitive impairment (MCI) to AD or VaD has not been well studied. To address the role of HFABP in neurodegeneration, we analyzed CSF levels of HFABP in 96 AD patients and 65 controls and also in 170 patients with MCI with an average follow up time of 5.7 years. For the stability analysis, two CSF samples were collected from 52 AD patients with a six month interval in between. HFABP levels in CSF were very stable over the six month period (r = 0.93, p < 0.001). Furthermore, the CSF levels of HFABP were significantly elevated in AD compared with controls after adjustments for age and gender (p < 0.001). They were also elevated in the patients with MCI that subsequently converted to AD or VaD compared with those that remained stable (p < 0.001 and p < 0.05, respectively). However, ROC curve analysis showed that HFABP had lesser predictive value in determining conversion from MCI to AD and VaD than Aß42, t-tau, and p-tau. In conclusion, HFABP seems to be a stable CSF biomarker that reflects neuronal cell death in several neurodegenerative disorders, including early stages of AD and VaD.

CSF levels of heart fatty acid binding protein are altered during early phases of Alzheimer's disease.

Heart fatty acid binding protein (HFABP) has been proposed as a putative marker for dementia disorders. To evaluate the value of this protein as an early marker of Alzheimer's disease (AD), we analyzed HFABP level and the classical biomarkers amyloid-ß (Aß)1-42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) followed up for four years (n=41), AD (n=32), and subjects with other neurological diseases without dementia (OND, n=25). HFABP levels were higher in AD patients and in MCI converting to AD (MCI-AD) with respect to OND and to cognitively stable MCI patients (MCI-MCI). The receiver operator characteristics analysis for HFABP alone showed a sensitivity of 87% and a specificity of 81% for AD versus OND (area under the curve, AUC=0.83); sensitivity and specificity were 46% and 94%, respectively, when comparing MCI-MCI versus MCI-AD. CSF HFABP levels showed a strong positive correlation with both t-tau and p-tau. Interestingly, the ratio between HFABP and Aß1-42 improved the performance in distinguishing AD from OND (sensitivity: 90%; specificity 82%, AUC=0.89), and gave the best accuracy in discriminating MCI-AD from MCI-MCI (sensitivity: 80%; specificity 100%, AUC=0.90). Survival analysis by means of Kaplan-Meier curve showed a significantly higher proportion of MCI patients converting to AD in the group with higher values of HFABP/Aß1-42 ratio (cut-off=0.7). A significant correlation between HFABP/Aß1-42 ratio and MMSE annual decrease rate was also documented (p<0.0001). HFABP /Aß1-42 ratio might be a useful predictor of conversion in MCI patients.

Development of an ultra-rapid diagnostic method based on heart-type fatty acid binding protein levels in the CSF of CJD patients.

Creutzfeldt-Jakob disease (CJD) is a transmissible, fatal, neurodegenerative disease in humans. Recently, various drugs have been reported to be useful in the treatment of CJD; however, for such treatments to be useful it is essential to rapidly and accurately diagnose CJD. 124 CJD patients and 87 with other diseases causing rapid progressive dementia were examined. Cerebral spinal fluid (CSF) from CJD patients was analyzed by 2D-PAGE and the protein expression pattern was compared with that from healthy subjects. One of three CJD-specific spots was found to be fatty acid binding protein (FABP), and heart-type FABP (H-FABP) was analyzed as a new biochemical marker for CJD. H-FABP ELISA results were compared between CJD patients and patients with other diseases (n = 211). Visual readout accuracy of the Rapicheck(®) H-FABP test panel for CSF was analyzed using an independent measure of CSF H-FABP concentration. The distribution of H-FABP in the brains of CJD patients was examined by immunohistochemistry. ELISA sensitivity and specificity were 90.3% and 92.9%, respectively, and Rapicheck(®) H-FABP sensitivity and specificity were 87.9% and 96.0%, respectively. ELISA and Rapicheck(®) H-FABP assays provided comparable results for 14-3-3 protein and total tau protein. Elevated H-FABP levels were associated with an accumulation of abnormal prion protein, astrocytic gliosis, and neuronal loss in the cerebral cortices of CJD patients. In conclusion, Rapicheck(®) H-FABP of CSF specimens enabled quick and frequent diagnosis of CJD. H-FABP represents a new biomarker for CJD distinct from 14-3-3 protein and total tau protein.

A combined CXCL10, CXCL8 and H-FABP panel for the staging of human African trypanosomiasis patients.

BACKGROUND: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a parasitic tropical disease. It progresses from the first, haemolymphatic stage to a neurological second stage due to invasion of parasites into the central nervous system (CNS). As treatment depends on the stage of disease, there is a critical need for tools that efficiently discriminate the two stages of HAT. We hypothesized that markers of brain damage discovered by proteomic strategies and inflammation-related proteins could individually or in combination indicate the CNS invasion by the parasite. METHODS: Cerebrospinal fluid (CSF) originated from parasitologically confirmed Trypanosoma brucei gambiense patients. Patients were staged on the basis of CSF white blood cell (WBC) count and presence of parasites in CSF. One hundred samples were analysed: 21 from stage 1 (no trypanosomes in CSF and 5 WBC/microL) patients. The concentration of H-FABP, GSTP-1 and S100beta in CSF was measured by ELISA. The levels of thirteen inflammation-related proteins (IL-1ra, IL-1beta, IL-6, IL-9, IL-10, G-CSF, VEGF, IFN-gamma, TNF-alpha, CCL2, CCL4, CXCL8 and CXCL10) were determined by bead suspension arrays. RESULTS: CXCL10 most accurately distinguished stage 1 and stage 2 patients, with a sensitivity of 84% and specificity of 100%. Rule Induction Like (RIL) analysis defined a panel characterized by CXCL10, CXCL8 and H-FABP that improved the detection of stage 2 patients to 97% sensitivity and 100% specificity. CONCLUSION: This study highlights the value of CXCL10 as a single biomarker for staging T. b. gambiense-infected HAT patients. Further combination of CXCL10 with H-FABP and CXCL8 results in a panel that efficiently rules in stage 2 HAT patients. As these molecules could potentially be markers of other CNS infections and disorders, these results should be validated in a larger multi-centric cohort including other inflammatory diseases such as cerebral malaria and active tuberculosis.

Increased levels of CSF heart-type fatty acid-binding protein and tau protein after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Heart-type Fatty Acid-Binding Protein (H-FABP) and tau protein (tau) have been shown to be novel biomarkers associated with brain injury and, therefore, they could represent a useful diagnostic tool in patients with subarachnoid hemorrhage (SAH). The goal of this study was to measure H-FABP and tau in cerebrospinal fluid (CSF) following SAH to test the hypothesis that a relationship exists between SAH severity and H-FABP/tau values. METHODS: Twenty-seven consecutive SAH patients admitted to our ICU were studied. Serial CSF samples were obtained in every patient starting on the day of SAH and daily for up to 2 weeks post-SAH. H-FABP/tau levels were measured by enzyme-linked immunosorbent assay. RESULTS: Patients with severe SAH showed significantly higher peak levels of H-FABP and tau compared to mild-SAH patients (FABP: p = 0.02; tay: p = 0.002). In addition the peak concentrations of H-FABP and tau in CSF from SAH patients correlated significantly with Glasgow Coma Scale motor score (H-FABP: Spearman r = -0.52, p = 0.006; tau: Spearman r = -0.63, p = 0.0004). Based on outcome at discharge from the hospital, patients were categorized into survivors and non-survivors. Peak concentrations of both proteins in the non-survivors group were significantly higher than in the survivors. CONCLUSIONS: H-FABP and tau CSF levels are proportional to SAH severity and may be novel biomarkers that can be used to predict the severity of outcome following clinical SAH.