Visinin-like protein 1 levels in blood and CSF as emerging markers for Alzheimer's and other neurodegenerative diseases.

BACKGROUND: Visinin-like protein 1 (VILIP-1) belongs to the group of emerging biomarkers with the potential to support the early diagnosis of Alzheimer's disease (AD). However, studies investigating the differential diagnostic potential in cerebrospinal fluid (CSF) are rare and are not available for blood. METHODS: We set up a novel, sensitive single molecule array (Simoa) assay for the detection of VILIP-1 in CSF and serum. In total, paired CSF and serum samples from 234 patients were investigated: 73 AD, 18 behavioral variant frontotemporal dementia (bvFTD), 26 parkinsonian syndromes, 20 amyotrophic lateral sclerosis (ALS), 22 Creutzfeldt-Jakob disease (CJD), and 75 non-neurodegenerative control (Con) patients. The differential diagnostic potential of CSF and serum VILIP-1 was assessed using the receiver operating characteristic curve analysis and findings were compared to core AD biomarkers. RESULTS: CSF and serum VILIP-1 levels correlated weakly (r=0.32 (CI: 0.20-0.43), p<0.0001). VILIP-1 concentrations in CSF and serum were elevated in AD compared to Con (p<0.0001 and p<0.01) and CJD (p<0.0001 for CSF and serum), and an increase in CSF was observed already in early AD stages (p<0.0001). In the discrimination of AD versus Con, we could demonstrate a strong diagnostic potential for CSF VILIP-1 alone (area under the curve (AUC): 0.87), CSF VILIP-1/CSF Abeta 1-42 (AUC: 0.98), and serum VILIP-1/CSF Abeta 1-42 ratio (AUC: 0.89). CONCLUSIONS: We here report on the successful establishment of a novel Simoa assay for VILIP-1 and illustrate the potential of CSF and serum VILIP-1 in the differential diagnosis of AD with highest levels in CJD.

Evaluation of Synaptic and Axonal Dysfunction Biomarkers in Alzheimer's Disease and Mild Cognitive Impairment Based on CSF and Bioinformatic Analysis.

Synaptic loss and dysfunction are one of the earliest signs of neurodegeneration associated with cognitive decline in Alzheimer's disease (AD) and other neurodegenerative diseases. This study aimed to assess the relationships between biological processes of the synaptic pathology underlying AD, molecular functions, and dynamics of the change concentrations of selected proteins reflecting synaptic and axonal pathology in dementia stages. Neurogranin (Ng), neuronal pentraxin receptor (NPTXR), and Visinin-like protein 1 (VILIP1) concentrations were measured in the cerebrospinal fluid (CSF) of MCI, AD, and non-demented controls (CTRL) using quantitative immunological methods. Gene ontology (GO) enrichment analysis was used for the functional analysis of tested proteins. The CSF Aß42/Ng ratio was significantly different between all the compared groups. The CSF NPTXR/Ng ratio was significantly different between MCI compared to CTRL and AD compared to CTRL. The GO enrichment analysis revealed that two terms (the Biological Process (BP) and Cellular Component (CC) levels) are significantly enriched for NPTXR and Ng but not for VILIP1. Both Ng and NPTXR concentrations in CSF are promising synaptic dysfunction biomarkers for the early diagnosis of the disease. Moreover, both proteins are biochemically associated with classical biomarkers and VILIP-1. Mapping shared molecular and biological functions for the tested proteins by GO enrichment analysis may be beneficial in screening and setting new research targets.

Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis.

OBJECTIVE: To determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals. METHODS: Biomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or LGI1/CASPR2 (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients. RESULTS: Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, >0.99). Younger age (ρ = -0.56; p = 0.01), lower VILIP-1 (ρ = -0.60; p < 0.01) and SNAP-25 (ρ = -0.54; p = 0.01), and higher log10(YKL-40/SNAP-25) (ρ = 0.48; p = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; p = 0.02) and neurogranin (ρ = 0.55; p = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge. CONCLUSIONS: CSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.

Neurogranin and VILIP-1 as Molecular Indicators of Neurodegeneration in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Neurogranin (Ng) and visinin-like protein 1 (VILIP-1) are promising candidates for Alzheimer's Disease (AD) biomarkers closely related to synaptic and neuronal degeneration. Both proteins are involved in calcium-mediated pathways. The meta-analysis was performed in random effects based on the ratio of means (RoM) with calculated pooled effect size. The diagnostic utility of these proteins was examined in cerebrospinal fluid (CSF) of patients in different stages of AD compared to control (CTRL). Ng concentration was also checked in various groups with positive (+) and negative (-) amyloid beta (Aß). Ng highest levels of RoM were observed in the AD (n = 1894) compared to CTRL (n = 2051) group (RoM: 1.62). Similarly, the VILIP-1 highest values of RoM were detected in the AD (n = 706) compared to CTRL (n = 862) group (RoM: 1.34). Concentrations of both proteins increased in more advanced stages of AD. However, Ng seems to be an earlier biomarker for the assessment of cognitive impairment. Ng appears to be related with amyloid beta, and the highest levels of Ng in CSF was observed in the group with pathological Aß+ status. Our meta-analysis confirms that Ng and VILIP-1 can be useful CSF biomarkers in differential diagnosis and monitoring progression of cognitive decline. Although, an additional advantage of the protein concentration Ng is the possibility of using it to predict the risk of developing cognitive impairment in normal controls with pathological levels of Aß1-42. Analyses in larger cohorts are needed, particularly concerning Aß status.

Longstanding psychological stress in relation to biomarkers of neuronal dysfunction in cerebrospinal fluid: a 25-year follow-up study in women.

Longstanding psychological stress has been associated with increased risk of neurodegenerative disorders, such as dementia and Alzheimer's disease. In a prospective population study of women (n = 81), we tested if midlife stress (mean age 49 years) was associated with late-life biomarkers of neurodegeneration in cerebrospinal fluid (CSF) (mean age 74 years) in linear regression models. It was found that women who report of stress at baseline (n = 20) had higher levels of CSF visinin-like protein-1 (VILIP-1) (age adjusted ß = 0.113, p = 0.017) and CSF myelin basic protein (ß = 0.060, p = 0.030) compared with women without midlife stress (n = 61). There was also a trend observed for higher CSF neurofilament light (ß = 0.133, p = 0.056). In addition, longer periods of stress (i.e., stress at 2-3 midlife examinations) were associated with higher levels of CSF VILIP-1. The results suggest that longstanding stress might be associated with neurodegenerative processes in the brain, as CSF VILIP-1 is an unspecific marker for neuronal injury and CSF myelin basic protein reflects neuroaxonal demyelination.

Emerging cerebrospinal fluid biomarkers in autosomal dominant Alzheimer's disease.

INTRODUCTION: Four less well-studied but promising "emerging" cerebrospinal fluid (CSF) biomarkers are elevated in late-onset Alzheimer disease (AD): neurogranin, synaptosomal-associated protein-25 (SNAP-25), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). METHODS: CSF neurogranin, SNAP-25, VILIP-1, and YKL-40 were measured in families carrying autosomal-dominant AD mutations. RESULTS: The four emerging CSF biomarkers were significantly elevated in the mutation carriers (n = 235) versus noncarriers (n = 145). CSF SNAP-25, VILIP-1, and YKL-40 were altered very early in the AD time course, approximately 15-19 years before estimated symptom onset. All CSF biomarkers predicted important AD-related outcomes including performance on a cognitive composite, brain amyloid burden as measured by amyloid positron emission tomography, and the estimated years from symptom onset. DISCUSSION: Early abnormalities in CSF tTau, pTau, SNAP-25, VILIP-1, and YKL-40 suggest that synaptic damage, neuronal injury, and neuroinflammation begin shortly after the commencement of brain amyloid accumulation.

Cerebrospinal fluid biomarkers for understanding multiple aspects of Alzheimer's disease pathogenesis.

Alzheimer's disease (AD) is a multifactorial age-related brain disease. Numerous pathological events run forth in the brain leading to AD. There is an initial long, dormant phase before the clinical symptoms become evident. There is a need to diagnose the disease at the preclinical stage since therapeutic interventions are most likely to be effective if initiated early. Undoubtedly, the core cerebrospinal fluid (CSF) biomarkers have a good diagnostic accuracy and have been used in clinical trials as end point measures. However, looking into the multifactorial nature of AD and the overlapping pathology with other forms of dementia, it is important to integrate the core CSF biomarkers with a broader panel of other biomarkers reflecting different aspects of pathology. The review is focused upon a panel of biomarkers that relate to different aspects of AD pathology, as well as various studies that have evaluated their diagnostic potential. The panel includes markers of neurodegeneration: neurofilament light chain and visinin-like protein (VILIP-1); markers of amyloidogenesis and brain amyloidosis: apolipoproteins; markers of inflammation: YKL-40 and monocyte chemoattractant protein 1; marker of synaptic dysfunction: neurogranin. These markers can highlight on the state and stage-associated changes that occur in AD brain with disease progression. A combination of these biomarkers would not only aid in preclinical diagnosis, but would also help in identifying early brain changes during the onset of disease. Successful treatment strategies can be devised by understanding the contribution of these markers in different aspects of disease pathogenesis.

Event-related Potentials Improve the Efficiency of Cerebrospinal Fluid Biomarkers for Differential Diagnosis of Alzheimer's Disease.

INTRODUCTION: The pathological process of Alzheimer's disease (AD) in the brain likely begins 20-30 years earlier than the emergence of its first clinical symptoms and symptoms of AD often overlap with the symptoms of other primary causes of dementia. Therefore, it is crucially important to improve early and differential diagnosis of the disease. Event-related potentials (ERP) measured non-invasively by electroencephalography have shown diagnostic potential in AD. AIMS: The aim of this study was to compare the efficiency of P300 and N200 potentials and reaction time (RT) with commonly used protein biomarkers measured in the cerebrospinal fluid (CSF), including amyloid ß peptide (ß1-42), total tau (t-tau), tau protein phosphorylated at threonine 181 (p-tau181), tau protein phosphorylated at serine 199 (p-tau199), tau protein phosphorylated at threonine 231 (p-tau231), and visinin-like protein 1 (VILIP-1) in differential diagnosis of AD in mild cognitive impairment (MCI) and AD patients. SUBJECTS: The study involved 49 AD patients, 28 patients with MCI, 4 healthy control subjects and 16 patients with other primary causes of dementia. RESULTS: ERP (P300RT, N200RT, P300 counting and N200 counting) showed a moderate to strong correlation with protein CSF biomarkers. We confirmed previous observations of moderate to strong correlation between ERP and neuropsychological testing and showed that P300 latency and RT are shortened in AD patients on therapy with acetylcholinesterase inhibitors. Using ERP and RT, a predictive model for determination of AD likelihood in MCI patients was developed, detecting 56.3% of MCI patients with high risk for development of AD in our cohort. MCI patients with pathological levels of Aß1-42 had prolonged P300 latency, indicating that a combination of ERP and CSF protein biomarkers could improve the differential diagnosis of AD in MCI patients. Additionally, the results suggested the potential of P300 latency in differentiating AD and FTD patients. CONCLUSION: Our data provide possible solutions for improvement of differential diagnosis of AD, and reveal that the diagnostic efficiency of CSF protein biomarkers t-tau, p-tau181, p-tau199, p-tau231 and VILIP-1 could be improved by adding ERP in clinical practice.

Longitudinal decreases in multiple cerebrospinal fluid biomarkers of neuronal injury in symptomatic late onset Alzheimer's disease.

INTRODUCTION: Individuals in early stages of Alzheimer's disease are a targeted population for secondary prevention trials aimed at preserving normal cognition. Understanding within-person biomarker(s) change over time is critical for trial enrollment and design. METHODS: Longitudinal cerebrospinal fluid samples from the Alzheimer's Disease Neuroimaging Initiative were assayed for novel markers of neuronal/synaptic injury (visinin-like protein 1, Ng, and SNAP-25) and neuroinflammation (YKL-40) and compared with ß amyloid 42, tau, and phospho-tau181. General linear mixed models were used to compare within-person rates of change in three clinical groups (cognitively normal, mild cognitive impairment, and Alzheimer's disease) further defined by ß amyloid status. RESULTS: Levels of injury markers were highly positively correlated. Despite elevated baseline levels as a function of clinical status and amyloid-positivity, within-person decreases in these measures were observed in the early symptomatic, amyloid-positive Alzheimer's disease group. DISCUSSION: Knowledge of within-person biomarker change will impact interpretation of biomarker outcomes in clinical trials that are dependent on disease stage.

The Relationship between Markers of Inflammation and Degeneration in the Central Nervous System and the Blood-Brain Barrier Impairment in Alzheimer's Disease.

BACKGROUND: It is known that YKL-40- a marker of glial inflammation, and VILIP-1- a marker of neuronal injury, reflect functional and structural changes in AD brains, although there is limited data concerning their potential influence on blood-brain barrier (BBB) homeostasis. OBJECTIVE: Therefore, the aim of our study was to investigate the relationship between markers of inflammation and degeneration in the central nervous system (CNS) of patients with AD and mild cognitive impairment (MCI) as well as immunological response in CNS and BBB function. METHODS: Cerebrospinal fluid (CSF) concentrations of proteins tested were determined in 45 AD patients, 18 MCI subjects, and 23 non-demented controls using ELISA method. RESULTS: CSF concentrations of YKL-40 were significantly higher in MCI and AD patients, whereas CSF levels of VILIP-1 were statistically higher in the AD group as compared to the subjects without cognitive deficits. Elevated concentrations of YKL-40 correlated significantly with increased albumin quotient and decreased Aß42/40 ratio in AD patients and with IgG quotient in the total study group. We did not find a relationship between VILIP-1 and immunological parameters reflecting BBB dysfunction and humoral immune response. CONCLUSION: Our findings indicate that YKL-40 may contribute to decreased stability and increased permeability of BBB in AD patients. It is assumed that YKL-40 is implicated in the development of brain barriers, although its precise mechanism of action in the BBB disruption remains unrevealed. Further studies on larger groups of patients are required to confirm our hypothesis.

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.

A meta-analysis of cerebrospinal fluid visinin-like protein-1 in alzheimers disease patients relative to healthy controls and mild cognitive impairment patients.

OBJECTIVE: To compare cerebrospinal fluid visinin-like protein-1 (CSF VLP-1) in alzheimer`s disease (AD) with that in healthy controls and mild cognitive impairment (MCI) patients and find out possible sources of heterogeneity. METHODS: "Visinin-like protein-1" and "alzheimer`s disease" were employed to search "PubMed", "Springer" and "Medline" databases until July 2016 and standard mean difference (Std.MD) was calculated. Besides, subgroup analysis and meta-regression were performed to explore the possible heterogeneity sources. RESULTS: Seven studies involved 1151 participants were pooled. The CSF VLP-1 in AD patients was higher than that in healthy controls and MCI patients (pooled Std.MD=0.81, 95% CI: [0.47, 1.16], p<0.00001). As shown by subgroup analysis, population variations were one of heterogeneity sources. Meta-regression revealed that Hedges`s g of CSF VLP-1 was correlated with Std.MD of t-tau (r=0.560, p=0.006) and amyloid beta42 (r=-0.386, p=0.013). CONCLUSION: The CSF VLP-1 in AD patients is higher than that in healthy controls and MCI patients. The changes of VLP-1 in AD patients relative to healthy controls and MCI patients is less pronounced than that of core biomarkers, such as amyloid beta42, t-tau and p-tau. Population variations, increasing t-tau and decreasing amyloid beta42 in AD patients relative to healthy controls and MCI patients were the main sources of heterogeneity.

Preclinical amyloid pathology biomarker positivity: effects on tau pathology and neurodegeneration.

Brain autopsy and biomarker studies indicate that the pathology of Alzheimer's disease (AD) is initiated at least 10-20 years before clinical symptoms. This provides a window of opportunity to initiate preventive treatment. However, this emphasizes the necessity for biomarkers that identify individuals at risk for developing AD later in life. In this cross-sectional study, originating from three epidemiologic studies in Sweden (n=1428), the objective was to examine whether amyloid pathology, as determined by low cerebrospinal fluid (CSF) concentration of the 42 amino acid form of ß-amyloid (Aß42), is associated with biomarker evidence of other pathological changes in cognitively healthy elderly. A total of 129 patients were included and CSF levels of Aß42, total tau, tau phosphorylated at threonine 181 (p-tau), neurogranin, VILIP-1, VEGF, FABP3, Aß40, neurofilament light, MBP, orexin A, BDNF and YKL-40 were measured. Among these healthy elderly, 35.6% (N=46) had CSF Aß42 levels below 530 pg ml-1. These individuals displayed significantly higher CSF concentrations of t-tau (P<0.001), p-tau (181) (P<0.001), neurogranin (P=0.009) and FABP3 (P=0.044) compared with amyloid-negative individuals. Our study indicates that there is a subpopulation among healthy older individuals who have amyloid pathology along with signs of ongoing neuronal and synaptic degeneration, as well as tangle pathology. Previous studies have demonstrated that increase in CSF tau and p-tau is a specific sign of AD progression that occurs downstream of the deposition of Aß. On the basis of this, our data suggest that these subjects are at risk for developing AD. We also confirm the association between APOE ɛ4 and amyloid pathology in healthy older individuals.

Diagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease.

IMPORTANCE: Synaptic loss is an early pathologic substrate of Alzheimer disease (AD). Neurogranin is a postsynaptic neuronal protein that has demonstrated utility as a cerebrospinal fluid (CSF) marker of synaptic loss in AD. OBJECTIVE: To investigate the diagnostic and prognostic utility of CSF neurogranin levels in a large, well-characterized cohort of individuals with symptomatic AD and cognitively normal controls. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional and longitudinal observational study of cognitive decline in patients with symptomatic AD and cognitively normal controls was performed. Participants were individuals with a clinical diagnosis of early symptomatic AD and cognitively normal controls who were enrolled in longitudinal studies of aging and dementia at the Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, from January 21, 2000, through March 21, 2011. Data analysis was performed from November 1, 2013, to March 31, 2015. MAIN OUTCOMES AND MEASURES: Correlations between baseline CSF biomarker levels and future cognitive decline in patients with symptomatic AD and cognitively normal controls over time. RESULTS: A total of 302 individuals (mean [SE] age, 73.1 [0.4] years) were included in this study (95 patients [52 women and 43 men] with AD and 207 controls [125 women and 82 men]). The CSF neurogranin levels differentiated patients with early symptomatic AD from controls with comparable diagnostic utility (mean [SE] area under the receiver operating characteristic curve, 0.71 [0.03]; 95% CI, 0.64-0.77) to the other CSF biomarkers. The CSF neurogranin levels correlated with brain atrophy (normalized whole-brain volumes: adjusted r = -0.38, P = .02; hippocampal volumes: adjusted r = -0.36, P = .03; entorhinal volumes: adjusted r = -0.46, P = .006; and parahippocampal volumes: adjusted r = -0.47, P = .005, n = 38) in AD and with amyloid load (r = 0.39, P = .02, n = 36) in preclinical AD. The CSF neurogranin levels predicted future cognitive impairment (adjusted hazard ratio, 1.89; 95% CI, 1.29-2.78; P = .001 as a continuous measure, and adjusted hazard ratio, 2.78; 95% CI, 1.13-5.99; P = .02 as a categorical measure using the 85th percentile cutoff value) in controls and rates of cognitive decline (Clinical Dementia Rating sum of boxes score: ß estimate, 0.29; P = .001; global composite scores: ß estimate, -0.11; P = .001; episodic memory scores: ß estimate, -0.18; P < .001; and semantic memory scores: ß estimate, -0.06; P = .04, n = 57) in patients with symptomatic AD over time, similarly to the CSF proteins VILIP-1, tau, and p-tau181. CONCLUSIONS AND RELEVANCE: The CSF levels of the synaptic marker neurogranin offer diagnostic and prognostic utility for early symptomatic AD that is comparable to other CSF markers of AD. Importantly, CSF neurogranin complements the collective ability of these markers to predict future cognitive decline in cognitively normal individuals and, therefore, will be a useful addition to the current panel of AD biomarkers.

Predictive Value of Cerebrospinal Fluid Visinin-Like Protein-1 Levels for Alzheimer's Disease Early Detection and Differential Diagnosis in Patients with Mild Cognitive Impairment.

Visinin-like protein 1 (VILIP-1) recently emerged as a potential biomarker of Alzheimer's disease (AD). This neuronal calcium sensor protein previously used as a marker of acute ischemic stroke is elevated in the cerebrospinal fluid (CSF) of AD patients. The goal of this study was to assess CSF VILIP-1 potential in early AD diagnosis and in differentiating mild cognitive impairment (MCI) patients with and without risk of AD. Additionally, we tested VILIP-1 ability to differentiate AD from other primary causes of dementia, and predict the progression of AD-related cognitive decline. VILIP-1 levels were compared with five CSF AD biomarkers (t-tau, Aß1-42, p-tau181, p-tau199, and p-tau231). VILIP-1 successfully differentiated two MCI patient groups characterized by absence or presence of pathological levels of these CSF biomarkers, except for t-tau. VILIP-1/Aß(1-42) and VILIP-1/p-tau181 ratios also differentiated MCI patients with pathological CSF biomarker levels. However, there was no difference in VILIP-1 levels between AD and MCI patients. VILIP-1/Aß(1-42) and VILIP-1/p-tau231 ratios reached high sensitivities (above 70%) and very high specificities (above 85%) in differentiating AD patients from HC. Additionally, VILIP-1 differentiated AD from patients with Lewy body disease with 77.1% sensitivity and 100% specificity. VILIP-1 potential as a prognostic biomarker of cognitive decline in AD was also proved since VILIP-1/t-tau, VILIP-1/p-tau181, and VILIP-1/p-tau231 ratios correlated with MMSE scores. These data indicate that VILIP-1 alone or in combination with other AD CSF biomarkers represent a valuable marker for the early diagnosis of AD, recognition of MCI patients at higher risk to develop dementia, and in differentiating AD from LBD.

Altered Levels of Visinin-Like Protein 1 Correspond to Regional Neuronal Loss in Alzheimer Disease and Frontotemporal Lobar Degeneration.

Recent studies have implicated the neuronal calcium-sensing protein visinin-like 1 protein (Vilip-1) as a peripheral biomarker in Alzheimer disease (AD), but little is known about expression of Vilip-1 in the brains of patients with AD. We used targeted and quantitative mass spectrometry to measure Vilip-1 peptide levels in the entorhinal cortex (ERC) and the superior frontal gyrus (SF) from cases with early to moderate stage AD, frontotemporal lobar degeneration (FTLD), and cognitively and neuropathologically normal elderly controls. We found that Vilip-1 levels were significantly lower in the ERC, but not in SF, of AD subjects compared to normal controls. In FTLD cases, Vilip-1 levels in the SF were significantly lower than in normal controls. These findings suggest a unique role for cerebrospinal fluid Vilip-1 as a biomarker of ERC neuron loss in AD.

Cerebrospinal fluid markers of central nervous system injury in decompression illness - a case-controlled pilot study.

INTRODUCTION: Decompression sickness (DCS) may cause a wide variety of symptoms, including central nervous system (CNS) manifestations. The main objective of this study was to examine whether DCS is associated with neuronal injury, and whether DCS could result in altered amyloid metabolism. METHODS: Seven, male divers with DCS and seven age-matched controls were included in the study. All the divers were treated by recompression but the controls did not receive hyperbaric oxygen. Cerebrospinal fluid (CSF) samples were collected 7-10 days after the diving injury and at three months follow-up. CSF biomarkers of neuronal injury, astroglial Injury/activation, and a range of markers of amyloid ß (Aß) metabolism, as well as two proinflammatory interleukins, were analysed using immunochemical methods. RESULTS: There were no significant differences in the best-established CSF markers of neuronal injury, total tau (T-tau) and neurofilament light, between DCS patients and controls or between the two sampling time points. Also, there were no significant changes in the astroglial or amyloid (Aß)-related markers between DCS patients and controls. However, the only diver with CNS symptoms had the highest levels of CSF T-tau, Aß38, Aß40 and Aß42. CONCLUSION: The results of our study speak against subclinical CNS injury or induction of inflammation or amyloid build-up in the brain among the six DCS patients without neurological symptoms. Further research, including on divers with CNS DCS, is justified.

Cerebrospinal fluid VILIP-1 and YKL-40, candidate biomarkers to diagnose, predict and monitor Alzheimer's disease in a memory clinic cohort.

INTRODUCTION: We examined the utility of cerebrospinal fluid (CSF) proteins, Chitinase-3-like protein 1 (CHI3L1 or YKL-40), a putative marker of inflammation, and Visinin-like protein-1 (VILIP-1), a marker for neuronal injury, for diagnostic classification and monitoring of disease progression in a memory clinic cohort. METHODS: CSF levels of YKL-40 and VILIP-1 were measured in 37 cognitively normal, 61 Mild Cognitive Impairment (MCI) and 65 Alzheimer's disease (AD) patients from the memory clinic-based Amsterdam Dementia Cohort who underwent two lumbar punctures, with minimum interval of 6 months and a mean (SE) interval of 2.0(0.1) years. Mean(SE) cognitive follow-up was 3.8 (0.2) years. ANOVA was used to compare baseline differences of log-transformed CSF measures. Cox proportional hazard models were used to evaluate disease progression as a function of CSF tertiles. Linear mixed models were used to evaluate longitudinal change over time. All analyses were sex and age adjusted. RESULTS: Baseline levels of YKL-40, but not VILIP-1, were higher in MCI and AD patients compared to cognitively normal individuals (mean (SE) pg/mL, 304 (16) and 288 (12) vs. 231 (16), p = 0.03 and p = 0.006). Baseline levels of both YKL-40 and VILIP-1 in MCI predicted progression to AD (HR 95% CI = 3.0 (1.1-7.9) and 4.4 (1.5-13.0), respectively, for highest vs. lowest tertile). YKL-40 increased longitudinally in patients with MCI and AD (mean (SE) pg/mL per year, 8.9 (3.0) and 7.1 (3.1), respectively), but not in cognitively normal individuals, whereas levels of VILIP-1 increased only in MCI (mean (SE), 10.7 (2.6) pg/mL per year). CONCLUSIONS: CSF levels of YKL-40 may have utility for discriminating between cognitively normal individuals and patients with MCI or AD. Increased levels of both YKL-40 and VILIP-1 may be associated with disease progression. These CSF biomarkers should be considered for future evaluation in the characterization of the natural history of AD.

Longitudinal Cerebrospinal Fluid Biomarker Changes in Preclinical Alzheimer Disease During Middle Age.

IMPORTANCE: Individuals in the presymptomatic stage of Alzheimer disease (AD) are increasingly being targeted for AD secondary prevention trials. How early during the normal life span underlying AD pathologies begin to develop, their patterns of change over time, and their relationship with future cognitive decline remain to be determined. OBJECTIVE: To characterize the within-person trajectories of cerebrospinal fluid (CSF) biomarkers of AD over time and their association with changes in brain amyloid deposition and cognitive decline in cognitively normal middle-aged individuals. DESIGN, SETTING, AND PARTICIPANTS: As part of a cohort study, cognitively normal (Clinical Dementia Rating [CDR] of 0) middle-aged research volunteers (n = 169) enrolled in the Adult Children Study at Washington University, St Louis, Missouri, had undergone serial CSF collection and longitudinal clinical assessment (mean, 6 years; range, 0.91-11.3 years) at 3-year intervals at the time of analysis, between January 2003 and November 2013. A subset (n = 74) had also undergone longitudinal amyloid positron emission tomographic imaging with Pittsburgh compound B (PiB) in the same period. Serial CSF samples were analyzed for ß-amyloid 40 (Aß40), Aß42, total tau, tau phosphorylated at threonine 181 (P-tau181), visinin-like protein 1 (VILIP-1), and chitinase-3-like protein 1 (YKL-40). Within-person measures were plotted according to age and AD risk defined by APOE genotype (ε4 carriers vs noncarriers). Linear mixed models were used to compare estimated biomarker slopes among middle-age bins at baseline (early, 45-54 years; mid, 55-64 years; late, 65-74 years) and between risk groups. Within-person changes in CSF biomarkers were also compared with changes in cortical PiB binding and progression to a CDR higher than 0 at follow-up. MAIN OUTCOMES AND MEASURES: Changes in Aß40, Aß42, total tau, P-tau181, VILIP-1, and YKL-40 and, in a subset of participants, changes in cortical PiB binding. RESULTS: While there were no consistent longitudinal patterns in Aß40 (P = .001-.97), longitudinal reductions in Aß42 were observed in some individuals as early as early middle age (P ≤ .05) and low Aß42 levels were associated with the development of cortical PiB-positive amyloid plaques (area under receiver operating characteristic curve = 0.9352; 95% CI, 0.8895-0.9808), especially in mid middle age (P < .001). Markers of neuronal injury (total tau, P-tau181, and VILIP-1) dramatically increased in some individuals in mid and late middle age (P ≤ .02), whereas the neuroinflammation marker YKL-40 increased consistently throughout middle age (P ≤ .003). These patterns were more apparent in at-risk ε4 carriers (Aß42 in an allele dose-dependent manner) and appeared to be associated with future cognitive deficits as determined by CDR. CONCLUSIONS AND RELEVANCE: Longitudinal CSF biomarker patterns consistent with AD are first detectable during early middle age and are associated with later amyloid positivity and cognitive decline. Such measures may be useful for targeting middle-aged, asymptomatic individuals for therapeutic trials designed to prevent cognitive decline.

Serum visinin-like protein-1 in concussed professional ice hockey players.

PRIMARY OBJECTIVE: Visinin-like protein-1 (VILIP-1) has shown potential utility as a biomarker for neuronal injury in cerebrospinal fluid. This study investigated serum VILIP-1 as a diagnostic and prognostic marker in sports-related concussion. METHODS: This multi-centre prospective cohort study involved the 12 teams of the professional ice hockey league in Sweden. A total of 288 players consented to participate in the study. Thirty-five players sustained concussions, of whom 28 underwent repeated blood samplings at 1, 12, 36 and 144 hours after the trauma or when the player returned to play (7-90+ days). MAIN OUTCOMES AND RESULTS: The highest levels of VILIP-1 were measured 1 hour after concussion and the levels decreased during rehabilitation, reaching a minimum level at the 36-hour sampling. However, the levels of serum VILIP-1 at 1 hour after concussion were not significantly higher than pre-season baseline values. Serum levels of VILIP-1 1 hour post-concussion did not correlate with the number of days for the concussion symptoms to resolve. Further, serum levels of VILIP-1 increased after a friendly game in players who were not concussed. CONCLUSIONS: These results provide evidence that serum VILIP-1 may not be a useful biomarker for diagnosis and prognosis of sports-related concussion.