L1CAM is not associated with extracellular vesicles in human cerebrospinal fluid or plasma.

L1CAM is a transmembrane protein expressed on neurons that was presumed to be found on neuron-derived extracellular vesicles (NDEVs) in human biofluids. We developed a panel of single-molecule array assays to evaluate the use of L1CAM for NDEV isolation. We demonstrate that L1CAM is not associated with extracellular vesicles in human plasma or cerebrospinal fluid and therefore recommend against its use as a marker in NDEV isolation protocols.

Cerebrospinal fluid NCAM-1 concentration is associated with neurodevelopmental outcome in post-hemorrhagic hydrocephalus of prematurity.

OBJECTIVE: Efforts directed at mitigating neurological disability in preterm infants with intraventricular hemorrhage (IVH) and post hemorrhagic hydrocephalus (PHH) are limited by a dearth of quantifiable metrics capable of predicting long-term outcome. The objective of this study was to examine the relationships between candidate cerebrospinal fluid (CSF) biomarkers of PHH and neurodevelopmental outcomes in infants undergoing neurosurgical treatment for PHH. STUDY DESIGN: Preterm infants with PHH were enrolled across the Hydrocephalus Clinical Research Network. CSF samples were collected at the time of temporizing neurosurgical procedure (n = 98). Amyloid precursor protein (APP), L1CAM, NCAM-1, and total protein (TP) were compared in PHH versus control CSF. Fifty-four of these PHH subjects underwent Bayley Scales of Infant Development-III (Bayley-III) testing at 15-30 months corrected age. Controlling for false discovery rate (FDR) and adjusting for post-menstrual age (PMA) and IVH grade, Pearson's partial correlation coefficients were used to examine relationships between CSF proteins and Bayley-III composite cognitive, language, and motor scores. RESULTS: CSF APP, L1CAM, NCAM-1, and TP were elevated in PHH over control at temporizing surgery. CSF NCAM-1 was associated with Bayley-III motor score (R = -0.422, p = 0.007, FDR Q = 0.089), with modest relationships noted with cognition (R = -0.335, p = 0.030, FDR Q = 0.182) and language (R = -0.314, p = 0.048, FDR Q = 0.194) scores. No relationships were observed between CSF APP, L1CAM, or TP and Bayley-III scores. FOHR at the time of temporization did not correlate with Bayley-III scores, though trends were observed with Bayley-III motor (p = 0.0647 and R = -0.2912) and cognitive scores (p = 0.0506 and R = -0.2966). CONCLUSION: CSF NCAM-1 was associated with neurodevelopment in this multi-institutional PHH cohort. This is the first report relating a specific CSF protein, NCAM-1, to neurodevelopment in PHH. Future work will further investigate a possible role for NCAM-1 as a biomarker of PHH-associated neurological disability.

Tract-Specific Relationships Between Cerebrospinal Fluid Biomarkers and Periventricular White Matter in Posthemorrhagic Hydrocephalus of Prematurity.

BACKGROUND: Posthemorrhagic hydrocephalus (PHH) is associated with neurological morbidity and complex neurosurgical care. Improved tools are needed to optimize treatments and to investigate the developmental sequelae of PHH. OBJECTIVE: To examine the relationship between diffusion magnetic resonance imaging (dMRI) and cerebrospinal fluid (CSF) biomarkers of PHH. METHODS: A total of 14 preterm (PT) infants with PHH and 46 controls were included. PT CSF was collected at temporizing surgery in PHH infants (PHH PT CSF) or lumbar puncture in controls. Term-equivalent age (TEA) CSF was acquired via implanted device or at permanent CSF diversion surgery in PHH (PHH-TEA-CSF) or lumbar puncture in controls. TEA dMRI scans were used to measure fractional anisotropy (FA) and mean diffusivity (MD) in the genu of corpus callosum (gCC), posterior limb of internal capsule (PLIC), and optic radiations (OPRA). Associations between dMRI measures and CSF amyloid precursor protein (APP), neural cell adhesion-1 (NCAM-1), and L1 cell adhesion molecule (L1CAM) were assessed using Pearson correlations. RESULTS: APP, NCAM-1, and L1CAM were elevated over controls in PHH-PT-CSF and PHH-TEA-CSF. dMRI FA and MD differed between control and PHH infants across all tracts. PHH-PT-CSF APP levels correlated with gCC and OPRA FA and PLIC MD, while L1CAM correlated with gCC and OPRA FA. In PHH-TEA-CSF, only L1CAM correlated with OPRA MD. CONCLUSION: Tract-specific associations were observed between dMRI and CSF biomarkers at the initiation of PHH treatment. dMRI and CSF biomarker analyses provide innovative complementary methods for examining PHH-related white matter injury and associated developmental sequelae.

Increased L1CAM (CD171) levels are associated with glioblastoma and metastatic brain tumors.

L1 cell adhesion molecule (L1CAM) is a member of the immunoglobulin-like cell-adhesion molecule family that was shown to be associated with a worse prognosis in several human cancers. L1 ectodomain shedding via vesicles or exosomes has been detected in extracellular fluids after cleavage from the cell surface by metalloproteases. We evaluated the presence of L1CAM in cyst fluid and tissue from glioblastomas or brain metastases.The amount of L1CAM in cyst fluid of 9 glioblastomas and 11 brain metastases was assessed using enzyme-linked immunosorbent assay (ELISA). Corresponding tumor tissue slices were stained immunohistochemically for L1CAM. Cerebrospinal fluid of 20 non-tumor patients served as controls.Mean levels of L1CAM in tumor cyst fluid were significantly higher in glioblastoma (6118 ±â€Š4095 ng/mL) and metastasis patients (8001 ±â€Š6535 ng/mL) than in CSF of control patients (714 ±â€Š22 ng/mL). The immunohistochemical expression of L1CAM in corresponding tissue was significantly higher in metastases than in glioblastomas.The present study demonstrates high levels of L1CAM in cyst fluid of glioblastoma and metastatic brain tumors. Soluble L1CAM may represent a motility promoting molecule in cancer progression, a co-factor for development of tumor cysts and a target for new treatment strategies.

Lumbar Cerebrospinal Fluid Biomarkers of Posthemorrhagic Hydrocephalus of Prematurity: Amyloid Precursor Protein, Soluble Amyloid Precursor Protein α, and L1 Cell Adhesion Molecule.

BACKGROUND: Intraventricular hemorrhage (IVH) is the most frequent, severe neurological complication of prematurity and is associated with posthemorrhagic hydrocephalus (PHH) in up to half of cases. PHH requires lifelong neurosurgical care and is associated with significant cognitive and psychomotor disability. Cerebrospinal fluid (CSF) biomarkers may provide both diagnostic information for PHH and novel insights into its pathophysiology. OBJECTIVE: To explore the diagnostic ability of candidate CSF biomarkers for PHH. METHODS: Concentrations of amyloid precursor protein (APP), soluble APPα (sAPPα), soluble APPß, neural cell adhesion molecule-1 (NCAM-1), L1 cell adhesion molecule (L1CAM), tau, phosphorylated tau, and total protein (TP) were measured in lumbar CSF from neonates in 6 groups: (1) no known neurological disease (n = 33); (2) IVH grades I to II (n = 13); (3) IVH grades III to IV (n = 12); (4) PHH (n = 12); (5) ventricular enlargement without hydrocephalus (n = 10); and (6) hypoxic ischemic encephalopathy (n = 13). CSF protein levels were compared using analysis of variance, and logistic regression was performed to examine the predictive ability of each marker for PHH. RESULTS: Lumbar CSF levels of APP, sAPPα, L1CAM, and TP were selectively increased in PHH compared with all other conditions (all P < .001). The sensitivity, specificity, and odds ratios of candidate CSF biomarkers for PHH were determined for APP, sAPPα, and L1CAM; cut points of 699, 514, and 113 ng/mL yielded odds ratios for PHH of 80.0, 200.0, and 68.75, respectively. CONCLUSION: Lumbar CSF APP, sAPPα, L1CAM, and TP were selectively increased in PHH. These proteins, and sAPPα, in particular, hold promise as biomarkers of PHH and provide novel insight into PHH-associated neural injury and repair.

Cerebrospinal fluid levels of amyloid precursor protein are associated with ventricular size in post-hemorrhagic hydrocephalus of prematurity.

BACKGROUND: Neurological outcomes of preterm infants with post-hemorrhagic hydrocephalus (PHH) remain among the worst in infancy, yet there remain few instruments to inform the treatment of PHH. We previously observed PHH-associated elevations in cerebrospinal fluid (CSF) amyloid precursor protein (APP), neural cell adhesion molecule-L1 (L1CAM), neural cell adhesion molecule-1 (NCAM-1), and other protein mediators of neurodevelopment. OBJECTIVE: The objective of this study was to examine the association of CSF APP, L1CAM, and NCAM-1 with ventricular size as an early step toward developing CSF markers of PHH. METHODS: CSF levels of APP, L1CAM, NCAM-1, and total protein (TP) were measured in 12 preterm infants undergoing PHH treatment. Ventricular size was determined using cranial ultrasounds. The relationships between CSF APP, L1CAM, and NCAM-1, occipitofrontal circumference (OFC), volume of CSF removed, and ventricular size were examined using correlation and regression analyses. RESULTS: CSF levels of APP, L1CAM, and NCAM-1 but not TP paralleled treatment-related changes in ventricular size. CSF APP demonstrated the strongest association with ventricular size, estimated by frontal-occipital horn ratio (FOR) (Pearson R = 0.76, p = 0.004), followed by NCAM-1 (R = 0.66, p = 0.02) and L1CAM (R = 0.57,p = 0.055). TP was not correlated with FOR (R = 0.02, p = 0.95). CONCLUSIONS: Herein, we report the novel observation that CSF APP shows a robust association with ventricular size in preterm infants treated for PHH. The results from this study suggest that CSF APP and related proteins at once hold promise as biomarkers of PHH and provide insight into the neurological consequences of PHH in the preterm infant.

L1 cell adhesion molecule found in human CSF varies as a function of age.

Differences in the pattern and quantity of high molecular weight isoforms of L1 neural cell adhesion molecule were found between premature and term newborns compared to children and adults. These patterns were disrupted in two patients with neurologic disease.

Elevated levels of neural recognition molecule L1 in the cerebrospinal fluid of patients with Alzheimer disease and other dementia syndromes.

In this study we surveyed a total of 218 cerebrospinal fluid (CSF) samples from patients with different neurological diseases including Alzheimer disease, non-Alzheimer forms of dementia, other neurodegenerative diseases without dementia and normal controls to quantitate by capture ELISA the concentrations of the immunoglobulin superfamily adhesion molecules L1 and NCAM, and characterized by immunoblot analysis the molecular forms of L1 and NCAM. We found a significant increase of L1 and a strong tendency for increase of the soluble fragments of NCAM in the CSF of Alzheimer patients compared to the normal control group. The proteolytic fragments of L1, but not NCAM were also elevated in patients with vascular dementia and dementia of mixed type. Higher L1 concentrations were observed irrespective of age and gender. NCAM concentrations were independent of gender, but positively correlated with age and, surprisingly, also with incidence of multiple sclerosis. Thus, there was an influence of Alzheimer and non-Alzheimer dementias and neurodegeneration on L1, whereas age and neurodegeneration influenced NCAM concentrations. These observations point to an abnormal processing and/or shedding of L1 and NCAM in dementia-related neurodegeneration and age, respectively, reflecting changes in adhesion molecule-related cell interactions.