Fingerprint changes in CSF composition associated with different aetiologies in human neonatal hydrocephalus: glial proteins associated with cell damage and loss

Abstract

BackgroundIn hydrocephalus an imbalance between production and absorption of cerebrospinal fluid (CSF) results in fluid accumulation, compression and stretching of the brain parenchyma. In addition, changes in CSF composition have a profound influence on the development and function of the brain and together, these can result in severe life-long neurological deficits. Brain damage or degenerative conditions can result in release of proteins expressed predominantly in neurons, astroglia, or oligodendroglia into the brain interstitial fluid, CSF and blood. Determination of such products in the CSF might be of value in diagnosing cause, aetiology and/or assessing the severity of the neurological damage in patients with hydrocephalus. We therefore analysed CSF from human neonates with hydrocephalus for these proteins to provide an insight into the pathophysiology associated with different aetiologies.MethodsCSF was collected during routine lumbar puncture or ventricular tap. Samples were categorized according to age of onset of hydrocephalus and presumed cause (fetal-onset, late-onset, post-haemorrhagic or spina bifida with hydrocephalus). Glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), vimentin and 2′ , 3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) were analysed through Western blotting of hydrocephalic CSF samples (n = 17) and compared with data from CSF of normal infants without neurological deficits (n = 8).ResultsGFAP was significantly raised only in CSF from post-haemorrhagic hydrocephalus while MBP was significantly raised in post-haemorrhagic and in spina bifida with hydrocephalus infants. Vimentin protein was only detected in some CSF samples from infants with late-onset hydrocephalus but not from other conditions. Surprisingly, CNPase was found in all neonatal CSF samples, including normal and hydrocephalic groups, although it was reduced in infants with late onset hydrocephalus compared with normal and other hydrocephalic groups.ConclusionsApart from CNPase, which is an enzyme, the markers investigated are intracellular intermediate filaments and would be present in CSF only if the cells are compromised and the proteins released. Raised GFAP observed in post-haemorrhagic hydrocephalus must reflect damage to astrocytes and ependyma. Raised MBP in post-haemorrhagic and spina bifida with hydrocephalus indicates damage to oligodendrocytes and myelin. Vimentin protein detected in some of the late-onset hydrocephalic samples indicates damage to glial and other progenitors and suggests this condition affects periventricular regions. The presence of CNPase in all CSF samples was unexpected and indicates a possible novel role for this enzyme in brain development/myelination. Less CNPase in some cases of late-onset hydrocephalus could therefore indicate changes in myelination in these infants. This study demonstrates differential glial damage and loss in the developing human neonatal hydrocephalic brain associated with different aetiologies.

Glial fibrillary acidic protein is a body fluid biomarker for glial pathology in human disease

“…Interpretation of this data will need to be considered if the CSF was of ventricular or lumbar origin, as there is evidence of a rostrocaudal gradient with higher CSF GFAP levels in ventricular CSF (Tarnaris et al, 2010). Likewise, the presence of blood in the CSF was related to higher CSF GFAP levels in hydrocephalus (Naureen et al, 2013). This may partly explain the considerable elevation of ventricular CSF GFAP levels following SAH which required extra ventricular drainage for management of secondary hydrocephalus (Petzold et al, 2006).…”

Strain-dependent brain defects in mouse models of primary ciliary dyskinesia with mutations in Pcdp1 and Spef2

“…Myelin basic protein (MBP), a protein generally associated with the formation of myelin in oligodendrocytes, is elevated in the CSF of hydrocephalic patients (Beems et al, 2003; Longatti et al, 1993; Longatti et al, 1994; Naureen et al, 2013). Additionally, defects in myelination have been shown to result from hydrocephalus (Di Curzio et al, 2013; Goto et al, 2008; Hanlo et al, 1997).…”

Cerebrospinal fluid biomarkers of infantile congenital hydrocephalus

“…The pathophysiology of hydrocephalus is multifactorial with a pervasive impact on the brain. Previous studies of CSF composition in hydrocephalus (reviewed in [ 10 – 16 ] have suggested that periventricular axonal damage and demyelination [ 13 , 17 , 18 ], apoptosis [ 19 ], disruption of the blood-brain barrier [ 20 ], reduced cerebral blood flow accompanied by hypoxia and ischemia [ 14 ], altered metabolism [ 21 ], reductions in neurotransmitters and neuromodulators [ 18 , 22 – 24 ], and neuroinflammation [ 13 , 25 – 31 ] may all play important roles in the progression of hydrocephalus. Older studies of various biomarkers associated with these mechanisms in developing brains have suggested that none were robust enough to predict clinical outcome [ 10 , 32 ], but more recent reports, especially those on adult and aging patients with idiopathic normal pressure hydrocephalus (iNPH), indicate that CSF levels of Aβ 42 and tau, correlate well with clinical signs and symptoms [ 11 , 12 , 15 , 18 , 32 – 39 ].…”