Blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. The pattern of lower motor neuron loss along the spinal cord follows the pattern of deposition of phosphorylated TDP-43 aggregates. The blood-spinal cord barrier (BSCB) restricts entry into the spinal cord parenchyma of blood components that can promote motor neuron degeneration, but in ALS there is evidence for barrier breakdown. Here we sought to quantify BSCB breakdown along the spinal cord axis, to determine whether BSCB breakdown displays the same patterning as motor neuron loss and TDP-43 proteinopathy. Cerebrospinal fluid hemoglobin was measured in living ALS patients (n = 87 control, n = 236 ALS) as a potential biomarker of BSCB and blood-brain barrier leakage. Cervical, thoracic, and lumbar post-mortem spinal cord tissue (n = 5 control, n = 13 ALS) were then immunolabelled and semi-automated imaging and analysis performed to quantify hemoglobin leakage, lower motor neuron loss, and phosphorylated TDP-43 inclusion load. Hemoglobin leakage was observed along the whole ALS spinal cord axis and was most severe in the dorsal gray and white matter in the thoracic spinal cord. In contrast, motor neuron loss and TDP-43 proteinopathy were seen at all three levels of the ALS spinal cord, with most abundant TDP-43 deposition in the anterior gray matter of the cervical and lumbar cord. Our data show that leakage of the BSCB occurs during life, but at end-stage disease the regions with most severe BSCB damage are not those where TDP-43 accumulation is most abundant. This suggests BSCB leakage and TDP-43 pathology are independent pathologies in ALS.

Clinical application of intrathecal gadobutrol for assessment of cerebrospinal fluid tracer clearance to blood.

BACKGROUNDMethodology for estimation of cerebrospinal fluid (CSF) tracer clearance could have wide clinical application in predicting excretion of intrathecal drugs and metabolic solutes from brain metabolism and for diagnostic workup of CSF disturbances.METHODSThe MRI contrast agent gadobutrol (Gadovist) was used as a CSF tracer and injected into the lumbar CSF. Gadobutrol is contained outside blood vessels of the CNS and is eliminated along extravascular pathways, analogous to many CNS metabolites and intrathecal drugs. Tracer enrichment was verified and assessed in CSF by MRI at the level of the cisterna magna in parallel with obtaining blood samples through 48 hours.RESULTSIn a reference patient cohort (n = 29), both enrichment within CSF and blood coincided in time. Blood concentration profiles of gadobutrol through 48 hours varied between patients diagnosed with CSF leakage (n = 4), idiopathic normal pressure hydrocephalus dementia (n = 7), pineal cysts (n = 8), and idiopathic intracranial hypertension (n = 4).CONCLUSIONAssessment of CSF tracer clearance is clinically feasible and may provide a way to predict extravascular clearance of intrathecal drugs and endogenous metabolites from the CNS. The peak concentration in blood (at about 10 hours) was preceded by far peak tracer enhancement at MRI in extracranial lymphatic structures (at about 24 hours), as shown in previous studies, indicating a major role of the spinal canal in CSF clearance capacity.FUNDINGThe work was supported by the Department of Neurosurgery, Oslo University Hospital; the Norwegian Institute for Air Research; and the University of Oslo.

Spontaneous cerebrospinal fluid leak via foramen rotundum in a non-obese male presented as pseudo-Chiari malformation type I: a case report and literature review.

Spontaneous cerebrospinal fluid (sCSF) leak from the skull base has been previously reported, but there are few reports of sCSF leak from the foramen rotundum due to its rare occurrence. This case report describes a 15-year-old male patient that presented with left side watery rhinorrhoea that had been present since he was 4 years of age and a history of repeated bouts of meningitis of unknown cause. A discharge sample from the nose tested positive for beta-2 transferrin. Preoperative computed tomography (CT) revealed a fistula between the cerebellopontine angle and the left sphenoid sinus. There was also a pseudo-Chiari malformation type I with ectopia of the cerebellar tonsil. Endoscopic transnasal surgery identified a leak from the foramen rotundum that was repaired using autologous material and a contralateral pedicle nasoseptal flap. At 6 months after surgery, the patient reported no recurrence of the CSF leakage. Postoperative CT imaging revealed that the cerebellar tonsil was back in the normal position, indicating that the preoperative Chiari malformation was possibly due to decreased CSF volume. This current case shows that a rare case of sCSF leak from the foramen rotundum can be effectively repaired using the endoscopic transnasal approach.

Tau protein as a possible marker of cerebrospinal fluid leakage in cerebrospinal fluid rhinorrhoea: A pilot study.

INTRODUCTION: The management of posttraumatic cerebrospinal fluid (CSF) rhinorrhoea remains a clinical challenge. Cerebrospinal fistula is a dural defect responsible for possible CSF leakage into the contiguous air-filled cavities located at the skull base. The risk of central nervous system infection in these conditions is severe and can be life threatening. Consequently, a specific CSF biomarker might be used in case of difficult diagnosis of CSF rhinorrhoea. CSF Tau protein is a neuronal protein, commonly assessed for diagnosis of Alzheimer Disease (AD). The aim of this study was to determine whether the Tau protein could be a relevant marker of CSF leakage. MATERIALS AND METHODS: Tau protein measurement was performed by enzyme-linked immunosorbent assay in 13 patients with CSF leakage (CSF rhinorrhoea group), and 8 patients with spontaneous aqueous rhinorrhoea (non-CSF leakage group). The serum concentration of Tau protein was measured by ELISA in both CSF rhinorrhoea group and non-CSF leakage group. RESULTS: In patients with CSF leakage, CSF Tau protein median concentration was 479 ng/L (197 - 2325 ng/L). On the other hand, the Tau protein concentration was below the lower limit of quantification (LLoQ) (< 87 ng/L) in non-CSF leakage group. Serum Tau protein concentration by ELISA was also below LLoQ (< 87 ng/L) for all subjects. CONCLUSION: ELISA measurement of Tau protein in rhinorrhoea fluid may be a reliable and relevant marker for detecting the presence of CSF in the nasal discharge and sign the existence of a CSF leakage.