Miles D. Chapman

CSF and serum immune parameters in Sydenham's chorea: evidence of an autoimmune syndrome?

Previous investigations have suggested that Sydenhams chorea (SC) may be an autoantibody mediated disorder. We examined this autoimmune hypothesis by measuring Th1 (IFN-gamma, IL-12) and Th2 (IL-4, IL-10) cytokines, oligoclonal bands (OCB) and anti-basal ganglia antibodies (ABGA). CSF IL-4 was elevated in 31% of acute SC and 50% of persistent SC. CSF IL-10 was also elevated in 31% of acute SC but 0% of persistent SC. CSF IFN-gamma was undetectable in all patients. Serums IL-4, IL-10 and IL-12 were elevated in acute compared to persistent SC. OCB were found in 46% of acute SC, ABGA were in 93% of acute SC and 50% of persistent SC was of IgG(1) and IgG(3) subclass. These findings support an autoantibody pathogenesis.

Phosphorylation and compactness of neurofilaments in multiple sclerosis: Indicators of axonal pathology

Aims Axonal pathology extends to the axonal cytoarchitecture leaving its signature on axoskeletal proteins. This study investigated whether neurofilament (NfH) phosphorylation would relate to the dynamics of axonal pathology in multiple sclerosis (MS). Methods NfH phosphoforms (SMI32, SMI34, SMI35) were quantified by ELISA from microdissected samples of control and MS brain and spinal cord. Individual axons were analysed by electron microscopy, densitometrically and morphologically in adjacent tissue sections. Experiments were carried out pre- and post enzymatic dephosphorylation. Results In control tissue a rostro-caudal gradient of NfH indicated an increase in axonal density from the brain gray matter towards the spinal cord. The highest levels of phosphorylated and hyperphosphorylated NfH were found in acute lesions of brain and spinal cord, in contrast to chronic lesions where levels were lower than in white matter, consistent with axonal loss. Dephosphorylated NfH was higher, but less densly packed in MS white matter axons compared to control tissue. Conclusions The findings suggest that a less organised/compact axoskeleton or impaired axonal transport may represent an early sign of axonal pathology within the normal appearing white matter in MS. Subsequently a proportional increase of dephosphorylated NfH, aberrant phosphorylation and/or aggregation may occur whilst the protein is transported through the white matter towards the MS plaque, where hyperphosphorylated NfH dominates.

Post-streptococcal opsoclonus-myoclonus syndrome associated with anti-neuroleukin antibodies

Background: Adult opsoclonus-myoclonus (OM), a disorder of eye movements accompanied by myoclonus affecting the trunk, limbs, or head, is commonly associated with an underlying malignancy or precipitated by viral infection. Methods: We present the first two reports of post-streptococcal OM associated with antibodies against a 56 kDa protein. Two young girls presented with opsoclonus and myoclonus following a febrile illness and pharyngitis. Protein purification techniques were employed. Amino acid sequences of human neuroleukin (NLK) and streptococcal proteins were compared using the protein-protein BLAST application. Results: The antigen was identified as NLK (glucose-6-phosphate isomerase, GPI). GPI is present on the cell surface of streptococcus making the protein a candidate target for molecular mimicry. Conclusions: We have identified NLK as an antigenic target in two patients with post-streptococcal OM. The pathogenicity of the antibodies is uncertain. The potential role of anti-neuroleukin antibodies in the pathogenesis of OM is discussed. We propose that OM may represent a further syndrome in the growing spectrum of post-streptococcal neurological disorders. The role of streptococcus in OM and the frequency with which anti-NLK responses occur in both post-infectious and paraneoplastic OM should be investigated further.

Rostrocaudal Dynamics of CSF Biomarkers

The rostrocaudal gradient (RCG) of markers present in cerebrospinal fluid (CSF) has not been studied adequately due to lack of appropriate control populations and ethical restrictions. The aim of this study is to understand the rostrocaudal gradient of CSF biomarkers. We contacted a study comparing CSF levels of seven biomarkers from cisternal (rostral) and lumbar (caudal) CSF obtained from patients with trigeminal neuralgia and tension-type headache. The RCGs of CSF/serum albumin ratio, 8-isoprostane. GFAP, total tau and beta amyloid protein were higher than one. The RCGs of lactate, VEGF and the heavy chain of neurofilament protein were lower than one. The study provides new values for several commonly examined markers of cisternal CSF. Knowledge of the RCG gradient of different CSF markers is important in interpreting studies reporting ventricular CSF values.

Use of cerebrospinal fluid amyloid-β and total tau protein to predict favorable surgical outcomes in patients with idiopathic normal pressure hydrocephalus

OBJECT The prognostic value of CSF biomarkers in patients with idiopathic normal pressure hydrocephalus (iNPH) has not been adequately studied to date. The aim of this study was to identify CSF markers of favorable surgical outcome in patients with iNPH undergoing the insertion of a ventriculoperitoneal shunt. METHODS Ventricular CSF was collected intraoperatively from 22 patients with iNPH and enzyme-linked immunosorbent assay was used to analyze the levels of amyloid-β 1-42 (Aβ(1-42)) and total tau protein. The Black grading scale was used to assess outcomes at 6 months. Receiver operating characteristic (ROC) curves were obtained and discriminant function analysis was undertaken to provide sensitivity and specificity figures for each marker as well as their combination. RESULTS The mean age of the patients was 71.45 years (± 9.5 years [SD]). Follow-up was achieved in 21 patients. Seventeen patients had a favorable outcome and 4 patients had unfavorable outcome at 6 months. An Aβ(1-42) level of 180 pg/ml had a sensitivity of 35% and a specificity of 20% for predicting a favorable outcome at 6 months. A total tau level of 767 pg/ml will have a sensitivity of 17% and a specificity of 20% for predicting a favorable outcome at 6 months. A combination of Aβ(1-42) and total tau levels predicted favorable outcomes with a sensitivity of 80% and specificity of 82.4%. CONCLUSIONS In this pilot study a combination of Aβ(1-42) levels and total tau protein levels predicted favorable surgical outcomes at 6 months with adequate accuracy to be of clinical use. Further study in a larger group with longer follow-up is warranted.

Cognitive, biochemical, and imaging profile of patients suffering from idiopathic normal pressure hydrocephalus

It has still not been clearly established whether the cognitive deficits of idiopathic normal pressure hydrocephalus (iNPH) are caused by a disturbance in cerebrospinal fluid (CSF) dynamics or an underlying metabolic disturbance.

Axonal loss influences the response to rituximab treatment in neuropathy associated with IgM monoclonal gammopathy with anti-myelin-associated glycoprotein antibody

Polyneuropathy associated with anti-Myelin-Associated Glycoprotein (MAG) antibody is a well-defined immune-mediated disease that develops in individuals with IgM monoclonal gammopathy. Factors related to response to rituximab treatment in anti-MAG neuropathy have not been clarified so far. We prospectively evaluated the clinical status, immunological changes, and electrophysiological parameters before and 12 months after rituximab treatment in 7 patients with anti-MAG neuropathy. Pathological indices of sural nerve biopsy specimens before rituximab treatment were investigated. Overall, 4 patients improved by more than 5% either clinical scale, expressed according to the Medical Research Council (MRC) sum score or sensory sum score (SSS) 12 months after rituximab treatment. The modified Rankin Scale (mRS) scores improved in 2 patients. With respect to the relationship between the response to rituximab treatment and the clinicopathological findings, short disease duration and preservation of nerve fiber density were significantly related. The immunohistochemical assessment suggested that low-intensity binding of anti-IgM antibody to the myelin sheath may contribute to the degree of response to rituximab treatment. The degree of axonal loss and the deposition of pathogenic autoantibodies in myelinated fibers may determine the therapeutic response to rituximab treatment in anti-MAG neuropathy.

The longitudinal profile of CSF markers during external lumbar drainage

Background: External lumbar drainage (ELD) is known as a good predictor of favourable outcome in shunting patients suffering from idiopathic normal pressure hydrocephalus (iNPH). Methods: Eleven patients suffering from iNPH had a lumbar drain (LD) inserted for 72 h and participated in a research study to quantify any improvement in their clinical symptoms. The lumbar cerebrospinal fluid (CSF) levels of lactate, 8-isoprostane, vascular endothelial growth factor (VEGF), glial fibrillar acidic protein (GFAP), neurofilament (heavy chain) protein (NF (h)), Aβ1–42 (β-amyloid) and total tau were assayed samples from all three time points. Results: The concentrations of lactate, VEGF, GFAP and tau increased significantly during the 72 h of drainage. There were also increases in 8-isoprostane and Aβ1–42 (non significant). The concentration of NF (h) was reduced significantly following 72 h of drainage. There was a significant positive correlation between Aβ1–42 and total tau in the first sample. GFAP was negatively correlated in a significant fashion with both Aβ1–42 and total tau. NF (h) was negatively correlated with VEGF. Conclusion: Evidence is provided that ELD is producing measurable changes in the CSF composition of patients with iNPH. The present paper discusses how such changes may be implicated in the pathophysiology of the condition.

An unbiased, staged, multicentre, validation strategy for Alzheimer's disease CSF tau levels

Newly proposed diagnostic criteria for Alzheimers disease include cerebrospinal fluid (CSF) tau levels as one core supportive criterion. The published high sensitivity and specificity figures for CSF tau levels in Alzheimers disease are offset by the large range of proposed cutoff values (9.6 pg/mL to 1140 pg/mL). This study aimed to provide guidance on how to establish, validate and audit CSF tau cutoff values using an unbiased, two-stage multicentre strategy. Both receiver operator characteristics (ROC) optimised and population-based cutoff values were calculated on a pilot dataset (n=99), validated in a large dataset (n=560) and then compared to the literature. The data suggest using an ROC optimised cutoff level of 323+/-51.7 pg/mL allowing for the published inter-laboratory coefficient of variation of 16%. This cutoff level was confirmed in a prospective audit (n=100). As demand for CSF tau levels will increase globally, the accuracy of local CSF hTau cutoff levels can be compared against this benchmark.

Do cerebrospinal fluid transfer methods affect measured amyloid β42, total tau, and phosphorylated tau in clinical practice?

Cerebrospinal fluid (CSF) neurodegenerative markers are measured clinically to support a diagnosis of Alzheimers disease. Several preanalytical factors may alter the CSF concentrations of amyloid β 1–42 (Aβ1–42) in particular with the potential to influence diagnosis. We aimed to determine whether routine handling of samples alters measured biomarker concentration compared with that of prompt delivery to the laboratory.