Sigurd D. Süssmuth

Axonal damage markers in cerebrospinal fluid are increased in ALS

Objective: To test whether biomarkers for axonal degeneration correlated with clinical subtypes and were of use in predicting progression of ALS. Methods: Patients with ALS (n = 69), patients with Alzheimer disease (AD; n = 73), and age-matched controls (n = 33) were included in this prospective study. CSF levels of tau protein and neurofilaments (NfHSMI35) were measured using ELISA. In 49 patients with ALS, follow-up data were available (median follow-up 7 months). Results: CSF levels of NfHSMI35 were five times higher in patients with ALS (1.7 ng/mL) than in controls (0.3 ng/mL, p < 0.001) and 10 times higher than in patients with AD (0.14 ng/mL, p < 0.001). NfHSMI35 values were also higher in patients with upper motor neuron–dominant ALS than in patients with typical ALS (upper motor neuron + lower motor neuron) at p = 0.02. Values of NfHSMI35 were higher in ALS of more rapid progression. The values of NfH and tau did not correlate with CSF protein content. Conclusions: The authors propose that axonal damage markers in CSF may discriminate between subtypes of ALS and that they could be used as markers for therapeutic trials. CSF NfH was superior to tau in these discriminations.

Tau protein in cerebrospinal fluid (CSF): a blood–CSF barrier related evaluation in patients with various neurological diseases

Tau protein (tau) is primarily localised in neurons, and after brain parenchymal damage its release into cerebrospinal fluid (CSF) is increased. The particular influences of blood-CSF barrier function and of disease topography on CSF tau levels have not been studied yet. CSF tau concentrations determined by enzyme-immunoassay in various neurological diseases (n = 61) were not dependent upon blood-CSF barrier dysfunction. Significant elevation of tau levels in patients with meningoencephalitis and cerebral hemorrhage indicates brain parenchymal damage. In contrast, tau levels remained normal in patients with bacterial meningitis if encephalitic complications did not occur. In patients with Guillain-Barré syndrome tau levels were low. Increased tau levels in active multiple sclerosis compared to clinically nonactive states indicate axonal pathology in active disease.

Amyotrophic lateral sclerosis: disease stage related changes of tau protein and S100 beta in cerebrospinal fluid and creatine kinase in serum.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to progressive cell death of upper and lower motor neurons and reactive astrogliosis. Two proteins which may be relevant in this respect (tau and S100 beta) were studied in cerebrospinal fluid (CSF) next to routine parameters in 20 patients with sporadic ALS and 20 age-matched controls. Serum levels of creatine kinase (CK) were also determined to monitor the muscular involvement. S100 beta showed a significant decrease in CSF over the disease course (P=0.024). CSF tau as well as serum CK were elevated in 70% of the ALS patients. While highest CSF tau levels were found rather in the early disease stages, serum CK showed a shift of the peak values to several months later. Elevation of the CSF/serum albumin quotient occurred in 20% of the cases most likely representing a non-specific finding in ALS.

Cerebrospinal fluid biomarkers in Guillain-Barré syndrome--where do we stand?

Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy affecting the myelin-protein sheathing and the axons themselves to various degrees. Damage to these structures causes biomarkers to be released into the adjacent body fluid compartment. In case of the proximal nerve roots these biomarkers diffuse into the cerebrospinal fluid (CSF). Here we review the literature on CSF biomarkers in GBS, including a discussion of CSF basic findings, myelin sheath-associated markers (myelin basic protein), axonal damage markers (neurofilaments, tau, anti-ganglioside antibodies), glial and neuronal markers (neuron specific enolase, 14-3-3 proteins, S100B, hypocretin-1), immunological markers (different chemokines and complement factors, cystatin C, tumor necrosis factor-α) as well as recent advances in the field of CSF proteome analysis in GBS. Second, the different pathophysiological mechanisms reflected by these biomarkers are discussed. Finally, candidate biomarkers are reviewed with regard to their clinical relevance to act as a surrogate for the disease process, their value for improving prognostic accuracy and their potential to be used as predictors of treatment response.

Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases

Chronic neurological diseases (CND) like amyotrophic lateral sclerosis (ALS), dementia or multiple sclerosis (MS) share a chronic progressive course of disease that frequently leads to the common pathological pathway of neurodegeneration, including neuroaxonal damage, apoptosis and gliosis. There is an ongoing search for biomarkers that could support early diagnosis of CND and help to identify responders to interventions in therapeutic treatment trials. Cerebrospinal fluid (CSF) is a promising source of biomarkers in CND, since the CSF compartment is in close anatomical contact with the brain interstitial fluid, where biochemical changes related to CND are reflected. We review recent advances in CSF biomarkers research in CND and thereby focus on markers associated with neurodegeneration.

Roadmap and standard operating procedures for biobanking and discovery of neurochemical markers in ALS

Abstract Despite major advances in deciphering the neuropathological hallmarks of amyotrophic lateral sclerosis (ALS), validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis, defining prognosis and unlocking key pathophysiological pathways are lacking. Although several candidate biomarkers exist, translation into clinical application is hindered by small sample numbers, especially longitudinal, for independent verification. This review considers the potential routes to the discovery of neurochemical markers in ALS, and provides a consensus statement on standard operating procedures that will facilitate multicenter collaboration, validation and ultimately clinical translation.

Neurofilament heavy-chain NfHSMI35 in cerebrospinal fluid supports the differential diagnosis of Parkinsonian syndromes

We aimed to evaluate the potential of the cerebrospinal fluid (CSF) axonal damage biomarker NfHSMI35 in the laboratory‐supported differential diagnosis of parkinsonian syndromes. Patients with idiopathic Parkinsons disease (PD; n = 22), multiple‐system atrophy (MSA; n = 21), progressive supranuclear palsy (PSP; n = 21), corticobasal degeneration (CBD; n = 6), and age‐matched controls (n = 45) were included. CSF levels of NfHSMI35 were measured using ELISA. Levels of CSF NfHSMI35 were elevated in PSP compared to PD and controls (P < 0.05 each). They were also significantly higher in MSA than in PD and controls (P < 0.05 each). NfHSMI35 differentiated PD from PSP with a sensitivity of 76.5% and a specificity of 94.4%. Axonal damage as measured by CSF NfHSMI35 is most prominent in the more rapidly progressive syndromes PSP and MSA as compared to PD or CBD. CSF NfHSMI35 may therefore be of some value for the laboratory‐supported differential diagnosis of atypical parkinsonian syndromes.

CSF glial markers correlate with survival in amyotrophic lateral sclerosis.

Background: In neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), CSF biomarkers are increasingly studied to evaluate their relevance for differential diagnosis, disease progression, and understanding of pathophysiologic processes. Objective: To identify a biomarker profile of neuronal and glial CSF proteins to discriminate ALS from other motor neuron diseases (MND) and to assess whether baseline levels of CSF measures in ALS are associated with the course of the disease. Methods: A total of 122 consecutive subjects with MND were included in this cross-sectional study (ALS, n = 75; lower motor neuron syndrome, n = 39; upper motor neuron diseases, n = 8). Clinical follow-up included 76 patients. We determined baseline levels of protein tau and astroglial S100beta in CSF and microglial sCD14 in CSF and serum in relation to diagnosis, duration of disease, and survival. Results: CSF tau was significantly elevated in ALS and upper motor neuron diseases as compared to lower motor neuron diseases and controls. CSF S100beta levels were significantly lower in lower motor neuron diseases as compared to other MND. CSF concentrations of S100beta and sCD14 correlated with the survival time in patients with ALS. Conclusions: In motor neuron diseases, CSF tau elevation indicates the degeneration of upper motor neurons, while S100 beta and sCD14 may indicate the activation of CNS glial cells. Because S100beta and sCD14 concentrations correlate with survival in amyotrophic lateral sclerosis (ALS), we suppose that the combination of both markers may be useful to obtain prognostic information in patients with ALS.

Biochemical markers in CSF of ALS patients.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron diseases (MND) characterized by progressive selective degeneration of motor neurons. Although several mutations underlying rare cases of familial ALS were identified during the last decade, the pathogenesis of ALS remains poorly understood. Various mechanisms have been suggested to contribute to disease pathology such as excitotoxicity, oxidative stress, protein aggregation, and inflammation. Accordingly, several candidate biochemical markers related to these pathomechanisms were investigated in cerebrospinal fluid (CSF). Although none of these markers gained clinical importance so far, CSF might reflect pathophysiological alterations in the course of the disease and could therefore provide an insight into pathomechanisms in vivo. It is suggested that cellular and proteinchemical processes are better reflected in the CSF than in other body fluids such as blood or urine due to the proximity of the affected motor neurons to the CSF compartment. Accordingly, alterations in protein expression, post-translational modification or turnover within the tissue of the central nervous system may be mirrored in corresponding changes in CSF protein content. Research on biomarkers in CSF using novel discovery technologies such as proteomics allows to search for a set of proteins that reflect different disease specific molecular pathways and might therefore be of relevance for the establishment of biomarkers for therapeutic monitoring and the development of novel therapies. In this review, an updated overview is given on CSF biomarkers related to the pathomechanisms supposed to be participating in the complex disease process of ALS.

An exploratory double‐blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease

AIMS Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntingtons disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers. METHODS This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers. RESULTS Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen. CONCLUSIONS Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.