Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases

Tumani, Hayrettin; Teunissen, Charlotte E.; Süßmuth, Sigurd D.; Otto, Markus; Ludolph, Albert C.; Brettschneider, Johannes

doi:10.1586/14737159.8.4.479

Cited by 78 publications

(57 citation statements)

References 153 publications

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“…Albumin is a blood-derived protein and the CSF/ serum concentration ratio (albumin quotient) will increase when the blood-CSF-barrier is impaired. Thus, it is used as a measure of the blood-CSF-barrier integrity (44). Correlation of a proteins CSF concentration with the albumin quotient indicates that at least a part of the protein comes from the blood as shown for ␣Syn here.…”

Section: Investigation Of Synuclein Origin and Hemolysis As Confoundingmentioning

confidence: 92%

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Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies

Oeckl

Metzger

Nagl

et al. 2016

Molecular & Cellular Proteomics

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␣-Synuclein (␣Syn) is a major constituent of proteinaceous aggregates in neurodegenerative diseases such as Parkinsons disease (PD) and a potential biomarker candidate for diagnosis and treatment effects. However, studies about ␣Syn in cerebrospinal fluid (CSF) in diseases are inconsistent and mainly based on immunological assays. Quantitative information about ␤-synuclein (␤Syn) and ␥-synuclein (␥Syn) in CSF is not available.Here, we present an alternative method for the simultaneous quantification of ␣Syn, ␤Syn and ␥Syn in CSF by multiple reaction monitoring (MRM) with a high sequence coverage (70%) of ␣Syn to validate previous, ELISA-based results and characterize synucleins in CSF in more detail.The MRM has high sensitivity in the low pg/ml range (3-30pg/ml full-length ␣Syn) using 200 l CSF. A high portion of CSF ␣Syn is present in the N-terminally acetylated form and the concentration of unmodified peptides in the nonamyloid component region is about 40% lower than in the N-terminal region. Synuclein concentrations show a high correlation with each other in CSF (r>0.80) and in contrast to ␣Syn and ␥Syn, ␤Syn is not affected by blood contamination. CSF ␣Syn, ␤Syn and ␥Syn concentrations were increased in Alzheimers and CreutzfeldtJakob disease but not altered in PD, PD dementia (PDD), Lewy body dementia and atypical parkinsonian syndromes. The ratio ␤Syn/␣Syn was increased in PDD (1.49 ؎ 0.38, p < 0.05) compared with PD (1.11 ؎ 0.26) and controls (1.15 ؎ 0.28). ␤Syn shows a high correlation with CSF tau concentrations (r ‫؍‬ 0.86, p < 0.0001, n ‫؍‬ 125).In conclusion, we could not confirm previous observations of reduced ␣Syn in PD and our results indicate that CSF synuclein concentrations are rather general markers of synaptic degeneration than specific for synucleinopathies. ␤syn is an attractive biomarker candidate that might be used as an alternative to or in combination with tau in AD and CJD diagnosis and in combination with ␣Syn it is a biomarker candidate for PDD.

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Section: Investigation Of Synuclein Origin and Hemolysis As Confoundingmentioning

confidence: 92%

“…3C) (25,43). Thus, 80% of CSF protein is blood-derived (44). For a possible clinical application of a CSF biomarker it is important to know whether it is brain-derived or originates (in part) in the blood.…”

Section: Investigation Of Synuclein Origin and Hemolysis As Confoundingmentioning

confidence: 99%

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies

Oeckl

Metzger

Nagl

et al. 2016

Molecular & Cellular Proteomics

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109

144

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“…To define good biomarkers for ALS are also needed the standardized statistical methods and protocols for the spinal tap, sample processing, storage, specialized laboratories and multicentre, large, controlled, longitudinal studies (Tumani et al 2008). This review summarizes the current literature about CSF markers possibly involved in the pathogenesis of ALS.…”

Section: Neurofilament Light Chain (Nfl)mentioning

confidence: 99%

CSF markers in amyotrophic lateral sclerosis

et al. 2012

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Amyotrophic lateral sclerosis (ALS, 'Lou Gehrig disease') is the most common, progressive, neurodegenerative, motor neuron disease, causing damage to upper and lower motor neurons, leading to paralysis and death within 3-5 years. Majority of ALS cases are sporadic ALS (SALS) and only 5-10 % of cases are familial ALS (FALS). Pathogenesis of ALS is complicated and still unclear, including genetic, glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, neurofilament accumulation, impaired trophic support, altered glial function, viral infection, immune imbalance and impairment of the blood-brain, blood-spinal cord and blood-cerebrospinal fluid barriers (BBB/BSCB/BCSFB). The CSF analysis is still one of the basic laboratory tools and might reflect pathophysiological alterations in the course of the disease and could provide an insight into disease pathomechanisms. The most important aim of its analysis is evaluation of blood-CSF barrier, which is altered in 46 % of ALS patients. The CSF biomarkers may give insight into ALS pathophysiology and may be useful for early, presymptomatic diagnosis, therapeutic monitoring and the development of new therapeutic strategies. This review summarizes the general concepts of biomarkers in CSF of ALS patients and their potential usefulness in further research.

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“…It does not develop in most neurological diseases nor in the normal aging brain. P-tau is only slightly increased in Creutzfeldt-Jakob disease [28] and it is not increased in non-AD dementias such as vascular dementia, Lewy body dementia and frontotemporal dementia [30]. For patients with multiple sclerosis, there are conflicting results.…”

Section: Discussionmentioning

confidence: 99%

CSF phospho-tau is independent of age, cognitive status and gender of neurological patients

2009

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CSF phospho-tau (p-tau(181)) levels have shown good diagnostic utility in differential diagnosis of Alzheimer disease (AD). Unlike total-tau (t-tau), age related changes of this promising biomarker are sparsely studied. The aim of the study was to determine whether p-tau(181) is dependent on age, cognitive status or gender in patients with different neurological diseases who underwent diagnostic lumbar puncture and who had no clinical evidence of neurodegenerative diseases. CSF levels of p-tau(181) and total-tau (t-tau) of 46 neurologic patients (age range 22-89 years; 22 male, 24 female) were analyzed. Clinical diagnoses were cerebral ischaemia (n = 6), multiple sclerosis (n = 13), epileptic seizures (n = 3), polyneuropathy (n = 9) and other neurological diagnoses (n = 15). Cognitive performance was assessed by the German version of the CERAD battery. The mean level of p-tau(181) was in accordance with previous findings in neurological patients (42.8 +/- 15.3 pg/ml) and did not differ between neurological diseases. In contrast to t-tau (r = 0.38; P = 0.009), p-tau(181) did not correlate significantly to age (r = 0.15; P = 0.308). No influence of cognitive status or gender on p-tau(181) levels could be detected. The study corroborates the independence of p-tau(181) from age, cognitive status, gender and a wide spectrum of neurological diseases. The findings suggest that neither age related neurodegenerative processes nor ischaemic or inflammatory processes are accompanied by tau protein phosphorylation. In contrast, the data support the view that p-tau(181) seems to be a sign of the highly AD-specific pattern of tau phosphorylation during formation of neurofibrillary tangles.

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Cerebrospinal fluid biomarkers of neurodegeneration in chronic neurological diseases

Cited by 78 publications

References 153 publications

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies

CSF markers in amyotrophic lateral sclerosis

CSF phospho-tau is independent of age, cognitive status and gender of neurological patients

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