Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias

Objective: To assess the utility of serum neurofilament for diagnosis and monitoring of primary progressive aphasia (PPA) variants. Methods: We investigated neurofilament light chain (NF-L) levels in blood of 99 patients with PPA (40 with nonfluent variant PPA [nfvPPA], 38 with semantic variant PPA [svPPA], 21 with logopenic variant PPA [lvPPA]) and compared diagnostic performance with that reached by CSF NF-L, phosphorylated neurofilament heavy chain (pNF-H), b-amyloid (Ab(1)-42), tau, and phosphorylated tau. The longitudinal change of blood NF-L levels was measured and analyzed for correlation with functional decline and brain atrophy. Results: Serum NF-L is increased in PPA compared to controls and discriminates between nfvPPA/svPPA and lvPPA with 81% sensitivity and 67% specificity (cutoff 31 pg/mL). CSF NF-L, pNF-H, tau, phosphorylated tau, and Ab1-42 achieved similar performance, and pNF-H was the only marker for discrimination of nfvPPA from svPPA/lvPPA. In most patients with nfvPPA and svPPA, but not lvPPA, serum NF-L increased within follow-up. The increase correlated with functional decline and progression of atrophy of the left frontal lobe of all patients with PPAs and the right middle frontal gyrus of patients with nfvPPA and svPPA. Conclusions: Blood level of NF-L can aid the differential diagnosis of PPA variants, especially in combination with CSF pNF-H. Because serum NF-L correlates with functional decline and atrophy in the disease course, it qualifies as an objective disease status marker. Extended follow-up studies with cases of known neuropathology are imperative

Establishment of mass spectrometric determination of the biomarkers cAMP and cGMP and investigation of potential pathogenic processes (GPR6, telomerase, microglial activation) in animal models of Parkinson´s disease

Parkinson´s disease (PD) is a neurodegenerative disorder with a characteristic loss of nigrostriatal dopaminergic neurons and disturbances of the motoric system. There is an unmet medical need for the discovery of disease modifying treatment strategies and identification of reliable biomarkers. The aim of my PhD thesis was to establish an analytical method for the determination of the free radical biomarkers o-, m-, p-tyrosine, nitrophenylalanine and nitrotyrosine by HPLC as well as the biomarkers cyclic adenosine-3´,5´-monophosphate (cAMP) and cyclic guanosine-3´,5´-monophosphate (cGMP) by liquid chromatography/tandem mass spectrometry (LC-MS/MS). In order to improve the knowledge about PD pathogenesis, I investigated the impact of astrocyte-specific IKK2 activation and telomerase deficiency in the MPTP model of PD using neurochemical and behavioural readouts as well as immunohistochemistry. I established the neuroinflammatory-based LPS (lipopolysaccharide) mouse model of PD and investigated new treatment strategies for PD including GPR6 deficiency, angiotensin II receptor 1 (AT1) antagonism by telmisartan, NADPH oxidase inhibition by apocynin and the increase of single, O-glycosidically linked -N-acetylglucosamine (O-GlcNAc) on proteins by Thiamet G. The HPLC method for the determination of the free radical biomarkers showed good sensitivity (up to 5 nM) and linearity (up to 100 µM). The increased formation of the free radical biomarkers after in vitro incubation of D-phenylalanine with peroxyinitrite and in vivo injection of 6-hydroxydopamine (6-OHDA) in mice verified the use of this biomarkers for free radical determination. The LC-MS/MS method for cAMP and cGMP showed high sensitivity (limit of quantification 0.5 nM). It was suitable to measure cAMP and cGMP in plasma, cerebrospinal fluid (CSF) and brain tissue. ..

Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome

The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 %) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 %) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 % CI 21-34) compared to 47 months in OCB-negative individuals (95 % CI 36-85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 % (18/30), whereas it was only 21 % (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria