Prospective CERAD Neuropsychological Assessment in Patients With Multiple System Atrophy.

The objective of the study was to characterize the pattern of cognitive dysfunction in patients with multiple system atrophy (MSA) applying a standardized neuropsychological assessment. A total of 20 patients with the diagnosis of probable or possible MSA were enrolled for neuropsychological assessment applying the CERAD plus battery. All patients were tested at baseline and 14/20 patients received additional follow-up assessments (median follow-up of 24 months). Additionally, relationship between cortical thickness values/subcortical gray matter volumes and CERAD subitems was evaluated at baseline in a subgroup of 13/20 patients. Trail Making Test (TMT) was the most sensitive CERAD item at baseline with abnormal performance (z-score < -1.28) in one or both pathological TMT items (TMT-A, TMT-B) in 60% of patients with MSA. Additionally, there was a significant inverse correlation between the volume of the left and the right accumbens area and the TMT A item after adjusting for age (left side: p = 0.0009; right side p = 0.003). Comparing both subtypes, patients with MSA-C had significant lower values in phonemic verbal fluency (p = 0.04) and a trend for lower values in semantic verbal fluency (p = 0.06) compared to MSA-P. Additionally, patients with MSA-C showed significantly worse performance in the TMT-B task (p = 0.04) and a trend for worse performance in the TMT-A task (p = 0.06). Concerning longitudinal follow-up, a significant worsening in the TMT-B (p = 0.03) can be reported in MSA. In conclusion, frontal-executive dysfunction presents the hallmark of cognitive impairment in MSA.

Validation of Plasma and CSF Neurofilament Light Chain as an Early Marker for Sporadic Creutzfeldt-Jakob Disease.

Biomarkers are becoming increasingly important for the differential diagnosis of neurodegenerative diseases. Previous observations indicated neurofilament light chain (NfL) as a potential blood-based biomarker for sporadic Creutzfeldt-Jakob disease (sCJD). Here, we investigated the stability, inter-assay/intra-assay variation and the regulation of NfL levels in CSF and plasma in a large cohort of sCJD patients by using a single-molecule array (SIMOA). We defined cutoffs for an accurate diagnosis and measured plasma NfL level in prion-infected mice models at different time points to identify the potential dynamics throughout the disease. Our analyses confirmed CSF and plasma NfL as stable and consistent marker for sCJD. Receiver operating characteristic (ROC) curve analysis showed an AUC of 0.92-0.93 to distinguish sCJD from control groups. Newly defined cutoffs revealed good diagnostic accuracies of CSF and plasma NfL, indicated by a sensitivity of 80-83.5% and a specificity of 87.4-91%. Studies on two humanized prion-infected mice lines (Tg340-PRNP 129MM and Tg361-PRNP 129VV) revealed increased plasma NfL levels in a late pre-clinical or very early clinical stage between 120-150 days post-inoculation. In conclusion, our work supports the potential use of CSF and plasma NfL as a very early biomarker in sCJD diagnostic with good diagnostic accuracies.

Baseline Cerebrospinal Fluid α-Synuclein in Parkinson's Disease Is Associated with Disease Progression and Cognitive Decline.

Biomarkers are increasingly recognized as tools in the diagnosis and prognosis of neurodegenerative diseases. No fluid biomarker for Parkinson's disease (PD) has been established to date, but α-synuclein, a major component of Lewy bodies in PD and dementia with Lewy bodies (DLB), has become a promising candidate. Here, we investigated CSF α-synuclein in patients with PD (n = 28), PDD (n = 8), and DLB (n = 5), applying an electrochemiluminescence immunoassay. Median values were non-significantly (p = 0.430) higher in patients with PDD and DLB (287 pg/mL) than in PD (236 pg/mL). A group of n = 36 primarily non-demented patients with PD and PDD was clinically followed for up to two years. A higher baseline α-synuclein was associated with increases in Hoehn and Yahr classifications (p = 0.019) and Beck Depression Inventory scores (p < 0.001) as well as worse performance in Trail Making Test A (p = 0.017), Trail Making Test B (p = 0.043), and the Boston Naming Test (p = 0.002) at follow-up. Surprisingly, higher levels were associated with a better performance in semantic verbal fluency tests (p = 0.046). In summary, CSF α-synuclein may be a potential prognostic marker for disease progression, affective symptoms, and executive cognitive function in PD. Larger-scaled studies have to validate these findings and the discordant results for single cognitive tests in this exploratory investigation.

Plasma Lipocalin 2 in Alzheimer's disease: potential utility in the differential diagnosis and relationship with other biomarkers.

BACKGROUND: Lipocalin-2 is a glycoprotein that is involved in various physiological and pathophysiological processes. In the brain, it is expressed in response to vascular and other brain injury, as well as in Alzheimer's disease in reactive microglia and astrocytes. Plasma Lipocalin-2 has been proposed as a biomarker for Alzheimer's disease but available data is scarce and inconsistent. Thus, we evaluated plasma Lipocalin-2 in the context of Alzheimer's disease, differential diagnoses, other biomarkers, and clinical data. METHODS: For this two-center case-control study, we analyzed Lipocalin-2 concentrations in plasma samples from a cohort of n = 407 individuals. The diagnostic groups comprised Alzheimer's disease (n = 74), vascular dementia (n = 28), other important differential diagnoses (n = 221), and healthy controls (n = 84). Main results were validated in an independent cohort with patients with Alzheimer's disease (n = 19), mild cognitive impairment (n = 27), and healthy individuals (n = 28). RESULTS: Plasma Lipocalin-2 was significantly lower in Alzheimer's disease compared to healthy controls (p < 0.001) and all other groups (p < 0.01) except for mixed dementia (vascular and Alzheimer's pathologic changes). Areas under the curve from receiver operation characteristics for the discrimination of Alzheimer's disease and healthy controls were 0.783 (95%CI: 0.712-0.855) in the study cohort and 0.766 (95%CI: 0.627-0.905) in the validation cohort. The area under the curve for Alzheimer's disease versus vascular dementia was 0.778 (95%CI: 0.667-0.890) in the study cohort. In Alzheimer's disease patients, plasma Lipocalin2 did not show significant correlation with cerebrospinal fluid biomarkers of neurodegeneration and AD-related pathology (total-tau, phosphorylated tau protein, and beta-amyloid 1-42), cognitive status (Mini Mental Status Examination scores), APOE genotype, or presence of white matter hyperintensities. Interestingly, Lipocalin 2 was lower in patients with rapid disease course compared to patients with non-rapidly progressive Alzheimer's disease (p = 0.013). CONCLUSIONS: Plasma Lipocalin-2 has potential as a diagnostic biomarker for Alzheimer's disease and seems to be independent from currently employed biomarkers.

Detection of Cerebrospinal Fluid Neurofilament Light Chain as a Marker for Alpha-Synucleinopathies.

Alpha-synucleinopathies, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are a class of neurodegenerative diseases. A diagnosis may be challenging because clinical symptoms partially overlap, and there is currently no reliable diagnostic test available. Therefore, we aimed to identify a suitable marker protein in cerebrospinal fluid (CSF) to distinguish either between different types of alpha-synucleinopathies or between alpha-synucleinopathies and controls. In this study, the regulation of different marker protein candidates, such as alpha-synuclein (a-Syn), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and total tau (tau) in different types of alpha-synucleinopathies, had been analyzed by using an ultrasensitive test system called single-molecule array (SIMOA). Interestingly, we observed that CSF-NfL was significantly elevated in patients with DLB and MSA compared to patients with PD or control donors. To differentiate between groups, receiver operating characteristic (ROC) curve analysis resulted in a very good diagnostic accuracy as indicated by the area under the curve (AUC) values of 0.87-0.92 for CSF-NfL. Furthermore, we observed that GFAP and tau were slightly increased either in DLB or MSA, while a-Syn levels remained unregulated. Our study suggests NfL as a promising marker to discriminate between different types of alpha-synucleinopathies or between DLB/MSA and controls.

Diagnostic and prognostic value of plasma neurofilament light and total-tau in sporadic Creutzfeldt-Jakob disease.

BACKGROUND: Blood neurofilament light (Nfl) and total-tau (t-tau) have been described to be increased in several neurological conditions, including prion diseases and other neurodegenerative dementias. Here, we aim to determine the accuracy of plasma Nfl and t-tau in the differential diagnosis of neurodegenerative dementias and their potential value as prognostic markers of disease severity. METHODS: Plasma Nfl and t-tau were measured in healthy controls (HC, n = 70), non-neurodegenerative neurological disease with (NND-Dem, n = 17) and without dementia syndrome (NND, n = 26), Alzheimer's disease (AD, n = 44), Creutzfeldt-Jakob disease (CJD, n = 83), dementia with Lewy bodies/Parkinson's disease with dementia (DLB/PDD, n = 35), frontotemporal dementia (FTD, n = 12), and vascular dementia (VaD, n = 22). Biomarker diagnostic accuracies and cutoff points for the diagnosis of CJD were calculated, and associations between Nfl and t-tau concentrations with other fluid biomarkers, demographic, genetic, and clinical data in CJD cases were assessed. Additionally, the value of Nfl and t-tau predicting disease survival in CJD was evaluated. RESULTS: Among diagnostic groups, highest plasma Nfl and t-tau concentrations were detected in CJD (fold changes of 38 and 18, respectively, compared to HC). Elevated t-tau was able to differentiate CJD from all other groups, whereas elevated Nfl concentrations were also detected in NND-Dem, AD, DLB/PDD, FTD, and VaD compared to HC. Both biomarkers discriminated CJD from non-CJD dementias with an AUC of 0.93. In CJD, plasma t-tau, but not Nfl, was associated with PRNP codon 129 genotype and CJD subtype. Positive correlations were observed between plasma Nfl and t-tau concentrations, as well as between plasma and CSF concentrations of both biomarkers (p < 0.001). Nfl was increased in rapidly progressive AD (rpAD) compared to slow progressive AD (spAD) and associated to Mini-Mental State Examination results. However, Nfl displayed higher accuracy than t-tau discriminating CJD from rpAD and spAD. Finally, plasma t-tau, but not plasma Nfl, was significantly associated with disease duration, offering a moderate survival prediction capacity. CONCLUSIONS: Plasma Nfl and t-tau are useful complementary biomarkers for the differential diagnosis of CJD. Additionally, plasma t-tau emerges as a potential prognostic marker of disease duration.

A new tetra-plex fluorimetric assay for the quantification of cerebrospinal fluid ß-amyloid42, total-tau, phospho-tau and α-synuclein in the differential diagnosis of neurodegenerative dementia.

BACKGROUND: Differential diagnosis of neurodegenerative dementia is currently supported by biomarkers including cerebrospinal fluid (CSF) tests. Among them, CSF total-tau (t-tau), phosphorylated tau (p-tau) and ß-amyloid42 (Aß42) are considered core biomarkers of neurodegeneration. In the present work, we hypothesize that simultaneous assessment of these biomarkers together with CSF α-synuclein (α-syn) will significantly improve the differential diagnostic of Alzheimer's disease and other dementias. To that aim, we characterized the analytical and clinical performance of a new tetra-plex immunoassay that simultaneously quantifies CSF Aß42, t-tau, p-tau and α-syn in the differential diagnosis of neurodegenerative dementia. METHODS: Biomarkers' concentrations were measured in neurological controls (n = 38), Alzheimer's disease (n = 35), Creutzfeldt-Jakob disease (n = 37), vascular dementia (n = 28), dementia with Lewy bodies/Parkinson's disease dementia (n = 27) and frontotemporal dementia (n = 34) using the new tetra-plex assay and established single-plex assays. Biomarker's performance was evaluated and diagnostic accuracy in the discrimination of diagnostic groups was determined using partial least squares discriminant analysis. RESULTS: The tetra-plex assay presented accuracies similar to individual single-plex assays with acceptable analytical performance. Significant correlations were observed between tetra-plex and single-plex assays. Using partial least squares discriminant analysis, Alzheimer's disease and Creutzfeldt-Jakob disease were well differentiated, reaching high accuracies in the discrimination from the rest of diagnostic groups. CONCLUSIONS: The new tetra-plex assay coupled with multivariate analytical approaches becomes a valuable asset for the differential diagnosis of neurodegenerative dementia and related applications.

Cerebrospinal fluid lipocalin 2 as a novel biomarker for the differential diagnosis of vascular dementia.

The clinical diagnosis of vascular dementia (VaD) is based on imaging criteria, and specific biochemical markers are not available. Here, we investigated the potential of cerebrospinal fluid (CSF) lipocalin 2 (LCN2), a secreted glycoprotein that has been suggested as mediating neuronal damage in vascular brain injuries. The study included four independent cohorts with a total n = 472 samples. LCN2 was significantly elevated in VaD compared to controls, Alzheimer's disease (AD), other neurodegenerative dementias, and cognitively unimpaired patients with cerebrovascular disease. LCN2 discriminated VaD from AD without coexisting VaD with high accuracy. The main findings were consistent over all cohorts. Neuropathology disclosed a high percentage of macrophages linked to subacute infarcts, reactive astrocytes, and damaged blood vessels in multi-infarct dementia when compared to AD. We conclude that CSF LCN2 is a promising candidate biochemical marker in the differential diagnosis of VaD and neurodegenerative dementias.

Chromogranin A Analysis in the Differential Diagnosis Across Lewy Body Disorders.

BACKGROUND: Chromogranin A (CgA) is a general marker of gut endocrine cells, which are part of the "gut-brain axis" in Parkinson's disease (PD). OBJECTIVE: We analyzed CgA as a marker of synaptic dysfunction to assess its role in the differential diagnosis across different Lewy body disorders. METHODS: We analyzed the CgA levels in the cerebrospinal fluid (CSF) and serum from 54 patients covering the spectrum of Lewy body disorders [13 Parkinson's disease (PD), 17 Parkinson's disease dementia (PDD), 24 dementia with Lewy bodies (DLB)] and 14 controls using an ELISA. RESULTS: A positive correlation was noted between CSF and serum CgA levels (ρ= 0.47, 95% CI: 0.24 to 0.65, p < 0.0001). The highest values of CgA in CSF and in serum were measured in DLB and there was a significant difference between DLB and PDD (p = 0.03 and p = 0.004). The serum levels of CgA in controls achieved lower values compared to DLB (p = 0.006). There was a gradual increase in serum levels from PD to PDD and DLB. An inverse correlation was seen between the CSF level of CgA and Aß42 (ρ  = -0.296, 95% CI: -0.51 to -0.04, p = 0.02). CONCLUSION: The incorporation of CgA analysis as an additional biomarker may be useful in the diagnostic work-up of Lewy body dementia. CgA analysis may be relevant in distinguishing DLB from PDD patients and presumably early stages of PD. Our data on altered serum levels in DLB pave the way to the development of blood-based parameters for the differential diagnosis, which however needs to be confirmed in a prospective study.

Cerebrospinal fluid markers analysis in the differential diagnosis of dementia with Lewy bodies and Parkinson's disease dementia.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) share a couple of clinical similarities that is often a source of diagnostic pitfalls. We evaluated the discriminatory potential of brain-derived CSF markers [tau, p-tau (181P), Aß1-42, NSE and S100B] across the spectrum of Lewy body disorders and assessed whether particular markers are associated with cognitive status in investigated patients. The tau CSF level, amyloid ß1-42 and p-tau/tau ratio were helpful in the distinction between DLB and PDD (p = 0.04, p = 0.002 and p = 0.02, respectively) as well as from PD patients (p < 0.001, p = 0.001 and p = 0.002, respectively). Furthermore, the p-tau/tau ratio enabled the differentiation of DLB with mild dementia from PDD patients (p = 0.02). The CSF tau and p-tau levels in DLB and CSF tau and p-tau/tau ratio in PDD patients reflected the severity of dementia. Rapid disease course was associated with the decrease of Aß1-42 in DLB but not in PDD. Elevation of S100B in DLB (p < 0.0001) as well as in PDD patients (p = 0.002) in comparison to controls was estimated. Hence, with the appropriate clinical context; the CSF marker profile could be helpful in distinguishing DLB from PDD patients even in early stages of dementia.

Plasma YKL-40 in the spectrum of neurodegenerative dementia.

BACKGROUND: Increased plasma YKL-40 has been reported in Alzheimer's disease (AD), but its levels in other neurodegenerative diseases are unknown. Here, we aimed to investigate plasma YKL-40 in the spectrum of neurodegenerative dementias. METHODS: YKL-40 was quantified in the plasma of 315 cases, including healthy controls (HC), neurological disease controls (ND), AD, vascular dementia (VaD), frontotemporal dementia (FTD), sporadic Creutzfeldt-Jakob disease (CJD) and Lewy body dementia (LBD). Diagnostic accuracy in the differential diagnostic context and influence of age and gender was assessed. RESULTS: Highest YKL-40 levels were detected in CJD, followed by LBD, VaD, AD, FTD, ND and HC. YKL-40 was associated to age but not to sex. After controlling for age, YKL-40 was significantly elevated in CJD compared to HC (p < 0.001), ND, AD and VaD (p < 0.01) and in LBD compared to HC (p < 0.05). In CJD, YKL-40 concentrations were significantly higher at late disease stages. CONCLUSIONS: Plasma YKL-40 is significantly elevated in CJD regardless of clinical and genetic parameters, with moderate diagnostic accuracy in the discrimination from control cases. Our study discards a potential use of this biomarker in the differential diagnostic context but opens the possibility to be explored as a marker for CJD monitoring.

Cerebrospinal Fluid Total and Phosphorylated α-Synuclein in Patients with Creutzfeldt-Jakob Disease and Synucleinopathy.

High levels of total α-synuclein (t-α-synuclein) in the cerebrospinal fluid (CSF) were reported in sporadic Creutzfeldt-Jakob disease (sCJD). The potential use of t-α-synuclein in the discrimination of Lewy body dementias (i.e., Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB)) is still under investigation. In addition, phospho-serine-129 α-synuclein (p-α-synuclein) has been described to be slightly increased in the CSF of synucleinopathies. Here, we analyzed t-α-synuclein and p-α-synuclein concentrations and their ratio in the context of differential diagnosis of neurodegenerative diseases. We quantified the levels of CSF t-α-synuclein and p-α-synuclein in a cohort of samples composed of neurological controls (NC), sCJD, PDD, and DLB by means of newly developed specific enzyme-linked immunosorbent assays. T-α-synuclein and p-α-synuclein were specifically elevated in sCJD compared to other disease groups. The area under the curve (AUC) values for t-α-synuclein were higher for the discrimination of sCJD from dementias associated to Lewy bodies as compared to the use of p-α-synuclein. A combination of both markers even increased the diagnostic accuracy. An inverse correlation was observed in CSF between t-α-synuclein and p-α-synuclein, especially in the DLB group, indicating a disease-relevant association between both markers. In conclusion, our data confirm t-α-synuclein and p-α-synuclein as robust biomarkers for sCJD and indicate the potential use of colorimetric t-α-synuclein ELISAs for differential diagnosis of dementia types.

Cerebrospinal fluid neurofilament light levels in neurodegenerative dementia: Evaluation of diagnostic accuracy in the differential diagnosis of prion diseases.

INTRODUCTION: Neurofilament light (NFL) levels in the cerebrospinal fluid are increased in several neurodegenerative dementias. However, their diagnostic accuracy in the differential diagnostic context is unknown. METHODS: Cerebrospinal fluid NFL levels were quantified in nonprimarily neurodegenerative neurological and psychiatric diseases (n = 122), mild cognitive impairment (n = 48), Alzheimer's disease (n = 108), dementia with Lewy bodies/Parkinson's disease dementia (n = 53), vascular dementia (n = 46), frontotemporal dementia (n = 41), sporadic Creutzfeldt-Jakob disease (sCJD, n = 132), and genetic prion diseases (n = 182). RESULTS: The highest NFL levels were detected in sCJD, followed by vascular dementia, frontotemporal dementia, dementia with Lewy bodies/Parkinson's disease dementia, Alzheimer's disease, and mild cognitive impairment. In sCJD, NFL levels correlated with cerebrospinal fluid tau and disease duration. NFL levels were able to differentiate sCJD from nonprimarily neurodegenerative neurological and psychiatric diseases (area under the curve = 0.99, 95% confidence interval: 0.99-1) and from the other diagnostic groups showing cognitive impairment/dementia of a non-CJD etiology (area under the curve = 0.90, 95% confidence interval: 0.87-0.92). Compared to nonprimarily neurodegenerative neurological and psychiatric diseases, NFL was also elevated in genetic prion diseases associated with the E200K, V210I, P102L, and D178N prion protein gene mutations. DISCUSSION: Increased NFL levels are a common feature in neurodegenerative dementias.

Neuropsychological Symptoms in Sporadic Creutzfeldt-Jakob Disease Patients in Germany.

BACKGROUND: The polymorphism at codon 129 of the prion protein gene (PRNP) and the PrPSc types 1 and 2 belong to a molecular classification of sporadic Creutzfeldt-Jakob disease (sCJD) that correlates well with the clinical and neuropathological phenotype of sCJD. OBJECTIVE: The aim of the study was to perform the first detailed evaluation of neuropsychological deficits in a large group of definite sCJD patients with known molecular subtype. METHODS: We analyzed neuropsychological symptoms in a cohort of 248 sCJD patients with known M129 V polymorphism of PRNP and prion protein type. RESULTS: Neuropsychological symptoms were very frequent in our patients (96%) and occurred as early as in the first third of the disease course. Besides amnesia and impaired attention (89% each), frontal lobe syndrome (75%), aphasia (63%), and apraxia (57%) were the most common neuropsychological deficits. There was no statistically significant difference with regard to frequency of neuropsychological symptoms between the subtypes. In MV2 and VV2 patients, the onset of neuropsychological symptoms was significantly later than in all other subtypes. CONCLUSION: We provide the first detailed analysis of neuropsychological symptoms in a large group of sCJD patients with known M129 V genotype and prion protein type. We suggest that the rate of progression of neuropsychological symptoms is subtype-specific. These data may improve the diagnosis in atypical sCJD subtypes.

Doxycycline in early CJD: a double-blinded randomised phase II and observational study.

OBJECTIVES: The main objective of the present study is to study the therapeutic efficiency of doxycycline in a double-blinded randomised phase II study in a cohort of patients with sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: From the National Reference Center of TSE Surveillance in Germany, patients with probable or definite sCJD were recruited for a double-blinded randomised study with oral doxycycline (EudraCT 2006-003934-14). In addition, we analysed the data from patients with CJD who received compassionate treatment with doxycycline in a separate group. Potential factors which influence survival such as age at onset, gender, codon 129 polymorphism and cognitive functions were evaluated. The primary outcome measure was survival. RESULTS: Group 1: in the double-blinded randomised phase II study, 7 patients in the treatment group were compared with 5 controls. Group 2: 55 patients with sCJD treated with oral doxycycline were analysed and compared with 33 controls by a stratified propensity score applied to a Cox proportional hazard analysis. The results of both studies were combined by means of a random-effects meta-analysis. A slight increase in survival time in the doxycycline treatment group was observed (p=0.049, HR=0.63 (95% CI 0.402 to 0.999)). CONCLUSIONS: On the basis of our studies, a larger trial of doxycycline should be performed in persons in the earliest stages of CJD. TRIAL REGISTRATION NUMBER: EudraCT 2006-003934-14; Results.

Evaluation of α-synuclein as a novel cerebrospinal fluid biomarker in different forms of prion diseases.

INTRODUCTION: Accurate diagnosis of prion diseases and discrimination from alternative dementias gain importance in the clinical routine, but partial overlap in cerebrospinal fluid (CSF) biomarkers impedes absolute discrimination in the differential diagnostic context. METHODS: We established the clinical parameters for prion disease diagnosis for the quantification of CSF α-synuclein in patients with sporadic (n = 234) and genetic (n = 56) prion diseases, in cases with cognitive impairment/dementia or neurodegenerative disease (n = 278), and in the neurologic control group (n = 111). RESULTS: An optimal cutoff value of 680 pg/mL α-synuclein results in 94% sensitivity and 96% specificity when diagnosing sporadic Creutzfeldt-Jakob disease (CJD). Genetic CJD cases showed increased CSF α-synuclein values. No increased α-synuclein levels were detected in non-CJD cases with rapid progression course. DISCUSSION: Detection of α-synuclein in the CSF of patients with suspected CJD is a valuable diagnostic test reaching almost full discrimination from non-prion disease cases. These data highlight the utility of CSF α-synuclein quantification in front of classical CSF biomarkers in clinical routine.

Cerebrospinal α-synuclein in α-synuclein aggregation disorders: tau/α-synuclein ratio as potential biomarker for dementia with Lewy bodies.

Several studies have addressed the utility of cerebrospinal (CSF) α-synuclein levels as a potential biomarker of α-synuclein aggregation disorders. However, its relevance in the differential diagnostic context of neurodegenerative and movement disorders is still a contentious subject. Here, we report total CSF α-synuclein levels in a cohort of clinically diagnosed α-synuclein-related disorders encompassing Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies and multiple system atrophy in comparison to essential tremor and neurological control cases. α-synuclein levels in α-synuclein-related disorders were significantly lower than in controls (p < 0.001). However, in the differential diagnostic context, only Parkinson's disease cases presented significant lower α-synuclein levels compared to essential tremor and neurological controls. In cases with clinically diagnosed α-synuclein pathology, CSF α-synuclein levels showed a moderate positive correlation with CSF tau and p-tau, but not with Aß42 levels. Due to elevated CSF tau levels in dementia with Lewy bodies samples, tau/α-synuclein ratio showed a good clinical accuracy in discriminating controls from dementia with Lewy bodies cases (AUC = 0.8776) compared to single α-synuclein (AUC = 0.7192) and tau (AUC = 0.7739) levels. In conclusion, α-synuclein alone lacks of clinical value as a biomarker of α-synuclein-related disorders, but in combination with total tau, it may improve the diagnosis of dementia with Lewy bodies.

Application of an in vitro-amplification assay as a novel pre-screening test for compounds inhibiting the aggregation of prion protein scrapie.

In vitro amplification assays, such as real-time quaking-induced conversion (RT-QuIC) are used to detect aggregation activity of misfolded prion protein (PrP) in brain, cerebrospinal fluid (CSF) and urine samples from patients with a prion disease. We believe that the method also has a much broader application spectrum. In the present study, we applied RT-QuIC as a pre-screening test for substances that potentially inhibit the aggregation process of the cellular PrP (PrP(C)) to proteinase (PK)-resistant PrP(res). We chose doxycycline as the test substance as it has been tested successfully in animal models and proposed in clinical studies as a therapeutic for prion diseases. The RT-QuIC-reaction was seeded with brain tissue or CSF from sCJD patients and doxycycline was then added in different concentrations as well as at different time points. In both experiments, we observed a dose- and time-dependent inhibition of the RT-QuIC seeding response and a decrease of PK resistant PrP(res) when doxycycline was added. In contrast, ampicillin or sucrose had no effect on the RT-QuIC seeding response. Our study is the first to apply RT-QuIC as a pre-screening assay for compounds inhibiting the PrP aggregation in vitro and confirms that doxycycline is an efficient inhibitor of the PrP aggregation process in RT-QuIC analysis.

Comparative analysis of cerebrospinal fluid biomarkers in the differential diagnosis of neurodegenerative dementia.

INTRODUCTION: The analysis of cerebrospinal fluid biomarkers gains importance in clinical routine and is effective in substantiating dementia diagnosis in the differential diagnostic context. METHODS: We evaluated the levels of ß-amyloid (Aß) 42, Aß40, tau, and P-tau in a large patient population subdivided into prion diseases, tauopathies, synucleinopathies, and controls. Diagnostic test evaluation was assessed by ROC area under the curve analysis. RESULTS: High tau levels were detected in sporadic Creutzfeldt-Jakob disease (sCJD) and high P-tau levels in Alzheimer's disease (AD) and sCJD. Aß40 was lower exclusively in prionopathies, but low Aß42 was detected in AD, sCJD, and Lewy body dementia. When disease groups were stratified according to the underlying proteinopathy, we detected disease-type specificities for all biomarkers. P-tau/tau, Aß42/40, Aß42/tau, and Aß40/tau ratios proved valuable in discriminating disease groups and controls, especially P-tau/tau ratio in the identification of sCJD cases. DISCUSSION: Combining the biomarker panel allows differentiating between various types of neurodegenerative dementias and contributes to a better understanding of their pathophysiological processes.