Combined use of CSF NfL and CSF TDP-43 improves diagnostic performance in ALS:A comprehensive analysis on diagnostic and prognostic significance of plasma and CSF NfL, TDP-43, and tau

Objective To determine the diagnostic and prognostic significance of neurofilament light chain (NfL), TAR DNA-binding protein 43 (TDP-43), and total tau (t-tau) in cerebrospinal fluid (CSF) and plasma of patients with amyotrophic lateral sclerosis (ALS) and to investigate whether the combined use of those biomarker candidates can improve their diagnostic performance. Methods This was a single-center, prospective, longitudinal study. CSF and plasma samples were collected at the time of enrollment from a discovery cohort of 29 patients with ALS and 29 age-matched controls without neurodegenerative disease. In a validation cohort, there were 46 patients with ALS, and 46 control (not age-matched) patients with motor weakness resulting from neuromuscular diseases. NfL, TDP-43, and t-tau levels in CSF and plasma were measured using ultrasensitive single molecule assay (Simoa) technology. Results The following findings were reproducibly observed among the discovery and validation cohorts: increased levels of CSF NfL, plasma NfL, and CSF TDP-43 in ALS compared with control groups; shorter survival associated with higher levels of CSF and plasma NfL. When the CSF NfL and CSF TDP-43 levels were combined, the areas under the ROC curves (AUC) were slightly improved relative to AUCs for each biomarker alone. Interpretation CSF and plasma NfL may not only serve as diagnostic biomarkers but also provide a measure of disease progression. CSF TDP-43 is also useful as a diagnostic biomarker of ALS, but has no prognostic value. The combined use of CSF NfL and CSF TDP-43 may be a useful biomarker for the diagnosis of ALS

Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid

Kakuda K., Ikenaka K., Araki K., et al. Ultrasonication-based rapid amplification of α-synuclein aggregates in cerebrospinal fluid. Scientific Reports 9, 6001 (2019); https://doi.org/10.1038/s41598-019-42399-0.α-Synuclein aggregates, a key hallmark of the pathogenesis of Parkinson’s disease, can be amplified by using their seeding activity, and the evaluation of the seeding activity of cerebrospinal fluid (CSF) is reportedly useful for diagnosis. However, conventional shaking-based assays are time-consuming procedures, and the clinical significance of the diversity of seeding activity among patients remains to be clarified. Previously, we reported a high-throughput ultrasonication-induced amyloid fibrillation assay. Here, we adapted this assay to amplify and detect α-synuclein aggregates from CSF, and investigated the correlation between seeding activity and clinical indicators. We confirmed that this assay could detect α-synuclein aggregates prepared in vitro and also aggregates released from cultured cells. The seeding activity of CSF correlated with the levels of α-synuclein oligomers measured by an enzyme-linked immunosorbent assay. Moreover, the seeding activity of CSF from patients with Parkinson’s disease was higher than that of control patients. Notably, the lag time of patients with Parkinson’s disease was significantly correlated with the MIBG heart-to-mediastinum ratio. These findings showed that our ultrasonication-based assay can rapidly amplify misfolded α-synuclein and can evaluate the seeding activity of CSF

Serum Levels of Coenzyme Q10 in Patients with Multiple System Atrophy.

The COQ2 gene encodes an essential enzyme for biogenesis, coenzyme Q10 (CoQ10). Recessive mutations in this gene have recently been identified in families with multiple system atrophy (MSA). Moreover, specific heterozygous variants in the COQ2 gene have also been reported to confer susceptibility to sporadic MSA in Japanese cohorts. These findings have suggested the potential usefulness of CoQ10 as a blood-based biomarker for diagnosing MSA. This study measured serum levels of CoQ10 in 18 patients with MSA, 20 patients with Parkinson's disease and 18 control participants. Although differences in total CoQ10 (i.e., total levels of serum CoQ10 and its reduced form) among the three groups were not significant, total CoQ10 level corrected by serum cholesterol was significantly lower in the MSA group than in the Control group. Our findings suggest that serum CoQ10 can be used as a biomarker in the diagnosis of MSA and to provide supportive evidence for the hypothesis that decreased levels of CoQ10 in brain tissue lead to an increased risk of MSA

Serum leucine-rich α2 glycoprotein as a potential biomarker for systemic inflammation in Parkinson's disease.

There is ample epidemiological and animal-model evidence suggesting that intestinal inflammation is associated with the development of Parkinson's disease (PD). Leucine-rich α2 glycoprotein (LRG) is a serum inflammatory biomarker used to monitor the activity of autoimmune diseases, including inflammatory bowel diseases. In this study, we aimed to investigate whether serum LRG could be used a biomarker of systemic inflammation in PD and to help distinguish disease states. Serum LRG and C-reactive protein (CRP) levels were measured in 66 patients with PD and 31 age-matched controls. We found that serum LRG levels were statistically significantly higher in the PD group than in the control group (PD: 13.9 ± 4.2 ng/mL, control: 12.1 ± 2.7 ng/mL, p = 0.036). LRG levels were also correlated with Charlson comorbidity index (CCI) and CRP levels. LRG levels in the PD group were correlated with Hoehn and Yahr stages (Spearman's r = 0.40, p = 0.008). LRG levels were statistically significantly elevated in PD patients with dementia as compared to those without dementia (p = 0.0078). Multivariate analysis revealed a statistically significant correlation between PD and serum LRG levels after adjusting for serum CRP levels, and CCI (p = 0.019). We conclude that serum LRG levels could be considered a potential biomarker for systemic inflammation in PD

Serum leucine-rich α2 glycoprotein as a potential biomarker for systemic inflammation in Parkinson’s disease

There is ample epidemiological and animal-model evidence suggesting that intestinal inflammation is associated with the development of Parkinson’s disease (PD). Leucine-rich α2 glycoprotein (LRG) is a serum inflammatory biomarker used to monitor the activity of autoimmune diseases, including inflammatory bowel diseases. In this study, we aimed to investigate whether serum LRG could be used a biomarker of systemic inflammation in PD and to help distinguish disease states. Serum LRG and C-reactive protein (CRP) levels were measured in 66 patients with PD and 31 age-matched controls. We found that serum LRG levels were statistically significantly higher in the PD group than in the control group (PD: 13.9 ± 4.2 ng/mL, control: 12.1 ± 2.7 ng/mL, p = 0.036). LRG levels were also correlated with Charlson comorbidity index (CCI) and CRP levels. LRG levels in the PD group were correlated with Hoehn and Yahr stages (Spearman’s r = 0.40, p = 0.008). LRG levels were statistically significantly elevated in PD patients with dementia as compared to those without dementia (p = 0.0078). Multivariate analysis revealed a statistically significant correlation between PD and serum LRG levels after adjusting for serum CRP levels, and CCI (p = 0.019). We conclude that serum LRG levels could be considered a potential biomarker for systemic inflammation in PD

Risk factors for neuropsychiatric symptoms in patients with Parkinson's disease during COVID-19 pandemic in Japan.

The worsening of neuropsychiatric symptoms such as depression, anxiety, and insomnia in patients with Parkinson's disease (PD) has been a concern during the COVID-19 pandemic, because most people worked in self-isolation for fear of infection. We aimed to clarify the impact of social restrictions imposed due to the COVID-19 pandemic on neuropsychiatric symptoms in PD patients and to identify risk factors associated with these symptoms. A cross-sectional, hospital-based survey was conducted from April 22, 2020 to May 15, 2020. PD patients and their family members were asked to complete paper-based questionnaires about neuropsychiatric symptoms by mail. PD patients were evaluated for motor symptoms using MDS-UPDRS part 2 by telephone interview. A total of 71 responders (39 PD patients and 32 controls) completed the study. Although there was no difference in the age distribution, the rate of females was significantly lower in PD patients (35%) than controls (84%) (P < 0.001). Participants with clinical depression (PHQ-9 score ≥ 10) were more common in PD patients (39%) than controls (6%) (P = 0.002). Multivariate logistic regression analysis revealed that an MDS-UPDRS part 2 score was correlated with the presence of clinical depression (PHQ-9 score ≥ 10) and clinical anxiety (GAD-7 score ≥ 7) (clinical depression: OR, 1.31; 95% CI, 1.04-1.66; P = 0.025; clinical anxiety: OR, 1.36; 95% CI, 1.07-1.72; P = 0.013). In the presence of social restrictions, more attention needs to be paid to the neuropsychiatric complications of PD patients, especially those with more severe motor symptoms

Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case-control studies including patients with Alzheimer’s disease and Down syndrome

Background: There is still a substantial unmet need for less invasive and lower-cost blood-based biomarkers to detect brain Alzheimer’s disease (AD) pathology. This study is aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181) is informative in the diagnosis of AD. Methods: We have developed a novel ultrasensitive immunoassay to quantify plasma p-tau181, and measured the levels of plasma p-tau181 in three cohorts. Results: In the first cohort composed of 20 AD patients and 15 age-matched controls, the plasma levels of p-tau181 were significantly higher in the AD patients than those in the controls (0.171 ± 0.166 pg/ml in AD versus 0.0405 ± 0.0756 pg/ml in controls, p = 0.0039). The percentage of the subjects whose levels of plasma p-tau181 exceeded the cut-off value (0.0921 pg/ml) was significantly higher in the AD group compared with the control group (60% in AD versus 16.7% in controls, p = 0.0090). In the second cohort composed of 20 patients with Down syndrome (DS) and 22 age-matched controls, the plasma concentrations of p-tau181 were significantly higher in the DS group (0.767 ± 1.26 pg/ml in DS versus 0.0415 ± 0.0710 pg/ml in controls, p = 0.0313). There was a significant correlation between the plasma levels of p-tau181 and age in the DS group (R2 = 0.4451, p = 0.0013). All of the DS individuals showing an extremely high concentration of plasma p-tau181 (> 1.0 pg/ml) were older than the age of 40. In the third cohort composed of 8 AD patients and 3 patients with other neurological diseases, the levels of plasma p-tau181 significantly correlated with those of CSF p-tau181 (R2 = 0.4525, p = 0.023). Conclusions: We report for the first time quantitative data on the plasma levels of p-tau181 in controls and patients with AD and DS, and these data suggest that the plasma p-tau181 is a promising blood biomarker for brain AD pathology. This exploratory pilot study warrants further large-scale and well-controlled studies to validate the usefulness of plasma p-tau181 as an urgently needed surrogate marker for the diagnosis and disease progression of AD

Quantification of Blood Caffeine Levels in Patients With Parkinson\u27s Disease and Multiple System Atrophy by Caffeine ELISA

Caffeine is considered to be a neuroprotective agent against Parkinson’s disease (PD)and is expected to offer a blood-based biomarker for the disease.We herein investigatedthe ability of this biomarker to discriminate between PD and neurodegenerative diseases.To quantify caffeine concentrations in serum and plasma, we developed a specificcompetitive enzyme-linked immunosorbent assay (ELISA). To validate the diagnosticperformance of the assay, we conducted a case control-study of two independentcohorts among controls and patients with PD and multiple system atrophy (MSA).Parallelism, recovery rate, and intra- and inter-assay precision of our assay were withinthe standard of acceptance. In the first cohort of 31 PD patients, 18 MSA patients and 33age-matched controls, serum caffeine levels were significantly lower in PD patients thanin Controls (p = 0.018). A similar trend was also observed in the MSA group, but did notreach the level of significance. In the second cohort of 50 PD patients, 50 MSA patientsand 45 age-matched controls, plasma caffeine levels were significantly decreased inboth PD and MSA groups compared to Controls (p < 0.001). This originally developedELISA offered sufficient sensitivity to detect caffeine in human serum and plasma. Wereproducibly confirmed decreased blood concentrations of caffeine in PD compared tocontrols using this ELISA. A similar trend was observed in the MSA group, despite a lackof consistent significant differences across cohorts

(A) Scatter plot for total CoQ10 level in serum in the MSA group (n = 18), PD group (n = 20), and control group (n = 18). Mean levels of total CoQ10 were lowest in the MSA group (593.2 nmol/l) and highest in the Control group (985.3 nmol/l), although no significant difference was seen between groups. (B) Scatter plot for total CoQ10/T-Cho ratio in serum in the three groups. A significant difference was seen between groups. Post-hoc analysis showed that mean level was significantly lower in the MSA group (3.04) than in the Control group (5.92). (C) The scatter plot for total CoQ10/T-Cho ratio in serum in the three groups after excluding an outlier from the Control group.

<p>Similar statistical results to those shown in Graph B were also found. Bars indicate mean values. One participant in the Control group showed an extremely high total CoQ10/T-Cho ratio (Graph B). Graph C therefore shows participants after excluding this outlier. P values over the columns were obtained using the Kruskal-Wallis test. When the Kruskal-Wallis test yielded significant findings, post-hoc analysis was conducted; the results of which are shown on the right side of the graph.</p

Plasma neurofilament light chain:A potential prognostic biomarker of dementia in adult Down syndrome patients

People with Down syndrome (DS) are at high risk of developing Alzheimer disease (AD) with aging. The diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. Plasma neurofilament light chain (NfL) is one of the established biomarkers of AD, suggesting that it may be useful as an indicator of dementia in DS patients. The aims of this study were: 1) to examine whether plasma levels of NfL in DS patients are correlated with decreased adaptive behavior scores one year after sample collection, and 2) to compare plasma levels of NfL in adults with DS and an age-matched healthy control population. In this study, plasma levels of NfL in 24 patients with DS and 24 control participants were measured by the single-molecule immunoarray (Simoa) method. We observed significantly increased plasma NfL levels in the DS compared with the control group. There was a significant correlation between age and levels of plasma NfL in both groups. This age-dependent elevation was steeper in the DS compared with the control group. Moreover, elevated plasma NfL was associated with decreased adaptive behavior scores one year later, after age-adjustment. Previously reported blood-based biomarkers available in Simoa for DS, plasma total tau and phosphorylated tau, were not significantly correlated with the annual decrement of adaptive behavior scores after age-adjustment. These results suggest that plasma NfL has the potential to serve as an objective biomarker to predict dementia in adult DS patients