Plasma biomarkers for predicting the development of dementia in a community-dwelling older Japanese population.

AIM: To assess the association between plasma amyloid ß (Aß) 42/40, phosphorylated tau (p-τ)181, glial fibrillary acidic protein (GFAP), or neurofilament light chain (NfL) and the risk of dementia and to determine whether these plasma biomarkers could improve the ability to predict incident dementia in a general older population. METHODS: A total of 1346 Japanese community-dwelling individuals aged ≥65 years without dementia were followed prospectively for 5.0 years. Plasma biomarkers were quantified using a Simoa HD-X analyzer. A Cox proportional hazards model was used to estimate the hazard ratios of each plasma biomarker level for the risk of dementia. RESULTS: During the follow-up, 151 participants developed dementia, of whom 108 had Alzheimer disease (AD) and 43 non-Alzheimer dementia (non-AD). Lower plasma Aß42/40 levels and higher plasma p-τ181 levels were significantly associated with developing AD but not non-AD, whereas significant associations were observed between higher plasma levels of GFAP and NfL and risk of both AD and non-AD (all P for trend <0.05). In addition, adding these four plasma biomarkers into a model consisting of the total score of the dementia risk model significantly improved the predictive ability for incident dementia. CONCLUSION: Our findings suggest that plasma Aß42/40 and p-τ181 are specific markers of AD, and plasma GFAP and NfL are potential biomarkers for all-cause dementia in the general Japanese older population. In addition, the measurement of these plasma biomarkers may be a useful and relatively low-invasive procedure for identifying individuals at high risk for developing dementia in clinical practice.

Validation of a newly developed immunoassay for TDP-43 in human plasma.

The level of TAR DNA-binding protein 43 (TDP-43) in human blood was reported to have potential for use as a specific fluid biomarker, which represents disease-specific pathologies, for TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), which involves the aggregation and deposition of TDP-43 in the nervous system. However, at present, no reliable immunoassay can precisely quantify TDP-43 in human plasma and detect the difference in plasma TDP-43 levels between patients with ALS and controls. We recently developed a novel ultrasensitive immunoassay to quantify TDP-43 in human plasma, and in this study, we analytically validated this assay for application as a diagnostic biomarker for TDP-43 proteinopathies. The novel TDP-43 assay was assessed for the limit of detection, lower limit of quantification, intra- and interassay variation, linearity, parallelism, and analytical spike recoveries. Additionally, 17 pilot plasma samples obtained from patients with ALS and age-matched controls were analyzed using the assay. Our novel TDP-43 assay showed sufficient analytical performance to quantify TDP-43 in human plasma, with high sensitivity (LOD and LLOQ of 0.109 and 0.759 pg/mL, respectively) and high intra- and interassay precision (%CV) below 15 %. The experimental results for spike recovery, parallelism, and dilution linearity were also acceptable. In addition, despite a small sample size, significant differences in the plasma levels of TDP-43 were found between patients with ALS and controls (ALS, 66.63 ± 20.52 pg/mL; control, 42.70 ± 23.06 pg/mL, p = 0.0330). These results support that our novel TDP-43 assay is a reliable and innovative method for the quantification of TDP-43 in human plasma and can be a potential blood-based biomarker for the diagnosis of TDP-43 proteinopathies. Further large-scale studies are warranted to validate its usefulness.

Soluble TREM2 and Alzheimer-related biomarker trajectories in the blood of patients with diabetes based on their cognitive status.

AIM: We aimed to elucidate the dynamics of blood biomarkers according to the severity of cognitive impairment in patients with type 2 diabetes mellitus (DM) and to identify useful biomarkers for diabetes-related dementia. METHODS: This was a cross-sectional, nested case-control study of 121 Japanese DM and non-DM patients with different levels of cognitive functioning. We evaluated participants' cognitive functions, blood biomarkers related to Alzheimer's disease, and soluble triggering receptors expressed on myeloid cells 2 (sTREM2). We then compared these biomarkers between the DM and non-DM and across the different cognitive strata. RESULTS: In all cognitive strata, significantly lower levels of serum sTREM2 were observed in the DM than in the non-DM. We also found that plasma levels of phosphorylated tau (p-tau) increased with increasing levels of cognitive decline in both the DM and non-DM. However, this was accompanied by a decrease in plasma amyloid-ß(Aß42/Aß40 ratios in non-DM only. CONCLUSION: This study revealed novel characteristic trajectories of dementia-related blood biomarkers in diabetes-related dementia, suggesting the pathological involvement of molecular cascades initiated by impaired microglial activation. This results in decreased serum sTREM2, followed by tauopathy without substantial amyloid plaques, reflected by plasma p-tau elevation with no decrease in the Aß42/Aß40 ratio. Clinical trials (the unique trial number and the name of the registry): UMIN000048032, https://www.umin.ac.jp.