Dataset Information

Plasma neurofilament light chain and amyloid-β are associated with the kynurenine pathway metabolites in preclinical Alzheimer's disease.

ABSTRACT:

Background

Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer's disease amyloid pathology (amyloid-β; Aβ), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aβ correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation.

Methods

Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aβ concentrations, measured using single molecule array (Simoa) assays, were investigated in elderly individuals aged 65-90 years, with normal global cognition (Mini-Mental State Examination Score ≥ 26) from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort.

Results

A positive correlation between NFL and the kynurenine to tryptophan ratio (K/T) reflecting indoleamine 2,3-dioxygenase activity was observed (r = .451, p < .0001). Positive correlations were also observed between NFL and kynurenine (r = .364, p < .0005), kynurenic acid (r = .384, p < .0001), 3-hydroxykynurenine (r = .246, p = .014), anthranilic acid (r = .311, p = .002), and quinolinic acid (r = .296, p = .003). Further, significant associations were observed between plasma Aβ40 and the K/T (r = .375, p < .0005), kynurenine (r = .374, p < .0005), kynurenic acid (r = .352, p < .0005), anthranilic acid (r = .381, p < .0005), and quinolinic acid (r = .352, p < .0005). Significant associations were also observed between plasma Aβ42 and the K/T ratio (r = .215, p = .034), kynurenic acid (r = .214, p = .035), anthranilic acid (r = .278, p = .006), and quinolinic acid (r = .224, p = .027) in the cohort. On stratifying participants based on their neocortical Aβ load (NAL) status, NFL correlated with KP metabolites irrespective of NAL status; however, associations between plasma Aβ and KP metabolites were only pronounced in individuals with high NAL while associations in individuals with low NAL were nearly absent.

Conclusions

The current study shows that KP metabolite changes are associated with biomarker evidence of neurodegeneration. Additionally, the association between KP metabolites and plasma Aβ seems to be NAL status dependent. Finally, the current study suggests that an association between neurodegeneration and neuroinflammation manifests in the periphery, suggesting that preventing cytoskeleton cytotoxicity by KP metabolites may have therapeutic potential.

SUBMITTER: Chatterjee P

PROVIDER: S-EPMC6788092 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-?, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-?40 and amyloid-?42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer's disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ?4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer's disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer's disease dementia. A log2 higher baseline amyloid-?42 plasma level was associated with a lower risk of developing all-cause or Alzheimer's disease dementia, adjusted hazard ratio (HR) 0.61 [95% confidence interval (CI), 0.47-0.78; P?<?0.0001] and 0.59 (95% CI, 0.43-0.79; P?=?0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia [adjusted HR 1.59 (95% CI, 1.38-1.83); P?<?0.0001] or Alzheimer's disease [adjusted HR 1.50 (95% CI, 1.26-1.78); P?<?0.0001]. Combining the lowest quartile group of amyloid-?42 with the highest of NfL resulted in a stronger association with all-cause dementia [adjusted HR 9.5 (95% CI, 2.3-40.4); P?<?0.002] and with Alzheimer's disease [adjusted HR 15.7 (95% CI, 2.1-117.4); P?<?0.0001], compared to the highest quartile group of amyloid-?42 and lowest of NfL. Total-tau and amyloid-?40 levels were not associated with all-cause or Alzheimer's disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer's disease compared to those who remained dementia-free (P?<?0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer's disease diagnosis. Amyloid-?42 levels began to decrease in Alzheimer's disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-?42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer's disease dementia. These data indicate that plasma NfL and amyloid-?42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer's disease dementia.