BackgroundTREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer’s disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid β-peptide (Aβ) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.MethodsA cross-sectional study of 1027 participants of the Alzheimer’s Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of Aβ1-42 (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.ResultsCSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal Aβ pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.ConclusionsAβ pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, Aβ pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.Electronic supplementary materialThe online version of this article (10.1186/s13024-018-0301-5) contains supplementary material, which is available to authorized users.
Progranulin (PGRN) is predominantly expressed by microglia in the brain, and genetic and experimental evidence suggests a critical role in Alzheimer's disease (AD). We asked whether PGRN expression is changed in a disease severity‐specific manner in AD. We measured PGRN in cerebrospinal fluid (CSF) in two of the best‐characterized AD patient cohorts, namely the Dominant Inherited Alzheimer's Disease Network (DIAN) and the Alzheimer's Disease Neuroimaging Initiative (ADNI). In carriers of AD causing dominant mutations, cross‐sectionally assessed CSF PGRN increased over the course of the disease and significantly differed from non‐carriers 10 years before the expected symptom onset. In late‐onset AD, higher CSF PGRN was associated with more advanced disease stages and cognitive impairment. Higher CSF PGRN was associated with higher CSF soluble TREM2 (triggering receptor expressed on myeloid cells 2) only when there was underlying pathology, but not in controls. In conclusion, we demonstrate that, although CSF PGRN is not a diagnostic biomarker for AD, it may together with sTREM2 reflect microglial activation during the disease.
Besides motor symptoms, many individuals with Parkinson’s disease develop cognitive impairment perhaps due to co-existing α-synuclein and Alzheimer’s disease pathologies and impaired brain insulin signaling. Discovering biomarkers for cognitive impairment in Parkinson’s disease could help clarify the underlying pathogenic processes and improve Parkinson’s disease diagnosis and prognosis. This study used plasma samples from 271 participants: 103 Parkinson’s disease individuals with normal cognition, 121 Parkinson’s disease individuals with cognitive impairment (81 with mild cognitive impairment, 40 with dementia), and 49 age and sex-matched Controls. Plasma extracellular vesicles enriched for neuronal origin were immunocaptured by targeting L1 cell adhesion molecule, then biomarkers were quantified using immunoassays. α-synuclein was lower in Parkinson’s disease compared to Control individuals (p = 0.004) and in cognitively impaired Parkinson’s disease individuals compared to Parkinson’s disease with normal cognition (p < 0.001) and Control (p < 0.001) individuals. Amyloid-beta42 did not differ between groups. Phosphorylated Tau (T181) was higher in Parkinson’s disease than Control individuals (p = 0.003), and in cognitively impaired compared to cognitively normal Parkinson’s disease individuals (p < 0.001) and Controls (p < 0.001). Total tau was not different between groups. Tyrosine-phosphorylated insulin receptor substrate-1 was lower in Parkinson’s disease compared to Control individuals (p = 0.03), and in cognitively impaired compared to cognitively normal Parkinson’s disease individuals (p = 0.02) and Controls (p = 0.01), and also decreased with increasing motor symptom severity (p = 0.005); Serine312-phosphorylated insulin receptor substrate-1 was not different between groups. Mechanistic target of rapamycin was not different between groups, whereas phosphorylated mechanistic target of rapamycin trended lower in cognitively impaired compared to cognitively normal Parkinson’s disease individuals (p = 0.05). The ratio of α-synuclein to phosphorylated Tau181 was lower in Parkinson’s disease compared to Controls (p = 0.001), in cognitively impaired compared to cognitively normal Parkinson’s disease individuals (p < 0.001), and decreased with increasing motor symptom severity (p < 0.001). The ratio of insulin receptor substrate-1 phosphorylated Serine312 to insulin receptor substrate-1 phosphorylated Tyrosine was higher in Parkinson’s disease compared to Control individuals (p = 0.01), in cognitively impaired compared to cognitively normal Parkinson’s disease individuals (p = 0.02) and increased with increasing motor symptom severity (p = 0.003). α-synuclein, phosphorylated Tau181, and insulin receptor substrate-1 phosphorylated Tyrosine contributed in diagnostic classification between groups. These findings suggest that both α-synuclein and Tau pathologies and impaired insulin signaling underlie Parkinson’s disease with cognitive impairment. Plasma neuronal extracellular vesicles biomarkers may inform cognitive prognosis in Parkinson’s disease.
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