Extracellular vesicle biomarkers for cognitive impairment in Parkinson’s disease

Abstract

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.

Empagliflozin Induced Ketosis, Upregulated IGF-1/Insulin Receptors and the Canonical Insulin Signaling Pathway in Neurons, and Decreased the Excitatory Neurotransmitter Glutamate in the Brain of Non-Diabetics

“…Recently, we published additional evidence on the characterization of NEVs, demonstrating by WBs that L1CAM+ NEVs display the full length 220 kD characteristic band for L1CAM, which is present in brain lysate. This is unlike other sub-populations of plasma EVs that display solely the 200 kD band, a band which corresponds to soluble L1CAM [ 21 ]. Moreover, L1CAM+ NEVs contain many-fold higher L1CAM (normalized to canonical EV marker CD9) compared to other plasma EV sub-populations, suggesting the specificity of the anti-L1CAM immunoprecipitation [ 21 ].…”

“…Moreover, L1CAM+ NEVs contain many-fold higher L1CAM (normalized to canonical EV marker CD9) compared to other plasma EV sub-populations, suggesting the specificity of the anti-L1CAM immunoprecipitation [ 21 ]. Finally, using confocal fluorescence microscopy after double immunolabeling with L1CAM and neuronal marker VAMP2, we demonstrated the co-existence of L1CAM and VAMP2 on particles at the size range of single EVs [ 21 ].…”

Challenges in anti‐aging medicine–trends in biomarker discovery and therapeutic interventions for a healthy lifespan

“…Over the last couple of years, several blood‐based biomarkers have been identified in epidemiological studies based on different types of omics‐based measurements 44,45 . Much attention was given to the prediction of neurodegenerative diseases and a couple of interesting tracks are to be explored for the prediction of early cognitive impairment and dementia in older adults: the decline of the sense of smell, 46 the level of toxic beta‐amyloid oligomers in the blood, 47 or neuronal extracellular vesicles containing phosphorylated tau and alpha‐synuclein 48 . From a broader perspective, the most promising biomarkers are those created based on clinically relevant outcomes, such as mortality, instead of chronological age 49,50 .…”

METTL14 is decreased and regulates m6A modification of α‐synuclein in Parkinson's disease

“…Cerebral spinal fluid (CSF) α‐syn concentrations have been investigated for PD diagnosis, but a collection of CSF is moderately invasive and involves potentially adverse effects, leading to investigations of blood as an alternative (Du, Wang, et al, 2021). Although promising, reports on α‐syn concentrations of blood for PD remain controversial (Blommer et al, 2022; Zhao et al, 2022; Zubelzu et al, 2022). Therefore, novel diagnostic and therapeutic targets are urgently needed for PD.…”