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.

Background: Mitochondrial dysfunction plays an important role in multiple sclerosis (MS) disease progression. Plasma extracellular vesicles are a potential source of novel biomarkers in MS, and some of these are derived from mitochondria and contain functional mitochondrial components. Objective: To evaluate the relationship between levels of mitochondrial complex IV and V activity in neuronally enriched extracellular vesicles (NEVs) and brain and retinal atrophy as assessed using serial magnetic resonance imaging (MRI) and optical coherence tomography (OCT). Methods: Our cohort consisted of 48 people with MS. NEVs were immunocaptured from plasma and mitochondrial complex IV and V activity levels were measured. Subjects underwent OCT every 6 months and brain MRI annually. The associations between baseline mitochondrial complex IV and V activities and brain substructure and retinal thickness changes were estimated utilizing linear mixed-effects models. Results: We found that higher mitochondrial complex IV activity and lower mitochondrial complex V activity levels were significantly associated with faster whole-brain volume atrophy. Similar results were found with other brain substructures and retinal layer atrophy. Conclusion: Our results suggest that mitochondrial measures in circulating NEVs could serve as potential biomarkers of disease progression and provide the rationale for larger follow-up longitudinal studies.

No abstract

Traumatic brain injury (TBI) is a common neurological disorder whose outcomes vary widely depending on a variety of environmental factors, including diet. Using a Drosophila melanogaster TBI model that reproduces key aspects of TBI in humans, we previously found that the diet consumed immediately following a primary brain injury has a substantial effect on the incidence of mortality within 24 h (early mortality). Flies that receive equivalent primary injuries have a higher incidence of early mortality when fed high-carbohydrate diets versus water. Here, we report that flies fed high-fat ketogenic diet (KD) following TBI exhibited early mortality that was equivalent to that of flies fed water and that flies protected from early mortality by KD continued to show survival benefits weeks later. KD also has beneficial effects in mammalian TBI models, indicating that the mechanism of action of KD is evolutionarily conserved. To probe the mechanism, we examined the effect of KD in flies mutant for Eip75B, an ortholog of the transcription factor PPARγ (peroxisome proliferator-activated receptor gamma) that contributes to the mechanism of action of KD and has neuroprotective effects in mammalian TBI models. We found that the incidence of early mortality of Eip75B mutant flies was higher when they were fed KD than when they were fed water following TBI. These data indicate that Eip75B/PPARγ is necessary for the beneficial effects of KD following TBI. In summary, this work provides the first evidence that KD activates PPARγ to reduce deleterious outcomes of TBI and it demonstrates the utility of the fly TBI model for dissecting molecular pathways that contribute to heterogeneity in TBI outcomes.

Background: Parkinson's Disease (PD) pathogenesis involves intraneuronal asynuclein accumulation, but also insulin resistance, characterized by decreased Tyr and increased Ser insulin receptor substrate-1 (IRS-1) phosphorylations. Besides motor symptoms, some PD patients develop mild cognitive impairment (PD-MCI) or dementia (PD-D), partly due to overlapping Alzheimer's disease (AD) pathology. For PD prognosis, there is a need for biomarkers distinguishing PD with normal cognition (PD-N) from PD-MCI/D. Neuronal-origin extracellular vesicles (NEVs) contain signaling and pathogenic proteins that may serve as biomarkers.Method: From 104 PD-N, 83 PD-MCI, 39 PD-D patients and 48 age/sex-matched Controls, we immunocaptured plasma NEVs using anti-L1CAM antibody. We measured biomarkers by immunoassays for: 1) PD and AD pathogenic proteins (a-synuclein, Aβ42, total tau and p181-tau) 2) insulin signaling mediators (pTyr20 and pSer312 IRS-1). Particle concentration was measured by Nanoparticle Tracking Analysis and immunoblots were used to characterize NEV preparations.Result: a-synuclein was lower in PD compared to Controls (p = 0.005) and stepwise lower in PD-MCI (p = 0.007) and PD-D (p < 0.001) compared to PD-N; it tended to decrease with increasing motor symptom severity by MDS-UPDRS III (p = 0.06). Aβ42 trended towards being higher in PD-MCI compared to PD-N (p = 0.06). pTau181 was higher in PD patients compared to Controls (p = 0.003) and in PD-MCI compared to PD-N (p = 0.02). Total Tau was not different between groups. pTyr20-IRS-1 was lower in PD compared to Controls (p = 0.03) and in PD-MCI compared to PD-N (p = 0.01) and decreased with increasing motor symptom severity by MDS-UPDRS III (p = 0.008). The ratio pSer312/pTyr20 IRS-1 (indicating insulin resistance) was higher in PD patients compared to Controls (p = 0.02) and in PD-MCI and PD-D compared to PD-N (p = 0.01). Conclusion:PD patients with cognitive impairment exhibited lower NEV levels of a-synuclein and pTyr20-IRS-1 and higher levels of pTau181 than cognitively intact PD patients. Additionally, a-synuclein and IRS-1pTyr20 were associated with PD motor symptom severity. Plasma NEVs offer novel biomarkers for PD and indicate Alzheimer's pathology and insulin resistance partially underly cognitive impairment in the disease.