The oral microbiome of early stage Parkinson's disease and its relationship with functional measures of motor and non-motor function.

Changes in the function and microbiome of the upper and lower gastrointestinal tract have been documented in Parkinson's disease (PD), although most studies have examined merely fecal microbiome profiles and patients with advanced disease states. In the present study we sought to identify sensitive and specific biomarkers of changes in the oral microbiome of early stage PD through shotgun metatranscriptomic profiling. We recruited 48 PD subjects and 36 age- and gender-matched healthy controls. Subjects completed detailed assessments of motor, cognitive, balance, autonomic and chemosensory (smell and taste) functions to determine their disease stage. We also obtained a saliva sample for profiling of microbial RNA and host mRNA using next generation sequencing. We found no differences in overall alpha and beta diversity between subject groups. However, changes in specific microbial taxa were observed, including primarily bacteria, but also yeast and phage. Nearly half of our findings were consistent with prior studies in the field obtained through profiling of fecal samples, with others representing highly novel candidates for detection of early stage PD. Testing of the diagnostic utility of the microbiome data revealed potentially robust performance with as few as 11 taxonomic features achieving a cross-validated area under the ROC curve of 0.90 and overall accuracy of 84.5%. Bioinformatic analysis of 167 different metabolic pathways supported shifts in a small set of distinct pathways involved in amino acid and energy metabolism among the organisms comprising the oral microbiome. In parallel with the microbial analysis, we also examined the evidence for changes in human salivary mRNAs in the same subjects. This revealed significant changes in a set of 9 host mRNAs, several of which mapped to various brain functions and showed correlations with some of the significantly changed microbial taxa. Unexpectedly, we also observed robust correlations between many of the microbiota and functional measures, including those reflecting cognition, balance, and disease duration. These results suggest that the oral microbiome may represent a highly-accessible and informative microenvironment that offers new insights in the pathophysiology of early stage PD.

Comparison of serum and saliva miRNAs for identification and characterization of mTBI in adult mixed martial arts fighters.

Traumatic brain injury (TBI) is a major cause of death and disability worldwide, with mild TBI (mTBI) accounting for 85% of cases. mTBI is also implicated in serious long-term sequelae including second impact syndrome and chronic traumatic encephalopathy. mTBI often goes undiagnosed due to delayed symptom onset and limited sensitivity of conventional assessment measures compared with severe TBI. Current efforts seek to identify accurate and reliable non-invasive biomarkers associated with functional measures relevant to long-term outcomes. Here we evaluated the utility of serum and salivary microRNAs (miRNAs) to serve as sensitive and specific peripheral biomarkers of possible mTBI. Our primary objectives were to establish the relationship between peripheral measures of miRNA, objective quantification of head impacts, and sensitive indices of balance and cognitive function in healthy young adult athletes. A secondary objective was to compare the sensitivity of miRNA versus commonly used blood-based protein biomarkers. 50 amateur mixed martial arts (MMA) fighters participated. 216 saliva and serum samples were collected at multiple time points, both pre- and post-fight. Levels of 10 serum proteins were compared in a subset of the fighters (n = 24). Levels of miRNAs were obtained by next generation sequencing. Functional outcomes were evaluated using a computerized assessment system that measured cognitive performance, body sway, and combined cognitive performance and body sway during dual task completion. Data were analyzed using multivariate logistic regression for predictive classification, analysis of variance, correlation analysis and principal component analysis. We identified a subset of salivary and serum miRNAs that showed robust utility at predicting TBI likelihood and demonstrated quantitative associations with head impacts as well as cognitive and balance measures. In contrast, serum proteins demonstrated far less utility. We also found that the timing of the responses varies in saliva and serum, which is a critical observation for biomarker studies to consider.

The control of reactive oxygen species production by SHP-1 in oligodendrocytes.

We have previously described reduced myelination and corresponding myelin basic protein (MBP) expression in the central nervous system of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) deficient motheaten (me/me) mice compared with normal littermate controls. Deficiency in myelin and MBP expression in both brains and spinal cords of motheaten mice correlated with reduced MBP mRNA expression levels in vivo and in purified oligodendrocytes in vitro. Therefore, SHP-1 activity seems to be a critical regulator of oligodendrocyte gene expression and function. Consistent with this role, this study demonstrates that oligodendrocytes of motheaten mice and SHP-1-depleted N20.1 cells produce higher levels of reactive oxygen species (ROS) and exhibit corresponding markers of increased oxidative stress. In agreement with these findings, we demonstrate that increased production of ROS coincides with ROS-induced signaling pathways known to affect myelin gene expression in oligodendrocytes. Antioxidant treatment of SHP-1-deficient oligodendrocytes reversed the pathological changes in these cells, with increased myelin protein gene expression and decreased expression of nuclear factor (erythroid-2)-related factor 2 (Nrf2) responsive gene, heme oxygenase-1 (HO-1). Furthermore, we demonstrate that SHP-1 is expressed in human white matter oligodendrocytes, and there is a subset of multiple sclerosis subjects that demonstrate a deficiency of SHP-1 in normal-appearing white matter. These studies reveal critical pathways controlled by SHP-1 in oligodendrocytes that relate to susceptibility of SHP-1-deficient mice to both developmental defects in myelination and to inflammatory demyelinating diseases.

Association between conformational mutations in neuroserpin and onset and severity of dementia.

BACKGROUND: The aggregation of specific proteins is a common feature of the familial dementias, but whether the formation of neuronal inclusion bodies is a causative or incidental factor in the disease is not known. To clarify this issue, we investigated five families with typical neuroserpin inclusion bodies but with various neurological manifestations. METHODS: Five families with neurodegenerative disease and typical neuronal inclusions had biopsy or autopsy material available for further examination. Immunostaining confirmed that the inclusions were formed of neuroserpin aggregates, and the responsible mutations in neuroserpin were identified by sequencing of the neuroserpin gene (SERPINI1) in DNA from blood samples or from extraction of histology specimens. Molecular modelling techniques were used to predict the effect of the gene mutations on three-dimensional protein structure. Brain sections were stained and the topographic distribution of the neuroserpin inclusions plotted. FINDINGS: Each of the families was heterozygous for an amino acid substitution that affected the conformational stability of neuroserpin. The least disruptive of these mutations (S49P), as predicted by molecular modelling, resulted in dementia after age 45 years, and presence of neuroserpin inclusions in only a few neurons. By contrast, the most severely disruptive mutation (G392E) resulted, at age 13 years, in progressive myoclonus epilepsy, with many inclusions present in almost all neurons. INTERPRETATION: The findings provide evidence that inclusion-body formation is in itself a sufficient cause of neurodegeneration, and that the onset and severity of the disease is associated with the rate and magnitude of neuronal protein aggregation.