Blood transcriptomic signatures associated with molecular changes in the brain and clinical outcomes in Parkinson's disease.

The ability to use blood to predict the outcomes of Parkinson's disease, including disease progression and cognitive and motor complications, would be of significant clinical value. We undertook bulk RNA sequencing from the caudate and putamen of postmortem Parkinson's disease (n = 35) and control (n = 40) striatum, and compared molecular profiles with clinical features and bulk RNA sequencing data obtained from antemortem peripheral blood. Cognitive and motor complications of Parkinson's disease were associated with molecular changes in the caudate (stress response) and putamen (endothelial pathways) respectively. Later and earlier-onset Parkinson's disease were molecularly distinct, and disease duration was associated with changes in caudate (oligodendrocyte development) and putamen (cellular senescence), respectively. Transcriptome patterns in the postmortem Parkinson's disease brain were also evident in antemortem peripheral blood, and correlated with clinical features of the disease. Together, these findings identify molecular signatures in Parkinson's disease patients' brain and blood of potential pathophysiologic and prognostic importance.

Alteration of Mitochondrial Function in Oxidative Stress in Parkinsonian Neurodegeneration: A Cross-Sectional Study.

CONTEXT: Appropriate mitochondrial function and oxidative balance are critical to neuronal survival. Accumulation of reactive oxygen species leads to oxidative stress that can cause free radical damage to biomolecules of the cell components and the molecules in the cellular milieu that eventually lead to a variety of chronic diseases including neurodegenerative disorders. Mitochondrial dysfunction initiates neuronal apoptosis thereby leading to neurodegenerative diseases including Parkinson's disease (PD). AIM: To evaluate oxidative stress vis-a-vis mitochondrial function (Cytochrome C oxidase activity) in PD patients, Parkinson plus syndrome (PPS) patients in comparison with healthy controls (HCs). SETTINGS AND DESIGN: Cross-sectional Study. METHODS: We assessed oxidative stress by chemiluminescence using luminol, and cytochrome c oxidase activity (CCO) by CCO kit using spectrophotometry in PD patients (n = 80), PPS patients (n = 40), and HCs (n = 40). STATISTICAL ANALYSIS: Data were presented as number (%) or mean ± SD/median as approximate. Quantitative baseline variables were compared among the groups using one-way ANOVA and qualitative variables were compared using Chi-square test. The difference in median was compared using Kruskal-Wallis test followed by Post-hoc Bonferronni correction. RESULTS: Compared to HCs (Median 7.53 ± 15.58 RLU/sec/cell), ROS level in PD (14.13 ± 29.5), and PPS (17.43 ± 15.91) patients was significantly higher (P = 0.0029: HC vs, PD & P = 0.0500: HC vs. PPS). Also, ROS in PD patients (14.13 ± 29.5) was higher that PPS patients (17. 43 ± 15.91) but the difference was not statistically significant (P = 0.84). The CCO activity was found to be diminished in PD (Median: 0.025 ± 0.013 units/ml) and PPS patients (0.027 ± 0.008) in comparison to HCs (0.117 ± 0.049). CONCLUSION: Mitochondrial dysfunction and oxidative stress is associated with PD and PPS and may play an important role in etiopathogenesis. Though the cause-effect conundrum has not been comprehensively probed but addressing oxidative stress and mitochondrial damage may serve as an adjunctive therapy for PD and PPS. Iron metabolism as reflected in the red cell indices may aid in differentiating PD from PPS.

Relevance of SARS-CoV-2 related factors ACE2 and TMPRSS2 expressions in gastrointestinal tissue with pathogenesis of digestive symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 patients.

COVID-19 is caused by a new strain of coronavirus called SARS-coronavirus-2 (SARS-CoV-2), which is a positive sense single strand RNA virus. In humans, it binds to angiotensin converting enzyme 2 (ACE2) with the help a structural protein on its surface called the S-spike. Further, cleavage of the viral spike protein (S) by the proteases like transmembrane serine protease 2 (TMPRSS2) or Cathepsin L (CTSL) is essential to effectuate host cell membrane fusion and virus infectivity. COVID-19 poses intriguing issues with imperative relevance to clinicians. The pathogenesis of GI symptoms, diabetes-associated mortality, and disease recurrence in COVID-19 are of particular relevance because they cannot be sufficiently explained from the existing knowledge of the viral diseases. Tissue specific variations of SARS-CoV-2 cell entry related receptors expression in healthy individuals can help in understanding the pathophysiological basis the aforementioned collection of symptoms. ACE2 mediated dysregulation of sodium dependent glucose transporter (SGLT1 or SLC5A1) in the intestinal epithelium also links it to the pathogenesis of diabetes mellitus which can be a possible reason for the associated mortality in COVID-19 patients with diabetes. High expression of ACE2 in mucosal cells of the intestine and GB make these organs potential sites for the virus entry and replication. Continued replication of the virus at these ACE2 enriched sites may be a basis for the disease recurrence reported in some, thought to be cured, patients. Based on the human tissue specific distribution of SARS-CoV-2 cell entry factors ACE2 and TMPRSS2 and other supportive evidence from the literature, we hypothesize that SARS-CoV-2 host cell entry receptor-ACE2 based mechanism in GI tissue may be involved in COVID-19 (i) in the pathogenesis of digestive symptoms, (ii) in increased diabetic complications, (iii) in disease recurrence.

A Novel Mathematical Model of Glaucoma Pathogenesis.

BACKGROUND: Conventional experimental approaches to understand glaucoma etiology and pathogenesis and, consequently, predict its course of progression have not seen much success due to the involvement of numerous molecular, cellular, and other moieties. An overwhelming number of these moieties at different levels combined with numerous environmental factors further complicate the intricacy. Interaction patterns between these factors are important to understand yet difficult to probe with conservative experimental approaches. METHODS: We performed a system-level analysis with mathematical modeling by developing and analyzing rate equations with respect to the cellular events in glaucoma pathogenesis. Twenty-two events were enlisted from the literature survey and were analyzed in terms of the sensitivity coefficient of retinal ganglion cells. A separate rate equation was developed for cellular stress also. The results were analyzed with respect to time, and the time course of the events with respect to various cellular moieties was analyzed. RESULTS: Our results suggest that microglia activation is among the earliest events in glaucoma pathogenesis. This modeling method yields a wealth of useful information which may serve as an important guide to better understand glaucoma pathogenesis and design experimental approaches and also identify useful diagnostic/predictive methods and important therapeutic targets. CONCLUSION: We here report the first mathematical model for glaucoma pathogenesis which provides important insight into the sensitivity coefficient and glia-mediated pathology of glaucoma. HOW TO CITE THIS ARTICLE: Faiq MA, Sidhu T, et al. A Novel Mathematical Model of Glaucoma Pathogenesis. J Curr Glaucoma Pract 2019; 13(1):3-8.

Alterations in mitochondrial membrane potential in peripheral blood mononuclear cells in Parkinson's Disease: Potential for a novel biomarker.

BACKGROUND: Progressive apoptosis in the dopaminergic neurons of substantia nigra lead to Parkinson's disease. Since neurons require substantially higher supply of energy, their mitochondria have a pivotal status in neuronal survival. These organelles have a key role to play in apoptosis and any impairment thereof may lead to apoptosis mediated cell death. OBJECTIVES: To evaluate and compare the mitochondrial membrane potential (Δψ) in Parkinson's disease patients and healthy controls. METHODS: We evaluated the mitochondrial membrane potential (Δψ) in the peripheral blood mononuclear cells by Flow cytometry using a lipophillic cationic dye JC-1 in Parkinson's disease patients (N = 61) and healthy controls (N = 37). RESULTS: JC-1 fluorescence was measured and represented as percentage positivity i.e., Mean±SEM in FL-2 (representing non-apoptotic aggregates) and FL-1 (indicating apoptotic cell population having depolarized or damaged mitochondria) channels. The ratio of % FL-2 and % FL-1, which is an indicator of cellular mitochondrial membrane potential, was found to be significantly higher in healthy controls (Mean±SEM = 60.48±18.42) as compared to patients (Mean±SEM = 24.30±4.671) in both stimulated and unstimulated conditions. CONCLUSIONS: Mitochondrial membrane potential is altered and hence its evaluation in peripheral blood mononuclear cells may serve as an early marker of apoptosis in PD and, therefore, may pave way for early interventions. Since Δψ has a role in the maintenance of electrochemical gradient, the disruption of which may lead to neuronal apoptosis, Δψ is intricately nested within etiopathogenesis of PD and may prove to be useful in design of diagnostics, prognostics and therapeutics for PD.

CYP1B1-mediated Pathobiology of Primary Congenital Glaucoma.

CYP1B1 is a dioxin-inducible enzyme belonging to the cytochrome P450 superfamily. It has been observed to be important in a variety of developmental processes including in utero development of ocular structures. Owing to its role in the developmental biology of eye, its dysfunction can lead to ocular developmental defects. This has been found to be true and CYP1B1 mutations have been observed in a majority of primary congenital glaucoma (PCG) patients from all over the globe. Primary congenital glaucoma is an irreversibly blinding childhood disorder (onset at birth or early infancy) typified by anomalous development of trabecular meshwork (TM). How CYP1B1 causes PCG is not known; however, some basic investigations have been reported. Understanding the CYP1B1 mediated etiopathomechanism of PCG is very important to identify targets for therapy and preventive management. In this perspective, we will make an effort to reconstruct the pathomechanism of PCG in the light of already reported information about the disease and the CYP1B1 gene. How to cite this article: Faiq MA, Dada R, Qadri R, Dada T. CYP1 B1-mediated Pathobiology of Primary Congenital Glaucoma. J Curr Glaucoma Pract 2015;9(3):77-80.

Serum neurotrophic factors in adolescent depression: gender difference and correlation with clinical severity.

BACKGROUND: Brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3) and glial cell line derived neurotrophic factor (GDNF) play critical role in growth, differentiation, maintenance and synaptic plasticity in neuronal systems which is more relevant in adolescence. The present study was undertaken to verify the 'neurotrophin hypothesis' in adolescent depression by (i) comparing serum concentrations of neurotrophic factors in depression patients and healthy control, and (ii) analyzing correlations between clinical severity and serum neurotrophin levels. METHODS: Eighty four adolescent (aged 13-18 years) depressed patients (56 males; 60 medication free/naive) and 64 healthy controls (39 males) were recruited. Severity of depression was measured by Beck's depression inventory, and anxiety by state-trait anxiety inventory. Measurement of serum neurotrophins was done by ELISA. RESULTS: Adolescents with depression had significantly lower levels of BDNF: mean diff. (95% C.I.): 2093.9 (1074.0, 3113.9), NGF: 813.3 (343.1, 1283.6) and GDNF: 158.8 (77.2, 240.4) compared to controls. On gender based analysis female controls had significantly increased trait anxiety scores [-1.1 (-1.8, -0.1)], as compared to control males. In the patient group, female patients had far lower level of NGF: 919.6 (210.9, 1628.3) and NT-3: 1288.8 (145.4, 2432.3) compared to male. BDI-II score showed a statistically significant (p<0.01) negative correlation with all four neurotrophins in male patients while in female patients such negative correlation was observed only with NGF and GDNF (p<0.01). LIMITATIONS: The study is cross-sectional from a tertiary care hospital. CONCLUSION: The novelty of the study lies in its large number of exclusively adolescent depression patients showing significant reduction of BDNF, NGF and GDNF serum levels as compared to controls. A gender bias with much reduction in female has also been recorded.