Metagenomic next-generation sequencing assistance in identifying Mycobacterium avium meningoencephalitis: A case report and literature review.

Nontuberculous mycobacteria associated intracranial infection is a rare disease that mainly occurs in HIV-infected patients. The disease has a poor prognosis. The authors report a case of non-tuberculous mycobacterial meningoencephalitis in a non-AIDS patient, but long history of poorly controlled type 2 diabetes mellitus. A 55-year-old, right-handed, male patient presented with an 8-day history of fever, episodes of severe headache with signs of meningeal irritation. MRI showed hyperintensities/contrast enhancement in the visual pathways, basal ganglia sellar region and leptomeninges. No etiological diagnosis was reached until metagenomic next-generation sequencing (mNGS) was used, showing the presence of Mycobacterium avium. The patient was cured with aggressive antimycobacterial therapy. The authors discuss the clinical manifestations and drug therapy of nontuberculous mycobacteria-related intracranial infections by reviewing relevant literature. As meningoencephalitis by Mycobacterium avium has a high mortality an early diagnosis and appropriate therapeutic interventions are warranted. For this reason, the use of mNGS can be helpful to avoid therapeutic delay.

Serum uric acid in patients with Parkinson's disease and vascular parkinsonism: a cross-sectional study.

BACKGROUND: Elevation of serum uric acid (UA) is correlated with a decreased risk of Parkinson's disease (PD); however, the association and clinical relevance of serum UA levels in patients with PD and vascular parkinsonism (VP) are unknown. OBJECTIVE: We performed a cross-sectional study of 160 Chinese patients with PD and VP to determine whether UA levels in patients could predict the outcomes. METHODS: Serum UA levels were divided into quartiles and the association between UA and the severity of PD or VP was investigated in each quartile. RESULTS: The serum levels of UA in PD were significantly lower than those in normal subjects and VP. The serum UA levels in PD patients were significantly correlated with some clinical parameters. Strong correlations were observed in male PD patients, but significant correlations were observed only between UA and the non-motor symptoms (NMS) of burden of sleep/fatigue and mood in female PD patients. PD patients in the lowest quartile of serum UA levels had significant correlations between UA and the unified Parkinson's disease rating scale, the modified Hoehn and Yahr staging scale and NMS burden for attention/memory. CONCLUSION: Our findings support the hypothesis that subjects with low serum UA levels may be more prone to developing PD and indicate that the inverse relationship between UA and severity of PD was robust for men but weak for women. Our results strongly imply that either low serum UA level is a deteriorative predictor or that serum UA level serves as an indirect biomarker of prediction in PD but not in VP patients.

Meningoencephalitis associated with GAD65 autoimmunity.

Background: Encephalitis has been recognized in patients with autoimmunity related to the 65-kDa isoform of glutamic acid decarboxylase (GAD65) antibodies; however, patients with meningoencephalitis associated with those antibodies have been rarely identified in the medical literature. We aimed to define the frequency, clinical features, response to therapy, and functional outcomes of patients with meningoencephalitis associated with GAD antibodies. Methods: We retrospectively studied consecutive patients attending a tertiary care center for evaluation of an autoimmune neurological disorder from January 2018 to June 2022. The modified Rankin Scale (mRS) was used to assess the functional outcome at the last follow-up. Results: We evaluated 482 patients with confirmed autoimmune encephalitis during the study period. Four among the 25 patients with encephalitis related to GAD65 antibodies were identified. One patient was excluded owing to the coexistence of NMDAR antibodies. Three male patients aged 36, 24, and 16 years had an acute (n = 1) or subacute (n = 2) onset of confusion, psychosis, cognitive symptoms, seizures, or tremor. No patient had fever or clinical signs of meningeal irritation. Mild pleocytosis (<100 leukocytes/106) was identified in two patients, whereas one patient had normal CSF. Following immunotherapy with corticosteroids (n = 3) or intravenous immunoglobulin (n = 1), significant improvement was observed in all three cases, achieving a good outcome (mRS 1) in all cases. Conclusion: Meningoencephalitis is an uncommon presentation of GAD65 autoimmunity. Patients present with signs of encephalitis but with meningeal enhancement and have good outcomes.

Characteristics of systemic inflammation and brain iron deposition in Parkinson's disease patients.

OBJECTIVE: This study aimed at determining the characteristics of systemic inflammation and brain iron deposition in Parkinson's disease (PD) patients. METHODS: Thirty two PD patients and 30 gender- as well as age-matched controls were enrolled. Serum interleukin (IL)-1ß, IL-33, tumor necrosis factor (TNF)-α, IL-6, IL-10, ferritin, iron, and total iron binding capacity (TIBC) levels were assayed. Quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron accumulation in the regions of interest (ROIs). Correlations between concentrations of inflammatory cytokines and biomarkers for peripheral iron metabolism, brain iron deposition were evaluated in the PD group. RESULTS: Serum concentrations of IL-1ß and IL-33 were found to be significantly elevated in the PD group compared to the control group, and in early-stage PD group compared to advanced-stage PD group. Total QSM value for bilateral ROIs was significantly elevated in the PD group compared to the control group, and in advanced-stage PD group compared to early-stage PD group. There was a significant inverse correlation between serum IL-1ß concentration and total QSM value for bilateral ROIs, between serum ferritin, iron, TIBC concentrations, and total QSM value for bilateral ROIs in PD patients. However, there was no significant correlation between serum IL-1ß concentrations and serum ferritin, iron, TIBC concentrations in PD patients. INTERPRETATION: The inflammatory state and chronic brain iron deposition progression in PD patients might be asynchronous. Alterations in systemic inflammation were not correlated with peripheral iron metabolism and might not contribute to the aggravation of brain iron deposition in PD patients.

Elevated Heme Oxygenase-1 Correlates With Increased Brain Iron Deposition Measured by Quantitative Susceptibility Mapping and Decreased Hemoglobin in Patients With Parkinson's Disease.

Background: Brain iron deposition, low hemoglobin (HGB), and increased heme oxygenase-1 (HO-1) have been implicated in Parkinson's disease (PD). However, the association among them in PD is poorly studied. Objective: To explore the association of the level of HO-1 with brain iron deposition and low level of HGB in PD. Methods: A total of 32 patients with PD and 26 controls were recruited for this study. C57BL/6 male mice were used in generating 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced chronic PD model. The Levels of serum HO-1 and HGB of human subjects and mice were assayed by ELISA, blood routine test, respectively. Quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron deposition in human subjects and mice. HO-1 inhibitor (Sn-protoporphyrin, SnPP) was used to suppress the function and expression of HO-1 in PD mice. Correlations between the concentration of serum HO-1 and iron deposition of the region of interests (ROIs), levels of HGB, between the three factors mentioned above, and scores of clinical scales were explored in PD patients. Results: This study revealed significant elevation of the serum HO-1 concentration, iron deposition within bilateral substantial nigra (SN), red nucleus (RN), and putamen (PUT) and decrease of HGB level in PD patients. There was a significantly positive correlation between the serum HO-1 concentration and iron deposition within SN, an inverse correlation between the serum HO-1 concentration and HGB level in PD patients. A significant increase in HO-1 expression of serum and iron deposition in SN was also observed in the PD mouse model, and the SnPP could significantly reduce iron deposition in the SN. Conclusions: The high level of HO-1 may be the common mechanism of iron deposition and low HGB in PD. Therefore, the findings presented in this study indicate that HO-1 correlates with brain iron deposition and anemia in PD.

Time-Specific Pattern of Iron Deposition in Different Regions in Parkinson's Disease Measured by Quantitative Susceptibility Mapping.

Studies have shown the spatial specificity of cranial iron deposition in different regions in Parkinson's disease (PD). However, the time-specific patterns of iron deposition are not yet clear. The purpose of this study was to investigate the time pattern of iron variations and its clinical relevance in multiple gray matter nuclei in PD using quantitative susceptibility mapping (QSM). Thirty controls and 33 PD patients were enrolled, namely, 11 cases of early stage of PD (ESP) and 22 cases of advanced stage of PD (ASP) according to the Hoehn-Yahr stages. The iron content in the subcortical nuclei covering substantia nigra (SN), red nucleus (RN), head of the caudate nucleus (CN), globus pallidus (GP), and putamen (PT) was measured using QSM, and the clinical symptoms of PD were evaluated by various rating scales. The QSM values in SN, RN, GP, and PT significantly increased in PD patients compared with the controls. Further subgroup comparison with the controls indicated that the iron content in SN and GP (paleostriatum) gradually elevated in the whole disease duration and was related to clinical features. While the iron content in RN and PT (neostriatum) only elevated significantly in ESP patients, further iron deposition was not obvious in ASP patients. Our study confirmed that QSM could be used as a disease biomarker and could be suitable for longitudinal monitoring. However, considering the temporal characteristics of iron deposition in neostriatum, iron deposition in the neostriatum should be paid more attention in the early stage of the disease, even in the preclinical stage, in future research.

Mitochondrial Creatine Kinase is Decreased in the Serum of Idiopathic Parkinson's Disease Patients.

Mitochondrial creatine kinase (MtCK) is vital in the process of mitochondrial energy metabolism, and mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD). Therefore, we speculated that MtCK activity could be altered in the serum of PD patients. However, no studies to date have investigated this specific topic, so we sought to investigate the serum MtCK activities among a cohort of PD patients. 50 patients with PD and 30 age-matched controls were recruited for this study. Serum ubiquitous MtCK (uMtCK) and sarcomeric MtCK (sMtCK) activities were assayed using an immunoinhibition method. Correlations between serum uMtCK/sMtCK activities and clinical features/parameters were explored in the PD group. Our study revealed a significant decrease in the uMtCK activity in the PD group when compared with the control group. No significant difference was found in the serum sMtCK activity between the PD and control groups. There was a significant correlation between serum uMtCK activities and the disease progression rate, duration, and age at onset in PD patients. While no significant relationship was found between the serum uMtCK activities and the Hoehn & Yahr stage or main non-motor symptoms scale. There was a significant decrease in the uMtCK activity in the serum of PD patients, which was associated with the rate of disease progression, duration, and age at onset of disease. Therefore, uMtCK activity in serum offers a useful clue for identification of PD biomarkers.

Trefoil Factor 3, Cholinesterase and Homocysteine: Potential Predictors for Parkinson's Disease Dementia and Vascular Parkinsonism Dementia in Advanced Stage.

Trefoil factor 3 (TFF3), cholinesterase activity (ChE activity) and homocysteine (Hcy) play critical roles in modulating recognition, learning and memory in neurodegenerative diseases, such as Parkinson's disease dementia (PDD) and vascular parkinsonism with dementia (VPD). However, whether they can be used as reliable predictors to evaluate the severity and progression of PDD and VPD remains largely unknown. METHODS: We performed a cross-sectional study that included 92 patients with PDD, 82 patients with VPD and 80 healthy controls. Serum levels of TFF3, ChE activity and Hcy were measured. Several scales were used to rate the severity of PDD and VPD. Receivers operating characteristic (ROC) curves were applied to map the diagnostic accuracy of PDD and VPD patients compared to healthy subjects. RESULTS: Compared with healthy subjects, the serum levels of TFF3 and ChE activity were lower, while Hcy was higher in the PDD and VPD patients. These findings were especially prominent in male patients. The three biomarkers displayed differences between PDD and VPD sub-groups based on genders and UPDRS (III) scores' distribution. Interestingly, these increased serum Hcy levels were significantly and inversely correlated with decreased TFF3/ChE activity levels. There were significant correlations between TFF3/ChE activity/Hcy levels and PDD/VPD severities, including motor dysfunction, declining cognition and mood/gastrointestinal symptoms. Additionally, ROC curves for the combination of TFF3, ChE activity and Hcy showed potential diagnostic value in discriminating PDD and VPD patients from healthy controls. CONCLUSIONS: Our findings suggest that serum TFF3, ChE activity and Hcy levels may underlie the pathophysiological mechanisms of PDD and VPD. As the race to find biomarkers or predictors for these diseases intensifies, a better understanding of the roles of TFF3, ChE activity and Hcy may yield insights into the pathogenesis of PDD and VPD.

Comparison of magnetic resonance spectroscopy (MRS) with arterial spin labeling (ASL) in the differentiation between mitochondrial encephalomyopathy, lactic Acidosis, plus stroke-like episodes (MELAS) and acute ischemic stroke (AIS).

To compare the utility and limitation of magnetic resonance spectroscopy (MRS) and arterial spin labeling (ASL) in the differentiation between mitochondrial encephalomyopathy, lactic acidosis, plus stroke-like episodes (MELAS) and acute ischemic stroke (AIS), a retrospective review of 17 MELAS and 26 AIS patients were performed. In all patients both MRS and ASL scans were performed within 1 week after admission. Demographic, clinical, laboratory and MR imaging data were reviewed and compared between the two groups. Compared with AIS, MELAS patients had a younger age of onset, a longer disease duration, a higher occurrence of epilepsy attack, occipital and parietal lesions, and dilated cerebral arteries (P < 0.05). In all MELAS patients lactate peak and hyperperfusion of the lesion was revealed. However in AIS lactate peak was observed in only 69.2% and hyperperfusion was observed in only 34.6% ischemic lesions (P < 0.05). Choline/Creatine ratios and Lactate/Creatine ratios were higher in AIS, while in MELAS cerebral blood flow and lesion-normal perfusion ratio was much higher (P < 0.05). No correlations was found between metabolite ratios and perfusion parameters in either group (P > 0.05). Area under curve (AUC) of perfusion for the differentiation between MELAS and AIS was 0.958 (P < 0.001). The cut-off value was 2.075, with a sensitivity of 88.2% and a specificity of 96.2%. AUC of Lactate/Creatine ratio was 0.469 (P = 0.737). Utility of MRS is limited in the differentiation between MELAS and AIS, while MR perfusion profiles are much more sensitive and specific.

Lower hemoglobin levels in patients with parkinson's disease are associated with disease severity and iron metabolism.

Although several lines of evidence suggest that low levels of hemoglobin are a risk factor for Parkinson's disease (PD), few studies have examined changes in hemoglobin after PD onset. In this study, we quantify alterations in hemoglobin after the onset of PD and explore possible mechanisms for changes in hemoglobin. We enrolled 213 PD and 219 control subjects between 2013 and 2014 at the Third Affiliated Hospital of Sun Yat-sen University and Nanfang Hospital of Southern Medical University. We collected data from routine blood tests (including markers of iron metabolism) and measured basic clinical parameters. The hemoglobin levels were lower in PD patients relative to control subjects (125.1±15.68g/L and 139.9±11.83g/L, respectively; p＜0.001). Serum iron levels did not change in PD patients compared to control subjects (14.92±4.88µmol/L and 15.73±4.40µmol/L, respectively; p=0.35). Total iron binding capacity (TIBC) was also unaltered (PD group: 48.29±9.13µmol/L; control group: 49.74±8.35 µmol/L; p=0.43). The level of ferritin in PD and control subjects was 174.07±74.04ng/mL and 191.82±91.49ng/mL (p=0.04), respectively. We further analyzed the relationship between iron metabolism and PD by stratifying the data by disease severity and found that late-stage PD patients have lower levels of iron, ferritin, and TIBC (14.36±4.95µmol/L, 162.24±71.25µmol/L and 46.84±10.15ng/mL) compared to age-matched controls. Significant correlations were observed between hemoglobin levels and iron metablism. Our results suggest that hemoglobin levels are lower in PD patients compared to controls and are associated with the severity of PD and iron metabolism.

Nur77 exacerbates PC12 cellular injury in vitro by aggravating mitochondrial impairment and endoplasmic reticulum stress.

The nuclear orphan receptor, Nur77 plays important roles in neuroimflammation, apoptosis, and dopaminergic neurodegeneration. We conducted a further mechanistic investigation into the association of Nur77 with cell death. Cytosporone B (Csn-B), an agonist for Nur77, and Nur77 knockdown were adopted in the 6-hydroxydopamine (OHDA)-lesioned PC12 cells to investigate the mechanisms underlying Nur77-mediated injury. The 6-OHDA incubation caused Nur77 translocation from the nucleus to cytosol and Endoplasm reticulum (ER) and induced co-localization of Tom20/Nur77 and Protein Disulfide Isomerase (PDI)/Nur77. Nur77 activation further decreased cell viability, aggravated intracellular LDH release, intracellular Ca2+, ROS levels, apoptosis, ER tress and, mitochondrial transmembrane potential (ΔΨm) decline. In addition, Nur77 activation significantly enhanced the efficiency of autophagy as indicated by an up-regulation of Beclin-1/LC-3 and downregulation of p62, and aggravated mitochondrial dysfunctions and ER stress as shown by increased HSP60/Cytochrome C (Cyt C) and CHOP-ATF3 levels respectively. These changes could be partially reversed by Nur77 knockdown. Moreover, Nur77 activation upregulated PINK1 and downregulated Parkin levels. We conclude that Nur77 exacerbates PC12 cell death at least partially by aggravating the mitochondrial impairment and ER stress and enhancing autophagy. We propose that Nur77 is likely a critical target in the PD therapy.

Simvastatin induces neuroprotection in 6-OHDA-lesioned PC12 via the PI3K/AKT/caspase 3 pathway and anti-inflammatory responses.

BACKGROUND: In addition to their original applications for lowering cholesterol, statins display multiple neuroprotective effects. Inflammatory reactions and the PI3K/AKT/caspase 3 pathway are strongly implicated in dopaminergic neuronal death in Parkinson's disease (PD). This study aims to investigate how simvastatin affects 6-hydroxydopamine-lesioned PC12 via regulating PI3K/AKT/caspase 3 and modulating inflammatory mediators. METHODS: 6-hydroxydopamine-treated PC12 cells were used to investigate the neuroprotection of simvastatin, its association with the PI3K/AKT/caspase 3 pathway, and antiinflammatory responses. Dopamine transporters (DAT) and tyrosine hydroxylase (TH) were examined in 6-hydroxydopamine-treated PC12 after simvastatin treatment. RESULTS: Simvastatin-mediated neuroprotection was associated with a robust reduction in the upregulation induced by 6-OHDA of inflammatory mediators including IL-6, COX2, and TNF-α. The downregulated DAT and TH levels in 6-OHDA-lesioned PC12 were restored after simvastatin treatment. Simvastatin reversed 6-OHDA-induced downregulation of PI3K/Akt phosphorylation and attenuated 6-OHDA-induced upregulation of caspase 3 in PC12. Furthermore, the PI3K inhibitor LY294002 pronouncedly abolished the simvastatin-mediated attenuation in caspase 3. CONCLUSIONS: Our results demonstrate that simvastatin provides robust neuroprotection against dopaminergic neurodegeneration, partially via antiinflammatory mechanisms and the PI3K/Akt/caspase 3 pathway. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD and might elucidate the molecular mechanisms of simvastatin effects in PD.