Weight Loss and Impact on Quality of Life in Parkinson’s Disease

IntroductionWeight loss is common in Parkinson’s Disease (PD) and sometimes may precede the diagnosis. Weight loss is associated with multiple factors but its impact on health-related quality of life (HRQL) in PD remains unknown. We sought to investigate the factors associated with weight change and to quantify its effect on HRQL.MethodsThe National Parkinson Foundation Quality Improvement Initiative (NPF-QII) data was used to analyze PD patients longitudinally between two visits, separated by 12±6 months. Multiple linear regression analyses were used to assess the associations between baseline covariates and body weight change per month, and to evaluate whether, and to what degree, Parkinson’s Disease Questionnaire (PDQ-39) scores were affected.ResultsA higher Hoehn & Yahr stage, higher number of comorbidities, older age, lower MOCA estimate, and higher rate of levodopa usage were observed in patients who lost weight. Multivariate regression analysis indicated that age and levodopa usage were significantly associated with weight loss. Furthermore, monthly body weight loss was significantly associated with HRQL decline in PD patients. Loss of 1 lb (0.45 kg) per month was associated with a decline in QOL: an increase of 0.5% in PDQ-39 Summary Index score (p=0.004), and 1.1% and 1.5% increases in the mobility and ADL dimensions, respectively.ConclusionWeight loss in PD is common and seems to correlate with worsened HRQL. Awareness of factors associated with weight loss and its relation to HRQL may help practitioners improve patient management and expectations.     

Effects of Long-Term Treatment with Quercetin on Cognition and Mitochondrial Function in a Mouse Model of Alzheimer’s Disease

Amyloid-β (Aβ)-induced mitochondrial dysfunction has been recognized as a prominent, early event in Alzheimer’s disease (AD). Therefore, therapeutics targeted to improve mitochondrial function could be beneficial. Quercetin, a bioflavanoid, has been reported to have potent neuro-protective effects, but its preventive effects on Aβ-induced mitochondrial dysfunction and cognitive impairment have not been well characterised. Three-month-old APPswe/PS1dE9 transgenic mice were randomly assigned to a vehicle group, two quercetin (either 20 or 40 mg kg^?1 day^?1) groups, or an Aricept (2 mg kg^?1 day^?1) group. After 16 weeks of treatment, we observed beneficial effects of quercetin (40 mg kg^?1 day^?1), including lessening learning and memory deficits, reducing scattered senile plaques, and ameliorating mitochondrial dysfunction, as evidenced by restoration of mitochondrial membrane potential, reactive oxygen species and ATP levels in mitochondria isolated from the hippocampus compared to control. Furthermore, the AMP-activated protein kinase (AMPK) activity significantly increased in the quercetin-treated (40 mg kg^?1 day^?1) group. These findings suggest that a reduction in plaque burden and mitochondrial dysfunction through the activation of AMPK may be one of the mechanisms by which quercetin improves cognitive functioning in the APPswe/PS1dE9 transgenic mouse model of AD.     

Contribution to the Data on Copper Concentration in Blood and Urine in Patients with Wilson’s Disease and in Normal Subjects

Determination of copper in human tissues and body fluids may be crucial in the diagnosis of Wilson’s disease. In this study we evaluated urinary copper excretion and urine and blood concentration in 14 patients in whom Wilson’s disease was confirmed (group A) and in 21 subjects in whom the disease was only suspected (group B). The following values (mean ± SD) were found: 24-h urine (μg Cu/24 h), 152 ± 135 (A) and 31.8 ± 10.9 (B); urine (μg Cu/ml), 0.091 ± 0.087 (A) and 0.028 ± 0.011 (B); and blood (μg Cu/ml), 0.62 ± 0.25 (A) and 0.72 ± 0.09 (B). By comparison, urine copper concentration in the group of apparently healthy subjects was 0.035 ± 0.010 (n = 50), and blood copper concentration in autopsy cases of nonpoisoned people was 0.85 ± 0.19 (n = 73).     

Peripheral Monocyte Functions and Activation in Patients with Quiescent Crohn’s Disease

Recent developments suggest a causal link between inflammation and impaired bacterial clearance in Crohn’s disease (CD) due to alterations of intestinal macrophages. Studies suggest that excessive inflammation is the consequence of an underlying immunodeficiency rather than the primary cause of CD pathogenesis. We characterized phenotypic and functional features of peripheral blood monocytes of patients with quiescent CD (n = 18) and healthy controls (n = 19) by analyses of cell surface molecule expression, cell adherence, migration, chemotaxis, phagocytosis, oxidative burst, and cytokine expression and secretion with or without lipopolysaccharide (LPS) priming. Peripheral blood monocytes of patients with inactive CD showed normal expression of cell surface molecules (CD14, CD16, CD116), adherence to plastic surfaces, spontaneous migration, chemotaxis towards LTB4, phagocytosis of E. coli, and production of reactive oxygen species. Interestingly, peripheral blood monocytes of CD patients secreted higher levels of IL1β (p<.05). Upon LPS priming we found a decreased release of IL10 (p<.05) and higher levels of CCL2 (p<.001) and CCL5 (p<.05). The expression and release of TNFα, IFNγ, IL4, IL6, IL8, IL13, IL17, CXCL9, and CXCL10 were not altered compared to healthy controls. Based on our phenotypic and functional studies, peripheral blood monocytes from CD patients in clinical remission were not impaired compared to healthy controls. Our results highlight that defective innate immune mechanisms in CD seems to play a role in the (inflamed) intestinal mucosa rather than in peripheral blood.     

Characterization of Regulatory B Cells in Graves’ Disease and Hashimoto’s Thyroiditis

A hallmark of regulatory B cells is IL-10 production, hence their designation as IL-10⁺ B cells. Little is known about the ability of self-antigens to induce IL-10⁺ B cells in Graves’ disease (GD), Hashimoto’s thyroiditis (HT), or other autoimmune disease. Here we pulsed purified B cells from 12 HT patients, 12 GD patients, and 12 healthy donors with the thyroid self-antigen, thyroglobulin (TG) and added the B cells back to the remaining peripheral blood mononuclear cells (PBMCs). This procedure induced IL-10⁺ B-cell differentiation in GD. A similar tendency was observed in healthy donors, but not in cells from patients with HT. In GD, B cells primed with TG induced IL-10-producing CD4⁺ T cells. To assess the maximal frequency of inducible IL-10⁺ B cells in the three donor groups PBMCs were stimulated with PMA/ionomycin. The resulting IL-10⁺ B-cell frequency was similar in the three groups and correlated with free T₃ levels in GD patients. IL-10⁺ B cells from both patient groups displayed CD25 or TIM-1 more frequently than did those from healthy donors. B-cell expression of two surface marker combinations previously associated with regulatory B-cell functions, CD24^hiCD38^hi and CD27⁺CD43⁺, did not differ between patients and healthy donors. In conclusion, our findings indicate that autoimmune thyroiditis is not associated with reduced frequency of IL-10⁺ B cells. These results do not rule out regulatory B-cell dysfunction, however. The observed phenotypic differences between IL-10⁺ B cells from patients and healthy donors are discussed.     

Peripheral Mitochondrial Dysfunction in Alzheimer’s Disease: Focus on Lymphocytes

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. Today, AD affects millions of people worldwide and the number of AD cases will increase with increased life expectancy. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the hippocampus and cerebral cortex. Recent findings suggest that these pathological changes are causally induced by mitochondrial dysfunction and increased oxidative stress. These changes are not only observed in the brain of AD patients but also in the periphery. In this review, we discuss the potential role of elevated apoptosis, increased oxidative stress and especially mitochondrial dysfunction as peripheral markers for the detection of AD in blood cells especially in lymphocytes. We discuss recent not otherwise published findings on the level of complex activities of the respiratory chain comprising mitochondrial respiration and the mitochondrial membrane potential (MMP). We obtained decreased basal MMP levels in lymphocytes from AD patients as well as enhanced sensitivity to different complex inhibitors of the respiratory chain. These changes are in line with mitochondrial defects obtained in AD cell and animal models, and in post-mortem AD tissue. Importantly, these mitochondrial alterations where not only found in AD patients but also in patients with mild cognitive impairment (MCI). These new findings point to a relevance of mitochondrial function as an early peripheral marker for the detection of AD and MCI.     

Mechanisms of NLRP3 Inflammasome Activation: Its Role in the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is a common neurodegenerative disease of progressive dementia which is characterized pathologically by extracellular neuritic plaques containing aggregated amyloid beta (Aβ) and intracellular hyperphosphorylated tau protein tangles in cerebrum. It has been confirmed that microglia-specific nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome-mediated chronic neuroinflammation plays a crucial role in the pathogenesis of AD. Stimulated by Aβ deposition, NLRP3 assembles and activates within microglia in the AD brain, leading to caspase-1 activation along with downstream interleukin (IL)-1β secretion, and subsequent inflammatory events. Activation of the NLRP3 inflammasome mediates microglia to exhibit inflammatory M1 phenotype, with high expression of caspase-1 and IL-1β. This leads to Aβ deposition and neuronal loss in the amyloid precursor protein (APP)/human presenilin-1 (PS1) mouse model of AD. However, NLRP3 or caspase-1 deletion in APP/PS1 mice promotes microglia to transform to an anti-inflammatory M2 phenotype, with decreased secretion of caspase-1 and IL-1β. It also results in improved cognition, enhanced Aβ clearance, and a lower cerebral inflammatory response. This result suggests that the NLRP3 inflammasome may be an appropriate target for reducing neuroinflammation and alleviating pathological processes in AD. In the present review, we summarize the generally accepted regulatory mechanisms of NLRP3 inflammasome activation, and explore its role in neuroinflammation. Furthermore, we speculate on the possible roles of microglia-specific NLRP3 activation in AD pathogenesis and consider potential therapeutic interventions targeting the NLRP3 inflammasome in AD.

     

Microglia Activation and Anti-inflammatory Regulation in Alzheimer’s Disease

Inflammatory regulators, including endogenous anti-inflammatory systems, can down-regulate inflammation thus providing negative feedback. Chronic inflammation can result from imbalance between levels of inflammatory mediators and regulators during immune responses. As a consequence, there are heightened inflammatory responses and irreversible tissue damage associated with many age-related chronic diseases. Alzheimer’s disease (AD) brain is marked by prominent inflammatory features, in which microglial activation is the driving force for the elaboration of an inflammatory cascade. How the regulation of inflammation loses its effectiveness during AD pathogenesis remains largely unclear. In this article, we will first review current knowledge of microglial activation and its association with AD pathology. We then discuss four examples of anti-inflammatory systems that could play a role in regulating microglial activation: CD200/CD200 receptor, vitamin D receptor, peroxisome proliferator-activated receptors, and soluble receptor for advanced glycation end products. Through this, we hope to illustrate the diverse aspects of inflammatory regulatory systems in brain and neurodegenerative diseases such as AD. We also propose the importance of neuronal defense systems, because they are part of the integral inflammatory and anti-inflammatory systems. Augmenting the anti-inflammatory defenses of neurons can be included in the strategy for restoration of balanced immune responses during aging and neurodegenerative diseases.     

Imaging Striatal Microglial Activation in Patients with Parkinson’s Disease

This study investigated whether the second-generation translocator protein 18kDa (TSPO) radioligand, [¹⁸F]-FEPPA, could be used in neurodegenerative parkinsonian disorders as a biomarker for detecting neuroinflammation in the striatum. Neuroinflammation has been implicated as a potential mechanism for the progression of Parkinson’s disease (PD). Positron Emission Tomography (PET) radioligand targeting for TSPO allows for the quantification of neuroinflammation in vivo. Based on genotype of the rs6791 polymorphism in the TSPO gene, 16 mixed-affinity binders (MABs) (8 PD and age-matched 8 healthy controls (HCs)), 16 high-affinity binders (HABs) (8 PD and age-matched 8 HCs) and 4 low-affinity binders (LABs) (3 PD and 1 HCs) were identified. Total distribution volume (V_T) values in the striatum were derived from a two-tissue compartment model with arterial plasma as an input function. There was a significant main effect of genotype on [¹⁸F]-FEPPA V_T values in the caudate nucleus (p = 0.001) and putamen (p < 0.001), but no main effect of disease or disease x genotype interaction in either ROI. In the HAB group, the percentage difference between PD and HC was 16% in both caudate nucleus and putamen; in the MAB group, it was -8% and 3%, respectively. While this PET study showed no evidence of increased striatal TSPO expression in PD patients, the current findings provide some insights on the possible interactions between rs6791 polymorphism and neuroinflammation in PD.     

Research Progress on Mechanism of Neuroprotective Roles of Apelin-13 in Prevention and Treatment of Alzheimer’s Disease

Neurochemical Research - Alzheimer’s disease (AD) is the most common type of dementia. Currently, more than 50 million people live with dementia worldwide, and this number is expected to...     

Etanercept in the Treatment of Intestinal Behcet’s Disease

Behcet’s disease (BD) accompanied by intestinal involvement is called intestinal BD. Although recent studies have attained positive feedback with the administration of anti-TNF-α agents in patients with BD, only a few reports on the study of etanercept in intestinal BD have been found. In this study, 35 cases of intestinal BD were treated with conventional therapy (prednisone or methotrexate) for a minimum period of 3 months (group 1). Another 19 patients who failed to respond to conventional therapy were then treated with etanercept (25 mg twice a week for 3 months). During each subsequent relapse, the patients were given the same treatment. The main outcome measures were the four criteria for diagnosis of BD (buccal ulcers, genital ulcers, ocular lesions, and skin lesions), the manifestation of intestinal involvement (abdominal symptoms, double-balloon enteroscopy), laboratory examinations of the acute phase reactants (erythrocyte sedimentation rate) and C-reactive protein, and relapses. As a result of the administered therapy, the healing rate of buccal and genital ulcers, the remission rate of ocular lesions, skin lesions, and abdominal symptoms, the healing rate of intestinal ulcers, and the recovery rate of ESR and CRP were significantly higher in group 2 than those of group 1. The relapse rate in the etanercept therapy was reduced significantly when compared with conventional therapy group. In conclusion, etanercept treatment, in contrast to the conventional therapy, can result in better curative effect and less adverse reactions in intestinal BD.     

Benefits of Iron Chelators in the Treatment of Parkinson’s Disease

As a novel discovered regulated cell death pattern, ferroptosis has been associated with the development of Parkinson’s disease (PD) and has attracted widespread attention. Nevertheless, the relationship between ferroptosis and PD pathogenesis is still unclear. This study aims to investigate the effect of iron overload on dopaminergic (DA) neurons and its correlation with ferroptosis. Here we use nerve growth factor (NGF) induced PC12 cells which are derived from pheochromocytoma of the rat adrenal to establish a classical PD in vitro model. We found significantly decreased cell viability in NGF-PC12 cell under ammonium ferric citrate (FAC) administration. Moreover, excessive intracellular iron ions induced the increase of (reactive oxygen species) ROS release as well as the decrease of mitochondrial membrane potential in PC12-NGF cells. In addition, we also found that overloaded iron can activate cell apoptosis and ferroptosis pathways, which led to cell death. Furthermore, MPP-induced PD cells were characterized by mitochondrial shrinkage, decreased expression of glutathione peroxidase 4 (Gpx4) and ferritin heavy chain (FTH1), and increased divalent metal transporter (DMT1) and transferrin receptor 1 (TfR1) expression level. In contrast, Lip-1 and DFO increased the expression level of GPX4 and FTH1 compared to MPP-induced PD cell. In conclusion, we indicated that overloaded intracellular iron contributes to neurons death via apoptosis and ferroptosis pathways, while DFO, an iron chelator, can inhibit ferroptosis in order to protect the neurons in vitro.

     

Beneficial Effects of Coconut Oil in Treatment of Parkinson’s Disease

Neurophysiology - Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder, characterized by depletion of dopamine resulted from the death of dopaminergic neurons in the...     

Hyperthyroidism due to Coexistence of Graves’ Disease and Struma Ovarii

ObjectiveTo report an unusual case of persistent thyrotoxicosis after treatment of Graves’ disease, because of coexistence of struma ovarii.MethodsWe report the clinical history, imaging studies, laboratory and pathologic data, and treatment in a patient with persistent hyperthyroidism after surgical treatment of Graves’ disease. In addition, we discuss some aspects of the pathogenesis of hyperthyroidism due to functioning struma ovarii.ResultsA 42-year-old woman underwent near-total thyroidectomy for treatment of Graves’ disease. Post-operatively, hyperthyroidism was still present. Methimazole was administered again, and performance of a ¹³¹I whole-body scan demonstrated a focus of intense uptake in the pelvis. Pelvic ultrasonography revealed a mass (11 by 8 by 7.1 cm) arising from the right ovary, with both solid and cystic components. Abdominal surgical exploration was performed, and the final histologic diagnosis was struma ovarii. The symptoms of hyperthyroidism diminished, and 3 weeks postoperatively, the thyroid hormone levels were in the hypothyroid range.ConclusionIn patients with refractory hyperthyroidism after thyroid surgical treatment, radioiodine scanning should be performed to diagnose or exclude the functioning profile of ovarian masses. (Endocr Pract. 2007;13:274-276)     

A High Frequency of Circulating Th22 and Th17 Cells in Patients with New Onset Graves’ Disease

T-helper (Th) 22 and Th17 cells are involved in the pathogenesis of autoimmune diseases. However, their roles in the pathogenesis of Graves’disease (GD) are unclear. This study is aimed at examining the frequency of peripheral blood Th22, Th17, and Th1 cells and the levels of plasma IL-22, IL-17, and IFN-γ in patients with GD. A total of 27 patients with new onset GD and 27 gender- and age-matched healthy controls (HC) were examined for the frequency of peripheral blood Th22, Th17, and IFN-γ cells by flow cytometry. The concentrations of plasma IL-22, IL-17, and IFN-γ were examined by enzyme-linked immunosorbent assay. The levels of serum TSHR antibodies (A-TSHR), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) were examined by radioimmunoassay and chemiluminescent assay, respectively. The levels of serum TSAb were examined by enzyme-linked immunosorbent assay. In comparison with those in the HC, significantly elevated percentages of Th22 and Th17 cells, but not Th1 cells, and increased levels of plasma IL-22 and IL-17, but not IFN-γ, were detected in GD patients (P<0.0001, for both). The percentages of both Th22 and Th17 cells and the levels of plasma IL-22 and IL-17 were correlated positively with the levels of serum TSAb in GD patients (r = 0.7944, P<0.0001; r = 0.8110, P<0.0001; r = 0.7101, p<0.0001; r = 0.7407, p<0.0001, respectively). Th22 and Th17 cells may contribute to the pathogenesis of GD.     

Effects of Textured Insoles on Balance in People with Parkinson’s Disease

Background

Degradation of the somatosensory system has been implicated in postural instability and increased falls risk for older people and Parkinson’s disease (PD) patients. Here we demonstrate that textured insoles provide a passive intervention that is an inexpensive and accessible means to enhance the somatosensory input from the plantar surface of the feet.

Methods

20 healthy older adults (controls) and 20 participants with PD were recruited for the study. We evaluated effects of manipulating somatosensory information from the plantar surface of the feet using textured insoles. Participants performed standing tests, on two different surfaces (firm and foam), under three footwear conditions: 1) barefoot; 2) smooth insoles; and 3) textured insoles. Standing balance was evaluated using a force plate yielding data on the range of anterior-posterior and medial-lateral sway, as well as standard deviations for anterior-posterior and medial-lateral sway.

Results

On the firm surface with eyes open both the smooth and textured insoles reduced medial-lateral sway in the PD group to a similar level as the controls. Only the textured insole decreased medial-lateral sway and medial-lateral sway standard deviation in the PD group on both surfaces, with and without visual input. Greatest benefits were observed in the PD group while wearing the textured insoles, and when standing on the foam surface with eyes closed.

Conclusions

Data suggested that textured insoles may provide a low-cost means of improving postural stability in high falls-risk groups, such as people with PD.     

Epigenetic Modulation in Parkinson’s Disease and Potential Treatment Therapies

In the recent past, huge emphasis has been given to the epigenetic alterations of the genes responsible for the cause of neurological disorders. Earlier, the scientists believed somatic changes and modifications in the genetic makeup of DNA to be the main cause of the neurodegenerative diseases. With the increase in understanding of the neural network and associated diseases, it was observed that alterations in the gene expression were not always originated by the change in the genetic sequence. For this reason, extensive research has been conducted to understand the role of epigenetics in the pathophysiology of several neurological disorders including Alzheimer’s disease, Parkinson’s disease and, Huntington’s disease. In a healthy person, the epigenetic modifications play a crucial role in maintaining the homeostasis of a cell by either up-regulating or down-regulating the genes. Therefore, improved understanding of these modifications may provide better insight about the diseases and may serve as potential therapeutic targets for their treatment. The present review describes various epigenetic modifications involved in the pathology of Parkinson’s Disease (PD) backed by multiple researches carried out to study the gene expression regulation related to the epigenetic alterations. Additionally, we will briefly go through the current scenario about the various treatment therapies including small molecules and multiple phytochemicals potent enough to reverse these alterations and the future directions for a better management of PD.

     

HIRSCHSPRUNG'S DISEASE—The Clinical Differentiation and Treatment of Children with Hirschsprung's Disease and Pseudo-Hirschsprung's Disease

Hirschsprung''s disease is marked by constipation from the time of birth, with the development, if uncorrected, of a protuberant abdomen and flared costal margins. The rectal ampulla is empty and the abdomen is filled with fecal masses. Pain is not prominent. Flatus is passed in large amounts. Encopresis does not occur. Barium enema shows the characteristic narrowed distal rectal segment and biopsy of the rectum shows absence of the ganglion cells of the myenteric plexus.Treatment is operative resection of the distal narrow segment and a primary anastomosis.Hirschsprung''s disease may be mimicked in children with:1. Psychogenic constipation—pseudo-Hirschsprung''s disease. Unlike Hirschsprung''s disease, symptoms do not appear at birth, encopresis is common, and the barium enema shows no narrow distal segment.2. Mental retardation and cerebral defect.3. Corrected imperforate anus—on the basis of stenosis, imperfect innervation or poor habit training.4. Cretinism—with severe constipation and intestinal dilatation perhaps the presenting symptoms.Treatment of these four groups of children with severe constipation not due to Hirschsprung''s disease is:For Group 1, open discussion with parent and child. Assumption by the physician of full control of the details of treatment, and relegation of parent to the role of the physician''s agent in following the prescribed regimen.For Group 2, an enema regimen. Whereas fairly rapid restoration (and then persistence) of normal bowel habit can be expected in Group 1, the basic defects in Group 2 may require indefinite continuation of treatment.For Group 3, regular enema regimen, in the less severe cases—one identical with that used in Group 1, and dilatation of strictures or anoplasty.In Group 4, thyroid hormone therapy relieves the constipation of hypothyroidism and causes reversion of radiographic changes in the colon and rectum.