Possible role of glial cell line-derived neurotrophic factor for predicting cognitive impairment in Parkinson’s disease: a case-control study

Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the protection of dopaminergic neurons, but there are few reports of the relationship between GDNF and its precursors (α-pro-GDNF and β-pro-GDNF) and cognitive impairment in Parkinson’s disease. This study aimed to investigate the relationship between the serum levels of GDNF and its precursors and cognitive impairment in Parkinson’s disease, and to assess their potential as a diagnostic marker. Fifty-three primary outpatients and hospitalized patients with Parkinson’s disease (23 men and 30 women) with an average age of 66.58 years were enrolled from the Affiliated Hospital of Xuzhou Medical University of China in this case-control study. The patients were divided into the Parkinson’s disease with cognitive impairment group (n = 27) and the Parkinson’s disease with normal cognitive function group (n = 26) based on their Mini-Mental State Examination, Montreal Cognitive Assessment, and Clinical Dementia Rating scores. In addition, 26 age- and sex-matched healthy subjects were included as the healthy control group. Results demonstrated that serum GDNF levels were significantly higher in the Parkinson’s disease with normal cognitive function group than in the other two groups. There were no significant differences in GDNF precursor levels among the three groups. Correlation analysis revealed that serum GDNF levels, GDNF/α-pro-GDNF ratios, and GDNF/β-pro-GDNF ratios were moderately or highly correlated with the Mini-Mental State Examination, Montreal Cognitive Assessment, and Clinical Dementia Rating scores. To explore the risk factors for cognitive impairment in patients with Parkinson’s disease, logistic regression analysis and stepwise linear regression analysis were performed. Both GDNF levels and Hoehn-Yahr stage were risk factors for cognitive impairment in Parkinson’s disease, and were the common influencing factors for cognitive scale scores. Neither α-pro-GDNF nor β-pro-GDNF was risk factors for cognitive impairment in Parkinson’s disease. A receiver operating characteristic curve of GDNF was generated to predict cognitive function in Parkinson’s disease (area under the curve = 0.859). This result indicates that the possibility that serum GDNF can correctly distinguish whether patients with Parkinson’s disease have cognitive impairment is 0.859. Together, these results suggest that serum GDNF may be an effective diagnostic marker for cognitive impairment in Parkinson’s disease. However, α-pro-GDNF and β-pro-GDNF are not useful for predicting cognitive impairment in this disease. This study was approved by Ethics Committee of the Affiliated Hospital of Xuzhou Medical University, China (approval No. XYFY2017-KL047-01) on November 30, 2017.

Chinese Library Classification No. R441; R447; R741     

Sensorimotor integration training in Parkinson’s disease

Objectives:To determine the effects of sensorimotor integration training on postural control in Parkinson’s disease.Methods:This prospective, randomized controlled trial was conducted at Hacettepe University (Ankara, Turkey). The study was carried out from August 2012 until March 2015 and included 24 Parkinson’s patients with stage 2–3 according to the Modified Hoehn&Yahr Rating Scale. The patients were divided into 2 groups (control and study). The control group received conventional physiotherapy; the study group received sensorimotor integration training combined with conventional physiotherapy, 2 times per week for 6 weeks. We assessed the patients with clinical balance tests and computerized dynamic posturography. Assessments were performed at baseline, 7- and 12-weeks follow-up.Results:Computerized dynamic posturography posturography values (5th and 6th positions, composite balance, and vestibular system scores) were higher in the study group than in the control group. The improvements were maintained at the 12-week follow up except 6th positions scores (p<0.05).Conclusions:Sensorimotor integration training combined with conventional physiotherapy approach ameliorated postural control by improving vestibular system in patients with Parkinson’s disease by improving sensory processes.

Postural instability is a symptom of Parkinson’s disease (PD) that causes severe disability.1 It involves a loss of postural control. The pathophysiology of postural instability in PD is complex and multi-factorial. Poor and slow anticipatory postural responses, inadequately organized automatic postural reactions, defective somatosensory integration and modulation of afferent sensory information, orthostatic hypotension, age-related sensory and postural changes, rigidity, and other Parkinsonian signs can occur in postural instability, resulting in an increase in its severity.2-3 Postural instability is poorly responsive to medications containing L-dopa. Therefore, other therapies, such as physiotherapy, have come into prominence.4 Many different modes of physiotherapy intervention can be used to decrease postural instability. This includes classical balance training, external cueing training, and movement strategy training.5 The most commonly used treatment is balance training.3,6 However, the pathophysiology of postural instability suggests that the therapeutic program for postural instability should be complex and multifaceted.The sensory integration training approach was devised by Jean Ayres to “take in, interpret, and integrate the spatial temporal aspect of sensory information from the body and the environment to plan and produce organized motor behaviors”.7 The approach usually used in children emphasizes the use of sensory and perceptual components to produce motor responses.8-9 The multi-sensory aspect of this approach could contribute to a decrease in postural instability in PD patients when considering the pathophysiology of postural instability. Sensorimotor integration training (SMIT) was created to keep in mind the principles of sensory integration training and the mechanisms of postural instability in PD. A pioneering study that we previously completed with fewer participants and no follow-up results has shown that SMIT has improved some parameters in Parkinson’s patients.10 Therefore, we planned this study was to investigate the short and long time effects of SMIT on postural instability in PD patients.     

Oxidative stress factors in Parkinson’s disease

Parkinson’s disease (PD) is the second most common cause of neurodegeneration. Over the last two decades, various hypotheses have been proposed to explain the etiology of PD. Among these is the oxidant-antioxidant theory, which asserts that local and systemic oxidative damage triggered by reactive oxygen species and other free radicals may promote dopaminergic neuron degeneration. Excessive reactive oxygen species formation, one of the underlying causes of pathology in the course of PD has been evidenced by various studies showing that oxidized macromolecules including lipids, proteins, and nucleic acids accumulate in brain tissues of PD patients. DNA oxidation may produce various lesions in the course of PD. Mutations incurred as a result of DNA oxidation may further enhance reactive oxygen species production in the brains of PD patients, exacerbating neuronal loss due to defects in the mitochondrial electron transport chain, antioxidant depletion, and exposure to toxic oxidized dopamine. The protein products of SNCA, PRKN, PINK1, DJ1, and LRRK2 genes are associated with disrupted oxidoreductive homeostasis in PD. SNCA is the first gene linked with familial PD and is currently known to be affected by six mutations correlated with the disorder: A53T, A30P, E46K, G51D, H50Q and A53E. PRKN encodes Parkin, an E3 ubiquitin ligase which mediates the proteasome degradation of redundant and disordered proteins such as glycosylated α-synuclein. Over 100 mutations have been found among the 12 exons of PRKN. PINK1, a mitochondrial kinase highly expressed in the brain, may undergo loss of function mutations which constitute approximately 1–8% of early onset PD cases. More than 50 PD-promoting mutations have been found in PINK1. Mutations in DJ-1, a neuroprotective protein, are a rare cause of early onset PD and constitute only 1% of cases. Around 20 mutations have been found in DJ1 among PD patients thus far. Mutations in the LRRK2 gene are the most common known cause of familial autosomal dominant PD and sporadic PD. Treatment of PD patients, especially in the advanced stages of the disease, is very difficult. The first step in managing progressive PD is to optimize dopaminergic therapy by increasing the doses of dopamine agonists and L-dopa. The next step is the introduction of advanced therapies, such as deep brain stimulation. Genetic factors may influence the response to L-dopa and deep brain stimulation therapy and the regulation of oxidative stress. Consequently, research into minimally invasive surgical interventions, as well as therapies that target the underlying etiology of PD is warranted.     

Prodromal non-motor symptoms of Parkinson’s disease

The motor symptoms of Parkinson’s disease (PD), bradykinesia, muscular rigidity, and tremor depend upon degeneration of the dopaminergic neurons in the substantia nigra pars compacta. Recent neuropathological studies show that the Lewy bodies, the intraneuronal landmark of PD, accumulate in several neuronal cell types in the brain. An ascending gradient of pathological involvement, from the medulla oblongata to neocortical areas has been reported. Thus the original view of PD as a disease characterized by selective damage of the dopaminergic neurons in the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerative disorder. Additionally, the neuropathological alterations outside the substantia nigra are soundly correlated with the non-motor symptoms of PD. As a result of these findings, interest is growing in the identification of prodromal non-motor symptoms of PD. Indeed, data from the literature suggest that autonomic disturbances, olfactory dysfunctions, depression and sleep disorders (in particular REM-sleep behavior disorder) may represent prodromal non-motor symptoms of PD. Several tests are available to detect most of these symptoms. Thus, the identification of prodromal non-motor symptoms may contribute to the precocious diagnosis of PD, and might be useful in the future to test the efficacy of neuroprotective agents.     

The under-recognition of depression in Parkinson’s disease

Depression is common in patients with Parkinson’s disease (PD) and has been identified as the main factor negatively impacting quality of life. It has been reported that depression in PD is under-recognized and under-treated. We report on 90 patients with PD who completed the Geriatric Depression Rating Scale (GDS). Thirteen subjects (14%) scored above 15, the proposed cut-off for diagnosing depression in this illness. Detailed medical record review for these subjects revealed that depression was recognized and treated in only about one-half of the cases. Comparison of mean subscale scores between subjects scoring above and below the cut-off for diagnosis of depression revealed that each of 6 proposed subscales effectively distinguished the two groups. Review of individual items demonstrated that many of the subjects endorsed low energy, regardless of whether they were depressed. This study supports the notion that efforts should be made to educate patients, caregivers and physicians about identifying depression in PD. The routine use of a depression rating scale may facilitate the recognition of depression in this illness.     

Lipopolysaccharide mouse models for Parkinson’s disease research: a critical appraisal

Parkinson’s disease, the most common movement disorder, has a strong neuroinflammatory aspect. This is evident by increased pro-inflammatory cytokines in the serum, and the presence of activated microglial cells, and inflammatory cytokines in the substantia nigra of post-mortem brains as well as cerebrospinal fluid of Parkinson’s disease patients. The central and peripheral neuroinflammatory aspects of Parkinson’s disease can be investigated in vivo via administration of the inflammagen lipopolysaccharide, a component of the cell wall of gram-negative bacteria. In this mini-review, we will critically evaluate different routes of lipopolysaccharide administration (including intranasal systemic and stereotasic), their relevance to clinical Parkinson’s disease as well as the recent findings in lipopolysaccharide mouse models. We will also share our own experiences with systemic and intrastriatal lipopolysaccharide models in C57BL/6 mice and will discuss the usefulness of lipopolysaccharide mouse models for future research in the field.Key Words: C57BL/6 mice, intranasal models, lipopolysaccharide models, neuroinflammation, Parkinson’s disease, stereotaxic models, substantia nigra, systemic models     

Rivastigmine for the treatment of dementia associated with Parkinson’s disease

Parkinson’s disease (PD) afflicts millions of people worldwide and leads to cognitive impairment or dementia in the majority of patients over time. Parkinson’s disease dementia (PDD) is characterized by deficits in attention, executive and visuospatial function, and memory. The clinical diagnostic criteria and neuropathology surrounding PDD remain controversial with evidence of overlap among PDD, dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Cortical cholinergic deficits are greater in PDD than in AD, and are well-correlated with the cognitive and neuropsychiatric dysfunction that occurs in PDD. Inhibition of acetylcholine metabolism is therefore a practical therapeutic strategy in PDD.     

Current approaches to the treatment of Parkinson’s disease

Enormous progress has been made in the treatment of Parkinson’s disease (PD). As a result of advances in experimental therapeutics, many promising therapies for PD are emerging. Levodopa remains the most potent drug for controlling PD symptoms, yet is associated with significant complications such as the “wearing off” effect, levodopa-induced dyskinesias and other motor complications. Catechol-o-methyl-transferase inhibitors, dopamine agonists and nondopaminergic therapy are alternative modalities in the management of PD and may be used concomitantly with levodopa or one another. The neurosurgical treatment, focusing on deep brain stimulation, is reviewed briefly. Although this review has attempted to highlight the most recent advances in the treatment of PD, it is important to note that new treatments are not necessarily better than the established conventional therapy and that the treatment options must be individualized and tailored to the needs of each individual patient.     

Autonomic Dysfunction in Parkinson’s Disease

Recognition of the importance of nonmotor dysfunction as a component of Parkinson’s disease has exploded over the past three decades. Autonomic dysfunction is a frequent and particularly important nonmotor feature because of the broad clinical spectrum it covers. Cardiovascular, gastrointestinal, urinary, sexual, and thermoregulatory abnormalities all can appear in the setting of Parkinson’s disease. Cardiovascular dysfunction is characterized most prominently by orthostatic hypotension. Gastrointestinal dysfunction can involve virtually all levels of the gastrointestinal tract. Urinary dysfunction can entail either too frequent voiding or difficulty voiding. Sexual dysfunction is frequent and frustrating for both patient and partner. Alterations in sweating and body temperature are not widely recognized but often are present. Autonomic dysfunction can significantly and deleteriously impact quality of life for individuals with Parkinson’s disease. Because effective treatment for many aspects of autonomic dysfunction is available, it is vitally important that assessment of autonomic dysfunction be a regular component of the neurologic history and exam and that appropriate treatment be initiated and maintained.Electronic supplementary materialThe online version of this article (10.1007/s13311-020-00897-4) contains supplementary material, which is available to authorized users.Key Words: Autonomic, gastrointestinal, orthostatic hypotension, urinary, erectile dysfunction, thermoregulatory     

Brain‐derived neurotrophic factor G196A polymorphism and clinical features in Parkinson’s disease

Gao L, Díaz‐Corrales FJ, Carrillo F, Díaz‐Martín J, Caceres‐Redondo MT, Carballo M, Palomino A, López‐Barneo J, Mir P. Brain‐derived neurotrophic factor G196A polymorphism and clinical features in Parkinson’s disease.
Acta Neurol Scand: 2010: 122: 41–45.
© 2010 The Authors Journal compilation © 2010 Blackwell Munksgaard. Objectives –  Parkinson’s disease (PD) is characterized by the dopaminergic neuronal death in substantia nigra, and genetic factors appear to be involved in the pathophysiology of this disease. Brain‐derived neurotrophic factor (BDNF) is widely expressed in the central nervous system and is necessary for the survival of dopaminergic neurons in substantia nigra. G196A, a common polymorphism of the BDNF gene, not only affects cognitive and motor processes, but also is associated with various psychiatric disorders. We evaluated whether G196A polymorphism is associated with PD and/or modifies clinical manifestations in PD patients. Methods –  We included 193 PD patients and 300 control subjects. G196A polymorphism was screened by restriction fragment length polymorphism analysis. Clinical features of each patient were examined in detail. The possible association between genotype and clinical characteristics were determined by bivariate and multivariate analyses. Results –  The distribution of G196A allele and genotype frequency was similar between PD and control subjects. Clinical characteristics, including Hoehn‐Yahr stage, motor symptoms, non‐motor symptoms (depression, cognitive dysfunction, psychiatric dysfunctions, and sleep behavior disorder), and dyskinesias, were not associated with this polymorphism. Conclusions –  G196A polymorphism is not a risk factor for PD and does not seem to modify clinical features in PD patients studied here.     

Hydrogen sulfide enhances adult neurogenesis in a mouse model of Parkinson’s disease

Hydrogen sulfide (H₂S) is regarded to be a protectant against diseases of the central nervous system and cardiovascular system. However, the mechanism by which H₂S elicits neuroprotective effects in the progression of Parkinson’s disease (PD) remains unclear. To investigate the role of H₂S in delaying the pathological process of PD, we used the most common sodium hydrosulfide (NaHS) as an H₂S donor and established a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p) in the present study. Our results show that H₂S reduced neuronal loss during the progression of PD. Notably, we found that H₂S exhibited protective effects on dopaminergic neurons. Excitingly, H₂S also increased the proliferation of neural stem cells in the subventricular zone. Next, we evaluated whether the neuroprotective effects of H₂S on dopaminergic neurons in PD are dependent on adult nerve regeneration by treating primary adult neural stem cells cultured ex vivo with 1-methyl-4-phenylpyridine. Our results show that H₂S could prevent nerve injury induced by 1-methyl-4-phenylpyridine, promote the growth of neurospheres, and promote neurogenesis by regulating Akt/glycogen synthase kinase-3β/β-catenin pathways in adult neural stem cells. These findings confirm that H₂S can increase neurogenesis in an adult mouse model of PD by regulating the Akt/glycogen synthase kinase-3β/β-catenin signaling pathway. This study was approved by the Animal Care and Use Committee of Nanjing Medical University, China (IACUC Approval No. 1601153-3).

Chinese Library Classification No. R453; R741; TQ125.1+2     

Parkinson’s disease and the frequent reasons for emergency admission

Introduction

Available data suggest that Parkinson’s disease (PD) patients have a significant socioeconomic impact owing partly to increased hospital and drug utilization. The aims of this study were to provide a profile of patients with PD who required admission to hospital and to determine the reasons for emergency admission.

Patients and methods

Between September 1st, 2004 and August 31st, 2006, patients with PD who were admitted to our emergency department (ED) were included in the study. Patients with PD who were diagnosed by a neurologist formerly, and admitted to the ED with any reason constituted the study population. Demographical data, reasons for admission, years exposed to PD, number of admissions to the emergency department in the past 12 months, prior Hoehn and Yahr (H&Y) scores were recorded. H&Y was performed again for all patients 4 weeks after discharge.

Results

Seventy-six patients with PD were included in the study. Reasons for admission to hospital were infectious diseases (31.6%), trauma (27.6%), cardiovascular emergencies (14.5%), cerebrovascular emergencies (11.8%), gastrointestinal emergencies (7.9%), and electrolyte disturbances (6.6%), respectively. There was no dependence between the time of exposure to PD and H&Y score. Number of emergency admittance in the last 12 months was independent from the last H&Y score (p = 0.297). However, there was a dependency between the reasons for emergency admittance and the H&Y scores (p = 0.023).

Discussion

H&Y score is not dependent on the emergency admittance or on the outcome after discharge from the emergency department. The motor disability by itself cannot predict the whole picture of PD and the systemic complications leading to emergency admittance.     

Parkinson’s disease and diabetes mellitus: common mechanisms and treatment repurposing

In the last decade, attention has become greater to the relationship between neurodegeneration and abnormal insulin signaling in the central nervous system, as insulin in the brain is implicated in neuronal survival, plasticity, oxidative stress and neuroinflammation. Diabetes mellitus and Parkinson’s disease are both aging-associated diseases that are turning into epidemics worldwide. Diabetes mellitus and insulin resistance not only increase the possibility of developing Parkinson’s disease but can also determine the prognosis and progression of Parkinsonian symptoms. Today, there are no available curative or disease modifying treatments for Parkinson’s disease, but the role of insulin and antidiabetic medications in neurodegeneration opens a door to treatment repurposing to fight against Parkinson’s disease, both in diabetic and nondiabetic Parkinsonian patients. Furthermore, it is essential to comprehend how a frequent and treatable disease such as diabetes can influence the progression of neurodegeneration in a challenging disease such as Parkinson’s disease. Here, we review the present evidence on the connection between Parkinson’s disease and diabetes and the consequential implications of the existing antidiabetic molecules in the severity and development of Parkinsonism, with a particular focus on glucagon-like peptide-1 receptor agonists.Key Words: antidiabetic, diabetes mellitus, dopamine, exenatide, glucagon-like peptide-1, insulin, neurodegeneration, neuroinflammation, Parkinson''s disease, repurposing