Olfactory dysfunction and its related molecular mechanisms in Parkinson’s disease

Changes in olfactory function are considered to be early biomarkers of Parkinson’s disease.Olfactory dysfunction is one of the earliest non-motor features of Parkinson’s disease,appearing in about 90%of patients with early-stage Parkinson’s disease,and can often predate the diagnosis by years.Therefore,olfactory dysfunction should be considered a reliable marker of the disease.However,the mechanisms responsible for olfactory dysfunction are currently unknown.In this article,we clearly explain the pathology and medical definition of olfactory function as a biomarker for early-stage Parkinson’s disease.On the basis of the findings of clinical olfactory function tests and animal model experiments as well as neurotransmitter expression levels,we further characterize the relationship between olfactory dysfunction and neurodegenerative diseases as well as the molecular mechanisms underlying olfactory dysfunction in the pathology of early-stage Parkinson’s disease.The findings highlighted in this review suggest that olfactory dysfunction is an important biomarker for preclinical-stage Parkinson’s disease.Therefore,therapeutic drugs targeting non-motor symptoms such as olfactory dysfunction in the early stage of Parkinson’s disease may prevent or delay dopaminergic neurodegeneration and reduce motor symptoms,highlighting the potential of identifying effective targets for treating Parkinson’s disease by inhibiting the deterioration of olfactory dysfunction.

Transcranial Direct Current Stimulation: Effects on Motor and Non-Motor Symptoms of Parkinson’s Disease

Introduction: In the last thirty years, brain neuromodulation techniques have been used as an alternative to pharmacological treatment of neurological disorders. Parkinson’s disease (PD) is a neurodegenerative disorder leading to bradykinesia, rest tremor, postural changes, and non-motor symptoms such as depression, anxiety, sleep disorders, pain, and cognitive decline that compromises executive functions (EFs), responsible for the orderly execution of behaviors and tasks of daily life and intentional and directed actions. To this date, a few studies with transcranial direct current stimulation (tDCS) have shown beneficial effects in PD patients concerning specific motor and non-motor symptoms, targeting the motor cortex and/or prefrontal regions. Objective: The main objective of this study was to evaluate the effects of left prefrontal tDCS across a broad spectrum of motor and non-motor symptoms of PD using established validated scales. Method: Single-blind randomized clinical trial with 18 volunteers with PD, aged between 45 and 80 years (66.1 ± 9.65), who met inclusion and exclusion criteria. Participants were submitted to assessments of motor and non-motor functions employing psychometric scales and tests to evaluate EFs and were randomly divided into two groups: control (sham stimulation) and experimental (active stimulation). All participants were involved in three separate tDCS sessions. The anode was positioned over the left dorsolateral prefrontal cortex and the cathode over the right supraorbital region, with a direct current intensity of 2 mA, lasting 20 minutes. At the end of the three sessions, all participants were reassessed. Results: Significant effects of tDCS on non-motor functions were observed for cognition (verbal fluency of actions, clock copy test, appointment by visual confrontation, and verbal memory with immediate free recall) and subjective assessment of sleep quality (overall restlessness and discomfort in the arms and legs at night, leg and arm cramps at night and distressing dreams). There was also an improvement in the rate of errors and successes for congruent and incongruent stimuli of the Stroop Test. The beneficial effects on motor function were decreased rigidity, improved gait, and greater agility in the finger-tapping test. Conclusion: Three tDCS sessions showed positive results for participants with PD, producing significant improvements in various motor and non-motor functions, including sleep quality, cognition, and EFs. Additionally, the present results indicate that tDCS neuromodulation of the left dorsolateral prefrontal cortex region is feasible, safe, and provides significant objective benefits for PD patients.

Effects of a Cocktail Supplement of Ginkgo Biloba and Acai Extract on Cognitive Symptoms of Parkinson’s Disease

Parkinson’s Disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, including cognitive impairment. Current treatments often involve synthetic drugs with significant side effects and potential for dependency. This study investigates the effects of a natural supplement combination of Ginkgo Biloba and Acai Extract on cognitive symptoms in a 77-year-old male with PD. The participant underwent a three-month supplementation regimen, with cognitive function assessed using the Montreal Cognitive Assessment (MoCA) test before and after the intervention. The results indicated an improvement in cognitive scores, suggesting that the combination of Ginkgo Biloba and Acai Extract may offer a promising alternative or adjunct to conventional PD treatments. This study highlights the potential of natural supplements in managing PD symptoms and calls for further research with larger sample sizes to confirm these findings. Human data was performed in accordance with the Declaration of Helsinki by the Roxbury District IRB Board (IRB Number: IRB00011767).

Clinical Characteristics of Sleep Disorders in Patients with Parkinson's Disease

In order to investigate the sleep quality and influencing factors in patients with Parkinson＇s disease（PD）, 201 PD patients were enrolled and underwent extensive clinical evaluations. Subjective sleep evaluation was assessed using the Pittsburgh Sleep Quality Index（PSQI）, and the Epworth Sleepiness Scale（ESS）. It was found that poor sleep quality（77.11%） and excessive daytime sleepiness（32.34%） were commonly seen in PD patients and positively correlated with disease severity. Then 70 out of the 201 PD patients and 70 age- and sex-matched controls underwent a polysomnographic recording. The parameters were compared between PD group and control group and the influencing factors of sleep in PD patients were analyzed. The results showed that sleep efficiency（SE） was significantly decreased（P〈0.01）, and sleep latency（SL） and the arousal index（AI） were increased（P〈0.05） in the PD group as compared with those in the control group. SE and total sleep time（TST） were positively correlated with the Hoehn and Yahr（H＆Y） stage. There was significant difference in the extent of hypopnea and hypoxemia between the PD group and the control group（P〈0.05）. Our results indicate that PD patients have an overall poor sleep quality and a high prevalence of sleep disorder, which may be correlated with the disease severity. Respiratory function and oxygen supply are also affected to a certain degree in PD patients.

Lack of Association between Impulse Control Disorders and REM Sleep Behavior Disorder in Patients with Parkinson’s Disease

Purpose: Rapid eye movement sleep behavior disorder (RBD) and impulse control disorders (ICDs) are common in subjects with Parkinson’s disease. The association between these two conditions has been contradictory. The aim of this study is to analyze the association between these two non-motor symptoms. Methods: Consecutive subjects with Parkinson’s disease attending the Movement Disorders Outpatient Clinic were included. The presence of ICDs was assessed using the Questionnaire for Impulse Control Disorders Rating Scale. RBD was diagnosed by an overnight, single night polysomnography. Results: Fifty-five consecutive subjects with Parkinson’s disease were included. The prevalence of ICDs and related behaviors was 23.6% (ICD in 14.5% and related behaviors in 9.1%). RBD was diagnosed in 47.2% of the patients. No differences were found in the frequency of ICDs and related behaviors when comparing subjects with and without RBD (23% versus 24.1%, p = 0.926, respectively). Conclusion: No association between the presence of RBD and the frequency of ICDs in subjects with Parkinson’s disease was found.

Antisense therapy:a potential breakthrough in the treatment of neurodegenerative diseases

Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.

Sleep disorders in Alzheimer’s disease:the predictive roles and potential mechanisms

Sleep disorders are common in patients with Alzheimer’s disease,and can even occur in patients with amnestic mild cognitive impairment,which appears before Alzheimer’s disease.Sleep disorders further impair cognitive function and accelerate the accumulation of amyloid-βand tau in patients with Alzheimer’s disease.At present,sleep disorders are considered as a risk factor for,and may be a predictor of,Alzheimer’s disease development.Given that sleep disorders are encountered in other types of dementia and psychiatric conditions,sleep-related biomarkers to predict Alzheimer’s disease need to have high specificity and sensitivity.Here,we summarize the major Alzheimer’s disease-specific sleep changes,including abnormal non-rapid eye movement sleep,sleep fragmentation,and sleep-disordered breathing,and describe their ability to predict the onset of Alzheimer’s disease at its earliest stages.Understanding the mechanisms underlying these sleep changes is also crucial if we are to clarify the role of sleep in Alzheimer’s disease.This paper therefore explores some potential mechanisms that may contribute to sleep disorders,including dysregulation of the orexinergic,glutamatergic,andγ-aminobutyric acid systems and the circadian rhythm,together with amyloid-βaccumulation.This review could provide a theoretical basis for the development of drugs to treat Alzheimer’s disease based on sleep disorders in future work.

Glyphosate Exposure Associated with Human Neurodegenerative Disorders: A Scoping Review

Chemically engineered agricultural products such as pesticides, insecticides, and herbicides, although used considerably for both industrialized and personal agricultural use, have recently been associated with a number of serious human health disorders. This rapid literature review aims to accumulate and analyze research from the last ten years, focusing specifically on the effects of exposure to glyphosate-based herbicide products such as Roundup as associated with the formation of various neurological disorders. Specifically, this review focuses on laboratory research using animal models or human cell cultures as well as human population-based epidemiological studies. It associates exposure to glyphosate or glyphosate-based products with the formation or exacerbation of neurological disorders such as Parkinson’s disease, Alzheimer’s disease, seizures, and autism spectrum disorder. In addition, it examines the correlation between the gut-brain axis, exposure to glyphosate, and neurodegeneration.

Concomitant Othello syndrome and impulse control disorders in a patient with Parkinson’s disease:A case report

BACKGROUND Othello syndrome(OS)is characterized by delusional beliefs concerning the infidelity of a spouse or sexual partner,which may lead to extreme behaviors.Impulse control disorders refer to behaviors involving repetitive,excessive,and compulsive activities driven by an intense desire.Both OS and impulse control disorders in Parkinson’s disease(PD)may be side effects of dopamine agonists.At present,there are only a few case reports and studies related to PD with concomitant OS and impulse control disorders.CASE SUMMARY We describe a 70-year-old male patient with PD,OS,and impulse control disorders,who presented with a six-month history of the delusional belief that his wife was having an affair with someone.He began to show an obvious increase in libido presenting as frequent masturbation.He had been diagnosed with PD ten years earlier and had no past psychiatric history.In his fourth year of PD,he engaged in binge eating,which lasted approximately one year.Both OS and hypersexuality were alleviated substantially after a reduction of his pramipexole dosage and a prescription of quetiapine.CONCLUSION Given its potential for severe consequences,OS should be identified early,especially in patients undergoing treatment with dopamine agonists.

ⅩⅩ World Congress on Parkinson's Disease and Related Disorders

Time:December 8-11,2013Venue:Palexpo Geneva Congress Center,Geneva,Switzerland Email:Parkinson@kenes.com Website:www2.kenes.com/parkinson/Pages/Home.aspxⅩⅩ World Congress on Parkinson’s Disease and Related Disorders will be held on December 8-11,2013 in Geneva,Switzerland.As the motto for this World Congress is'Integration by Translation',this Congress will deal in a most translational way with most recent research and updates on the etiology,pathogenesis,potential diagnostic markers and treatment modalities

S6B-3 Intracerebroventricular Streptozocin-Induced Alzheimer’s Disease-Like Sleep Disorders:Role of the GABAergic System in the Parabrachial Complex

Aim:Sleep disorders are common in Alzheimer’s disease(AD)and assumed to directly influence cognitive function and progression of the disease.The present study evaluated sleep characteristics in a rat model of AD that was induced by intracerebroventricular administration of streptozocin,and we assessed the possible underlying mechanisms.Methods:The cognition ability of rats was assessed by Morris water maze(MWM)trails.Sleep parameters were analyzed by electroencephalographic(EEG)and electromyographic(EMG)recordings.The neuronal activity in sleep-wake regulating brain areas was evaluated by double-staining immunohistochemistry test.High performance liquid chromatograph-electrochemical detection(HPLC-ECD)was used for the detection of neurotransmitters.Results:On day 14 after STZ injection,the rats exhibited sleep disorders that are similar to those in AD patients as evidenced by significant increase in wakefulness and decrease in rapid-eye movement sleep(REMS)and non-REMS.The c-Fos expression analysis indicated that neuronal activity and the number of neurons in the dorsal raphe nucleus and locus coeruleus decreased in STZ rats.In the ventrolateral preoptic nucleus(VLPO),the activity ofγ-aminobutyric acid(GABA)neurons was suppressed.In the arousal-driving parabrachial nucleus(PBN),GABAergic activity was suppressed,whereas glutamatergic activity was promoted.The neurotransmitter analysis revealed a reduction of GABA in the VLPO and PBN and elevations of glutamate in the PBN.A direct injection of the GABAA receptor antagonist bicuculline in the PBN in normal rats induced a similar sleep disorder pattern as in STZ rats.Furthermore,a microinjection of GABA in the PBN improved sleep disorders induced by STZ.Conclusion:These results suggest that the reduction of GABAergic inhibition in the PBN and VLPO may be involved in sleep disorders induced by STZ.Our novel findings encourage further study aimed at investigating the new mechanisms of sleep regulation in sporadic AD.

Sensor-Based Gait Analysis for Parkinson’s Disease Prediction

Parkinson’s disease is identified as one of the key neurodegenerative disorders occurring due to the damages present in the central nervous system.The cause of such brain damage seems to be fully explained in many research studies,but the understanding of its functionality remains to be impractical.Specifically,the development of a quantitative disease prediction model has evolved in recent decades.Moreover,accelerometer sensor-based gait analysis is accepted as an important tool for recognizing the walking behavior of the patients during the early prediction and diagnosis of Parkinson’s disease.This type of minimal infrastructure equipment helps in analyzing the Parkinson’s gait properties without affecting the common behavioral patterns during the clinical practices.Therefore,the Accelerometer Sensor-based Parkinson’s Disease Identi-fication System(ASPDIS)is introduced with a kernel-based support vector machine classifier model to make an early prediction of the disease.consequently,the proposed classifier can easily predict various severity levels of Parkinson’s disease from the sensor data.The performance of the proposed classifier is com-pared against the existing models such as random forest,decision tree,and k-near-est neighbor classifiers respectively.As per the experimental observation,the proposed classifier has more capability to differentiate Parkinson’s from non-Parkinson patients depending upon the severity levels.Also,it is found that the model has outperformed the existing classifiers concerning prediction time and accuracy respectively.

Insomnia and Excessive Daytime Sleepiness in Parkinson’s Disease Patient—A Review Article

Sleep-wake disorders play an important role among non-motor symptoms in Parkinson’s Disease, being a constant subject of research in recent years. There are a multitude of sleep-wake disturbances that worsen the patient’s quality of life, insomnia and excessive daytime sleepiness being two of the most frequent complaints. The aim of this review is to highlight the most relevant clinical trials conducted during the last 5 years, focusing on the problematic of insomnia and daytime sleepiness correlated with Parkinson’s Disease and its treatment. Three electronic databases (Pubmed, Science Direct and Google Scholar) were searched during March and April 2020 for articles on this topic, finally selecting 21 most relevant articles that we have included in this review. Interesting aspects regarding correlation between sleep-wake disorders and Parkinson’s disease were found, showing that non-motor symptoms may be independent of the disease itself. We discussed the most recent advances in treatment opportunities and the adverse effects, with insomnia and daytime sleepiness among the most common complaints. Besides newly developed pharmacological therapy, consisting in mostly dopaminergic agonists or levodopa adjuvant drugs. Other possibly effective therapies on sleep-wake disorders such as deep brain stimulation, dietary changes, bright light therapy and alternative medicine protocols are also reviewed. Insomnia and excessive daytime sleepiness are common complaints in Parkinson’s disease patients, being either self-standing non-motor symptoms or adverse effects of the antiparkinsonian medication, diminishing patient’s quality of life. The effervescence of research on this topic shows promising results, with new clinical trials still to come in the near future.

Sleep Disturbance in Parkinson’s Disease Varies with Age of Onset and Family History

Introduction: Parkinson’s disease (PD) is a progressive neurodegenerative disease more common in those over the age of 60. PD is classically characterized by motor features, although patients may also experience non-motor symptoms. Sleep disturbances, such as rapid eye movement (REM) behavior disorder (RBD), are common in patients with PD and may precede onset of PD. Methods: Data was collected on patients with PD (358 subjects)in a movement disorders clinic at a safety net hospital. In this retrospective database analysis, the association of PD complications with age of onset was evaluated using chi-square tests and logistic regression. Results: Of the PD complications analyzed, there was a significant difference in sleep disturbances by age. Among the 358 PD patients, 120 individuals (33.5%) had information regarding the presence or absence of sleep disturbances. There was a significant difference between the early (onset < 50) and later onset (≥50) groups (p = 0.03) with the odds of having a sleep disorder for the early group 1.6 times that of the late group. Those subjects with siblings who also had PD had 2.0 times the odds of having a sleep disorder compared those without (p = 0.02). Conclusion: Non-motor symptoms such as sleep disorders are a useful predictor of early onset PD. Genetic components of PD impact both motor and non-motor aspects of the disease.

Parkinson’s disease and affective disorder: The temporal relationship

In relationship between the affective disorders and Parkinson’s disease (PD) it was found that comorbidity was higher than expected in the majority of the studies. Patients with PD are at increased risk of developing depression and, conversely, recent studies have shown that patients with depressive disorders have increased risk of incident PD. However, the temporal associations between the disorders are not fully elucidated. From this review it could be learned that the temporal aspects strongly suggest that a neurobiological association exists between affective disorder and PD. This is illustrated with hitherto unpublished data. Some of these issues may be investigated in case register studies, e.g. by linkage of registers of somatic and psychiatric illness, and suggestions for future research are given. For GP’s, psychiatrists, geriatricians, and neurologists these new findings will lead to a better understanding and better treatment for patients with complicated comorbid conditions. Here timing is important!

Decoding degeneration:the implementation of machine learning for clinical detection of neurodegenerative disorders

Machine learning represents a growing subfield of artificial intelligence with much promise in the diagnosis,treatment,and tracking of complex conditions,including neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases.While no definitive methods of diagnosis or treatment exist for either disease,researchers have implemented machine learning algorithms with neuroimaging and motion-tracking technology to analyze pathologically relevant symptoms and biomarkers.Deep learning algorithms such as neural networks and complex combined architectures have proven capable of tracking disease-linked changes in brain structure and physiology as well as patient motor and cognitive symptoms and responses to treatment.However,such techniques require further development aimed at improving transparency,adaptability,and reproducibility.In this review,we provide an overview of existing neuroimaging technologies and supervised and unsupervised machine learning techniques with their current applications in the context of Alzheimer’s and Parkinson’s diseases.

Frequency of Comorbid Musculoskeletal Problems in Patients with Parkinson’s Disease: What and When?

Background: Musculoskeletal problems, deteriorating posture and pain are common complaints/comorbidities in Parkinson’s disease (PD). The aim of this study was to investigate the frequency of comorbid musculoskeletal problems in PD, and their relationship with disease stage and severity. Methods: The study was approved by the local ethical committee of Duzce University numbered with 2018/52 on date 26.03.2018. Patients with PD (pwPD) underwent a detailed examination to investigate the possible comorbidity of musculoskeletal findings in the orthopedics and traumatology clinic. Socio-demographic features, disease characteristics, motor and non-motor scores were recorded. Results: Thirty-seven pwPD were enrolled in the study. Mean age was 68.75 ± 10.75 years. Comorbid musculoskeletal problems were rotator cuff syndrome (27%), knee osteoarthritis (24.3%), meniscus (13.5%), lumber disc herniation (10.8%), kyphosis (8.1%), myotendinous diseases (16.3%). Rotator-cuff disease and knee osteoarthritis were most common comorbidities, especially in the “mild” and “moderate” stages of pwPD. Conclusion: Since most of the pwPD, especially the ones that have musculoskeletal complaints prior to the diagnosis of PD, present to the orthopedics and traumatology clinics or physiotherapists, it is mandatory to enhance the awareness of the orthopedic surgeons, and physiotherapy specialist in order to keep PD in mind.

Parkinson’s Disease: Examining the Role of the Pedunculopontine Nucleus via Animal Models

Parkinson’s disease is a neurodegenerative disease that spreads rapidly through the brain, and can influence a number of vital systems. The cause of this disease appears to be brought on by the progressive inability to produce adequate dopamine in the brain. People that suffer with Parkinson’s have reported REM sleep disruption at the onset of the condition. This paper reviews several animal model lesion studies related to the Pedunculopontine Nucleus, and how it plays a role in sleep regulation following a decline in dopamine production in those with parkinsonian conditions. The goal of this paper is to elucidate the functioning of the PPN and explain the nuclei’s possible role in the onset and progression of parkinsonian conditions in animal models.

Current application and future directions of photobiomodulation in central nervous diseases

Photobiomodulation using light in the red or near-infrared region is an innovative treatment strategy for a wide range of neurological and psychological conditions.Photobiomodulation can promote neurogenesis and elicit anti-apoptotic,antiinflammatory and antioxidative responses.Its therapeutic effects have been demonstrated in studies on neurological diseases,peripheral nerve injuries,pain relief and wound healing.We conducted a comprehensive literature review of the application of photobiomodulation in patients with central nervous system diseases in February 2019.The NCBI PubMed database,EMBASE database,Cochrane Library and ScienceDirect database were searched.We reviewed 95 papers and analyzed.Photobiomodulation has wide applicability in the treatment of stroke,traumatic brain injury,Parkinson’s disease,Alzheimer’s disease,major depressive disorder,and other diseases.Our analysis provides preliminary evidence that PBM is an effective therapeutic tool for the treatment of central nervous system diseases.However,additional studies with adequate sample size are needed to optimize treatment parameters.

Assessing gray matter volume in patients with idiopathic rapid eye movement sleep behavior disorder

Idiopathic rapid eye movement sleep behavior disorder(iRBD) is often a precursor to neurodegenerative disease. However, voxel-based morphological studies evaluating structural abnormalities in the brains of iRBD patients are relatively rare. This study aimed to explore cerebral structural alterations using magnetic resonance imaging and to determine their association with clinical parameters in iRBD patients. Brain structural T1-weighted MRI scans were acquired from 19 polysomnogram-confirmed iRBD patients(male:female 16:3; mean age 66.6 ± 7.0 years) and 20 age-matched healthy controls(male:female 5:15; mean age 63.7 ± 5.9 years). Gray matter volume(GMV) data were analyzed based on Statistical Parametric Mapping 8, using a voxel-based morphometry method and two-sample t-test and multiple regression analysis. Compared with controls, iRBD patients had increased GMV in the middle temporal gyrus and cerebellar posterior lobe, but decreased GMV in the Rolandic operculum, postcentral gyrus, insular lobe, cingulate gyrus, precuneus, rectus gyrus, and superior frontal gyrus. iRBD duration was positively correlated with GMV in the precuneus, cuneus, superior parietal gyrus, postcentral gyrus, posterior cingulate gyrus, hippocampus, lingual gyrus, middle occipital gyrus, middle temporal gyrus, and cerebellum posterior lobe. Furthermore, phasic chin electromyographic activity was positively correlated with GMV in the hippocampus, precuneus, fusiform gyrus, precentral gyrus, superior frontal gyrus, cuneus, inferior parietal lobule, angular gyrus, superior parietal gyrus, paracentral lobule, and cerebellar posterior lobe. There were no significant negative correlations of brain GMV with disease duration or electromyographic activity in iRBD patients. These findings expand the spectrum of known gray matter modifications in iRBD patients and provide evidence of a correlation between brain dysfunction and clinical manifestations in such patients. The protocol was approved by the Ethics Committee of Huashan Hospital(approval No. KY2013-336) on January 6, 2014. This trial was registered in the ISRCTN registry(ISRCTN18238599).