scholarly journals Nuclear and Mitochondrial Genome, Epigenome and Gut Microbiome: Emerging Molecular Biomarkers for Parkinson’s Disease

2021 ◽  
Vol 22 (18) ◽  
pp. 9839
Author(s):  
Gleyce Fonseca Cabral ◽  
Ana Paula Schaan ◽  
Giovanna C. Cavalcante ◽  
Camille Sena-dos-Santos ◽  
Tatiane Piedade de Souza ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Genome ◽  
Gut Microbiome ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Clinical Signs ◽  
Genomic Variation ◽  
Increasing Demand ◽  
Based Medicine

Background: Parkinson’s disease (PD) is currently the second most common neurodegenerative disorder, burdening about 10 million elderly individuals worldwide. The multifactorial nature of PD poses a difficult obstacle for understanding the mechanisms involved in its onset and progression. Currently, diagnosis depends on the appearance of clinical signs, some of which are shared among various neurologic disorders, hindering early diagnosis. There are no effective tools to prevent PD onset, detect the disease in early stages or accurately report the risk of disease progression. Hence, there is an increasing demand for biomarkers that may identify disease onset and progression, as treatment-based medicine may not be the best approach for PD. Over the last few decades, the search for molecular markers to predict susceptibility, aid in accurate diagnosis and evaluate the progress of PD have intensified, but strategies aimed to improve individualized patient care have not yet been established. Conclusions: Genomic variation, regulation by epigenomic mechanisms, as well as the influence of the host gut microbiome seem to have a crucial role in the onset and progress of PD, thus are considered potential biomarkers. As such, the human nuclear and mitochondrial genome, epigenome, and the host gut microbiome might be the key elements to the rise of personalized medicine for PD patients.

scholarly journals Gut microbiome signatures of risk and prodromal markers of Parkinson’s disease

2019 ◽  
Author(s):  
Sebastian Heinzel ◽  
Velma T. E. Aho ◽  
Ulrike Suenkel ◽  
Anna-Katharina von Thaler ◽  
Claudia Schulte ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gut Microbiome ◽  
Physical Inactivity ◽  
Disease Onset ◽  
Rem Sleep Behavior Disorder ◽  
Sleep Behavior ◽  
Microbiome Composition ◽  
Β Diversity ◽  
The Impact

AbstractObjectivesAlterations of the gut microbiome in Parkinson’s disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they may be related to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition.MethodsEstablished risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function and medication were studied in relation to bacterial α-/β-diversity, enterotypes, and taxonomic composition in stool samples of 666 elderly TREND study participants.ResultsAmong risk and prodromal markers, physical inactivity, constipation and age showed associations with α- and β-diversity, and for both measures subthreshold parkinsonism and physical inactivity showed interaction effects. Moreover, male sex, possible REM-sleep behavior disorder (RBD), smoking as well as body-mass-index, antidiabetic and urate-lowering medication were associated with β-diversity. Physical inactivity and constipation severity were increased in individuals with the Firmicutes-enriched enterotype. Subthreshold parkinsonism was least frequently observed in individuals with the Prevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical inactivity, possible RBD, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history and the overall prodromal PD probability showed no significant microbiome associations.InterpretationSeveral risk and prodromal markers of PD are associated with changes in gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases.

scholarly journals Machine Learning Prediction of Parkinson's Disease Onset and Subtype Using Germline Variants

2021 ◽  
Author(s):  
Saya R Dennis ◽  
Tanya Simuni ◽  
Yuan Luo
Keyword(s):  
Machine Learning ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
The United States ◽  
Machine Learning Algorithms ◽  
Progression Rate ◽  
High Importance ◽  
Germline Variants

Parkinson's Disease is the second most common neurodegenerative disorder in the United States, and is characterized by a largely irreversible worsening of motor and non-motor symptoms as the disease progresses. A prominent characteristic of the disease is its high heterogeneity in manifestation as well as the progression rate. For sporadic Parkinson's Disease, which comprises ~90% of all diagnoses, the relationship between the patient genome and disease onset or progression subtype remains largely elusive. Machine learning algorithms are increasingly adopted to study the genomics of diseases due to their ability to capture patterns within the vast feature space of the human genome that might be contributing to the phenotype of interest. In our study, we develop two machine learning models that predict the onset as well as the progression subtype of Parkinson's Disease based on subjects' germline mutations. Our best models achieved an ROC of 0.77 and 0.61 for disease onset and subtype prediction, respectively. To the best of our knowledge, our models present state-of-the-art prediction performances of PD onset and subtype solely based on the subjects' germline variants. The genes with high importance in our best-performing models were enriched for several canonical pathways related to signaling, immune system, and protein modifications, all of which have been previously associated with PD symptoms or pathogenesis. These high-importance gene sets provide us with promising candidate genes for future biomedical and clinical research.

scholarly journals Engaging cognitive circuits to promote motor recovery in degenerative disorders. exercise as a learning modality

2016 ◽  
Vol 52 (1) ◽  
pp. 35-51 ◽  
Author(s):  
Michael W. Jakowec ◽  
Zhou Wang ◽  
Daniel Holschneider ◽  
Jeff Beeler ◽  
Giselle M. Petzinger
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Wide Spectrum ◽  
Disease Onset ◽  
Short Review ◽  
Motor Recovery ◽  
Adult Brain ◽  
Brain Disorders ◽  
Dopamine Depletion

AbstractExercise and physical activity are fundamental components of a lifestyle essential in maintaining a healthy brain. This is primarily due to the fact that the adult brain maintains a high degree of plasticity and activity is essential for homeostasis throughout life. Plasticity is not lost even in the context of a neurodegenerative disorder, but could be maladaptive thus promoting disease onset and progression. A major breakthrough in treating brain disorders such as Parkinson’s disease is to drive neuroplasticity in a direction to improve motor and cognitive dysfunction. The purpose of this short review is to present the evidence from our laboratories that supports neuroplasticity as a potential therapeutic target in treating brain disorders. We consider that the enhancement of motor recovery in both animal models of dopamine depletion and in patients with Parkinson’s disease is optimized when cognitive circuits are engaged; in other words, the brain is engaged in a learning modality. Therefore, we propose that to be effective in treating Parkinson’s disease, physical therapy must employ both skill-based exercise (to drive specific circuits) and aerobic exercise (to drive the expression of molecules required to strengthen synaptic connections) components to select those neuronal circuits, such as the corticostriatal pathway, necessary to restore proper motor and cognitive behaviors. In the wide spectrum of different forms of exercise, learning as the fundamental modality likely links interventions used to treat patients with Parkinson’s disease and may be necessary to drive beneficial neuroplasticity resulting in symptomatic improvement and possible disease modification.

scholarly journals Olfaction and Colour Vision: What Can They Tell Us about Parkinson’s Disease?

2018 ◽  
Vol 119 (2-3) ◽  
pp. 85-96 ◽  
Author(s):  
Irene Dall’Antonia ◽  
Karel Šonka ◽  
Petr Dušek
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Colour Vision ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Alpha Synuclein ◽  
Nerve Tissue ◽  
Clinical Markers ◽  
Motor Abnormalities ◽  
Non Motor Symptoms

Parkinson’s disease is a neurodegenerative disorder with the pathological accumulation of alpha synuclein in the brain and peripheral nerve tissue. Early stages of synucleinopathies, often present clinically with rapid eye movement (REM) sleep disorder (RBD). Clinical markers that indicate early progression from RBD to manifest synucleinopathies include abnormal dopamine transporter (DAT) imaging, motor and non-motor symptoms. Despite the high diagnostic strength of DAT imaging and motor abnormalities, they are not the earliest biomarkers. Non-motor signs of neurodegeneration such as colour vision and olfaction abnormalities are detectable by clinical examination as early as 20 years before disease onset. Detailed analysis of olfactory and colour vision dysfunction can provide valuable information regarding brain pathologies, further specifying clinical phenotypes, and giving clues to underlying pathophysiological mechanisms in Parkinson’s disease and related disorders.

scholarly journals Neuroprotective mechanisms of red clover and soy isoflavones in Parkinson’s disease models

2020 ◽  
Author(s):  
Aurélie de Rus Jacquet ◽  
Abeje Ambaw ◽  
Mitali Arun Tambe ◽  
Sin Ying Ma ◽  
Michael Timmers ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Trifolium Pratense ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Red Clover ◽  
Antioxidant Response ◽  
Motor Dysfunction ◽  
Neuroprotective Effects ◽  
Dietary Polyphenols

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration and the spreading of aggregated forms of the presynaptic protein α-synuclein (aSyn) throughout the brain. PD patients are currently only treated with symptomatic therapies, and strategies to slow or stop the progressive neurodegeneration underlying the disease’s motor and cognitive symptoms are greatly needed. The time between the first neurobiochemical alterations and the initial presentation of symptoms is thought to span several years, and early neuroprotective dietary interventions could delay the disease onset or slow PD progression. This study aimed at characterizing the neuroprotective effects of isoflavones, a class of dietary polyphenols found in soy products and in the medicinal plant red clover (Trifolium pratense). We found that isoflavone-rich extracts and individual isoflavones rescued the loss of dopaminergic neurons and the shortening of neurites in primary mesencephalic cultures exposed to two PD-related insults, the environmental toxin rotenone and an adenovirus encoding the A53T aSyn mutant. The extracts and individual isoflavones also activated the Nrf2-mediated antioxidant response in astrocytes via a mechanism involving inhibition of the ubiquitin-proteasome system, and they alleviated deficits in mitochondrial respiration. Furthermore, an isoflavone-enriched soy extract reduced motor dysfunction exhibited by rats lesioned with the PD-related neurotoxin 6-OHDA. These findings suggest that plant-derived isoflavones could serve as dietary supplements to delay PD onset in at-risk individuals and mitigate neurodegeneration in the brains of patients.

scholarly journals O6E.4 Metabolome and exposome profiling: new opportunities to study risk factors for parkinson’s disease

2019 ◽  
Vol 76 (Suppl 1) ◽  
pp. A60.1-A60
Author(s):  
Susan Peters ◽  
Douglas Walker ◽  
Gary Miller ◽  
Marc Chadeau-Hyam ◽  
Paolo Vineis ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
High Resolution Mass Spectrometry ◽  
Association Studies ◽  
Disease Onset ◽  
Incidence Density ◽  
Exogenous Compounds ◽  
Nested Case Control

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease and is imposing an increasing social and economic burden in ageing populations. Although the role of environmental factors has been recognised, few established risk factors have been consistently identified. Evidence that exposure to pesticides, herbicides and metals increase PD risk is suggestive, but further research is needed to identify specific compounds that may play a causal role.Large established prospective population studies offer an important opportunity for investigating risk factors in relatively rare diseases such as PD. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, 734 incident PD cases have been ascertained, for whom pre-diagnostic blood has been stored. A nested case-control study will be conducted, where one control per case will be selected by incidence density sampling matched by age at recruitment, sex and study centre.Untargeted metabolomics can simultaneously characterize thousands of endogenous and exogenous compounds within a biological sample: the metabolome. Metabolome wide association studies (MWAS) have identified significant differences in the metabolomic profile of older adults with and without PD. We will employ an innovative approach combining liquid and gas phase chromatography with ultra-high-resolution mass spectrometry (LC/GC-UHRMS), to identify exogenous chemical exposures (e.g. pollutants, pesticides and medications), the exposome, in addition to the metabolome.Disease specific variability in blood metabolite compositions may signify the presence of mechanistic aberrations contributing to PD pathogenesis. The combination of metabolome and exposome profiling provides a measure of the continuum from exposure to disease. Allowing previously unavailable richness and depth for characterizing the metabolome and exposome upon which novel discoveries in PD can be made.The EPIC cohort allows us to perform a to study the metabolome and exposome well before disease onset, to eliminate possible effects of levodopa medication or disease-related processes.

scholarly journals Peripheral Delivery of Neural Precursor Cells Ameliorates Parkinson’s Disease-Associated Pathology

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1359 ◽  
Author(s):  
Edwards III ◽  
Gamez ◽  
Armijo ◽  
Kramm ◽  
Morales ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Stem Cell ◽  
Motor Function ◽  
Dopaminergic Neurons ◽  
Neurodegenerative Disorder ◽  
Clinical Signs ◽  
Alpha Synuclein ◽  
Neuroinflammatory Response ◽  
Impaired Motor Function

: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by loss of motor control due to a wide loss of dopaminergic neurons along the nigro-striatal pathway. Some of the mechanisms that contribute to this cell death are inflammation, oxidative stress, and misfolded alpha-synuclein-induced toxicity. Current treatments are effective at managing the early motor symptoms of the disease, but they become ineffective over time and lead to adverse effects. Previous research using intracerebral stem cell therapy for treatment of PD has provided promising results; however, this method is very invasive and is often associated with unacceptable side effects. In this study, we used an MPTP-injected mouse model of PD and intravenously administered neural precursors (NPs) obtained from mouse embryonic and mesenchymal stem cells. Clinical signs and neuropathology were assessed. Female mice treated with NPs had improved motor function and reduction in the neuroinflammatory response. In terms of safety, there were no tumorigenic formations or any detectable adverse effect after treatment. Our results suggest that peripheral administration of stem cell-derived NPs may be a promising and safe therapy for the recovery of impaired motor function and amelioration of brain pathology in PD.

Rapid Diagnosis of Parkinson’s Disease from Sebum using Paper Spray Ionisation Ion Mobility Mass Spectrometry

2020 ◽  
Author(s):  
Depanjan Sarkar ◽  
Drupad Trivedi ◽  
Eleanor Sinclair ◽  
Sze Hway Lim ◽  
Caitlin Walton-Doyle ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ion Mobility ◽  
Neurodegenerative Disorder ◽  
Treatment Options ◽  
Ion Mobility Mass Spectrometry ◽  
Paper Spray ◽  
Molecular Features ◽  
Validation Set

Parkinson’s disease (PD) is the second most common neurodegenerative disorder for which identification of robust biomarkers to complement clinical PD diagnosis would accelerate treatment options and help to stratify disease progression. Here we demonstrate the use of paper spray ionisation coupled with ion mobility mass spectrometry (PSI IM-MS) to determine diagnostic molecular features of PD in sebum. PSI IM-MS was performed directly from skin swabs, collected from 34 people with PD and 30 matched control subjects as a training set and a further 91 samples from 5 different collection sites as a validation set. PSI IM-MS elucidates ~ 4200 features from each individual and we report two classes of lipids (namely phosphatidylcholine and cardiolipin) that differ significantly in the sebum of people with PD. Putative metabolite annotations are obtained using tandem mass spectrometry experiments combined with accurate mass measurements. Sample preparation and PSI IM-MS analysis and diagnosis can be performed ~5 minutes per sample offering a new route to for rapid and inexpensive confirmatory diagnosis of this disease.

Visual Effects of Deep Brain Stimulation in a Patient with Parkinson’s Disease

2019 ◽  
pp. 158-173
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Visual System ◽  
Brain Stimulation ◽  
Neurodegenerative Disorder ◽  
Initial Examination ◽  
Before And After ◽  
Deep Brain ◽  
Cover Test

Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by a dopamine deficiency that presents with motor symptoms. Visual disorders can occur concomitantly but are frequently overlooked. Deep brain stimulation (DBS) has been an effective treatment to improve tremors, stiffness and overall mobility, but little is known about its effects on the visual system. Case Report: A 75-year-old Caucasian male with PD presented with longstanding binocular diplopia. On baseline examination, the best-corrected visual acuity was 20/25 in each eye. On observation, he had noticeable tremors with an unsteady gait. Distance alternating cover test showed exophoria with a right hyperphoria. Near alternating cover test revealed a significantly larger exophoria accompanied by a reduced near point of convergence. Additional testing with a 24-2 Humphrey visual field and optical coherence tomography (OCT) of the nerve and macula were unremarkable. The patient underwent DBS implantation five weeks after initial examination, and the device was activated four weeks thereafter. At follow up, the patient still complained of intermittent diplopia. There was no significant change in the manifest refraction or prism correction. On observation, the patient had remarkably improved tremors with a steady gait. All parameters measured were unchanged. The patient was evaluated again seven months after device activation. Although vergence ranges at all distances were improved, the patient was still symptomatic for intermittent diplopia. OCT scans of the optic nerve showed borderline but symmetric thinning in each eye. All other parameters measured were unchanged. Conclusion: The case found no significant changes on ophthalmic examination after DBS implantation and activation in a patient with PD. To the best of the authors’ knowledge, there are no other cases in the literature that investigated the effects of DBS on the visual system pathway in a patient with PD before and after DBS implantation and activation.

Peripheral Immunity, Immunoaging and Neuroinflammation in Parkinson’s Disease

2019 ◽  
Vol 26 (20) ◽  
pp. 3719-3753 ◽  
Author(s):  
Natasa Kustrimovic ◽  
Franca Marino ◽  
Marco Cosentino
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Immune System ◽  
Neurodegenerative Disorder ◽  
Neurodegenerative Process ◽  
Progressive Degeneration ◽  
Cytokine Levels ◽  
Inflammatory Phenotype ◽  
Immune Challenges

:Parkinson’s disease (PD) is the second most common neurodegenerative disorder among elderly population, characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, exact cause remains unknown and the mechanism of neurons death uncertain. It is typically considered as a disease of central nervous system (CNS). Nevertheless, numerous evidence has been accumulated in several past years testifying undoubtedly about the principal role of neuroinflammation in progression of PD. Neuroinflammation is mainly associated with presence of activated microglia in brain and elevated levels of cytokine levels in CNS. Nevertheless, active participation of immune system as well has been noted, such as, elevated levels of cytokine levels in blood, the presence of auto antibodies, and the infiltration of T cell in CNS. Moreover, infiltration and reactivation of those T cells could exacerbate neuroinflammation to greater neurotoxic levels. Hence, peripheral inflammation is able to prime microglia into pro-inflammatory phenotype, which can trigger stronger response in CNS further perpetuating the on-going neurodegenerative process.:In the present review, the interplay between neuroinflammation and the peripheral immune response in the pathobiology of PD will be discussed. First of all, an overview of regulation of microglial activation and neuroinflammation is summarized and discussed. Afterwards, we try to collectively analyze changes that occurs in peripheral immune system of PD patients, suggesting that these peripheral immune challenges can exacerbate the process of neuroinflammation and hence the symptoms of the disease. In the end, we summarize some of proposed immunotherapies for treatment of PD.

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