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Lancet (London, England) Jan 2024Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's... (Review)
Review
Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's disease have been derived from genetics and molecular pathology. Biochemical studies, investigation of transplanted neurons in patients with Parkinson's disease, and cell and animal model studies suggest that abnormal aggregation of α-synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson's disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson's disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson's disease. Although there are currently no disease-modifying treatments for Parkinson's disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.
Topics: Animals; Humans; Parkinson Disease; alpha-Synuclein; Brain; Models, Animal; Neurons
PubMed: 38245249
DOI: 10.1016/S0140-6736(23)01478-2 -
Nature Medicine Aug 2023Parkinson's disease is a progressive neurodegenerative movement disorder with a long latent phase and currently no disease-modifying treatments. Reliable predictive...
Parkinson's disease is a progressive neurodegenerative movement disorder with a long latent phase and currently no disease-modifying treatments. Reliable predictive biomarkers that could transform efforts to develop neuroprotective treatments remain to be identified. Using UK Biobank, we investigated the predictive value of accelerometry in identifying prodromal Parkinson's disease in the general population and compared this digital biomarker with models based on genetics, lifestyle, blood biochemistry or prodromal symptoms data. Machine learning models trained using accelerometry data achieved better test performance in distinguishing both clinically diagnosed Parkinson's disease (n = 153) (area under precision recall curve (AUPRC) 0.14 ± 0.04) and prodromal Parkinson's disease (n = 113) up to 7 years pre-diagnosis (AUPRC 0.07 ± 0.03) from the general population (n = 33,009) compared with all other modalities tested (genetics: AUPRC = 0.01 ± 0.00, P = 2.2 × 10; lifestyle: AUPRC = 0.03 ± 0.04, P = 2.5 × 10; blood biochemistry: AUPRC = 0.01 ± 0.00, P = 4.1 × 10; prodromal signs: AUPRC = 0.01 ± 0.00, P = 3.6 × 10). Accelerometry is a potentially important, low-cost screening tool for determining people at risk of developing Parkinson's disease and identifying participants for clinical trials of neuroprotective treatments.
Topics: Humans; Parkinson Disease; Movement; Prodromal Symptoms; Biomarkers; Wearable Electronic Devices
PubMed: 37400639
DOI: 10.1038/s41591-023-02440-2 -
The Lancet. Neurology Feb 2024With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically... (Review)
Review
With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.
Topics: Humans; Parkinson Disease; Neuroimaging; Precision Medicine
PubMed: 38267191
DOI: 10.1016/S1474-4422(23)00404-0 -
Journal of Advanced Research Aug 2023Parkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and... (Review)
Review
BACKGROUND
Parkinson's disease (PD) is a disease of ⍺-synuclein aggregation-mediated dopaminergic neuronal loss in the substantia nigra pars compacta, which leads to motor and non-motor symptoms. Through the last two decades of research, there has been growing consensus that inflammation-mediated oxidative stress, mitochondrial dysfunction, and cytokine-induced toxicity are mainly involved in neuronal damage and loss associated with PD. However, it remains unclear how these mechanisms relate to sporadic PD, a more common form of PD. Both enteric and central nervous systems have been implicated in the pathogenesis of sporadic PD, thus highlighting the crosstalk between the gut and brain.
AIM
of Review: In this review, we summarize how alterations in the gut microbiome can affect PD pathogenesis. We highlight various mechanisms increasing/decreasing the risk of PD development. Based on the previous supporting evidence, we suggest how early interventions could protect against PD development and how controlling specific factors, including our diet, could modify our perspective on disease mechanisms and therapeutics. We explain the strong relationship between the gut microbiota and the brain in PD subjects, by delineating the multiple mechanisms involved inneuroinflammation and oxidative stress. We conclude that the neurodetrimental effects of western diet (WD) and the neuroprotective effects of Mediterranean diets should be further exploredin humans through clinical trials. Key Scientific Concepts of Review: Alterations in the gut microbiome and associated metabolites may contribute to pathogenesis in PD. In some studies, probiotics have been shown to exert anti-oxidative effects in PD via improved mitochondrial dynamics and homeostasis, thus reducing PD-related consequences. However, there is a significant unmet need for randomized clinical trials to investigate the effectiveness of microbial products, probiotic-based supplementation, and dietary intervention in reversing gut microbial dysbiosis in PD.
Topics: Humans; Parkinson Disease; Gastrointestinal Microbiome; Inflammation; Probiotics; Diet
PubMed: 36332796
DOI: 10.1016/j.jare.2022.10.013 -
Journal of Integrative Neuroscience Sep 2023Continuous medical progress is significantly improving the quality of health care. As a result, people are living longer than during the past century, but this has also... (Review)
Review
Continuous medical progress is significantly improving the quality of health care. As a result, people are living longer than during the past century, but this has also caused an increase of the prevalence of many neurological disorders. Parkinson's disease (PD) is the fastest growing neurological condition, with a doubling of cases reported between 1995 and 2015 and a further doubling projected by 2030. Parkinson's disease is generally associated with characteristic motor symptoms (resting tremor, rigidity, bradykinesia and postural instability). However, patients with PD also experience many non-motor symptoms that might be at least as debilitating as the motor symptoms and which significantly impact patients' quality of life (QoL). Pain is a frequent yet underrecognized symptom; the incidence in PD is much higher than in the general population and constitutes a silent disability that significantly contributes to a deterioration in QoL. Accurate identification of parkinsonian pain is important for its diagnosis and effective treatment. In this review, we provide an overview of the pathophysiology, classification, and management of pain in PD. We define the various modalities of chronic PD pain, suggesting possible explanations for its relationship with PD pathology, and discuss its management and currently recommended therapies.
Topics: Humans; Parkinson Disease; Quality of Life; Chronic Pain
PubMed: 37735139
DOI: 10.31083/j.jin2205132 -
Translational Neurodegeneration Jul 2023Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. More than 200 years after its first clinical... (Review)
Review
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. More than 200 years after its first clinical description, PD remains a serious affliction that affects a growing proportion of the population. Prevailing treatments only alleviate symptoms; there is still neither a cure that targets the neurodegenerative processes nor therapies that modify the course of the disease. Over the past decades, several animal models have been developed to study PD. Although no model precisely recapitulates the pathology, they still provide valuable information that contributes to our understanding of the disease and the limitations of our treatment options. This review comprehensively summarizes the different animal models available for Parkinson's research, with a focus on those induced by drugs, neurotoxins, pesticides, genetic alterations, α-synuclein inoculation, and viral vector injections. We highlight their characteristics and ability to reproduce PD-like phenotypes. It is essential to realize that the strengths and weaknesses of each model and the induction technique at our disposal are determined by the research question being asked. Our review, therefore, seeks to better aid researchers by ensuring a concrete discernment of classical and novel animal models in PD research.
Topics: Animals; Parkinson Disease; Disease Models, Animal; Neurotoxins; Mutation
PubMed: 37468944
DOI: 10.1186/s40035-023-00368-8 -
Der Nervenarzt Oct 2023Hallmarks of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease are pathological protein aggregation, neuroinflammation, neurodegeneration... (Review)
Review
BACKGROUND
Hallmarks of neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease are pathological protein aggregation, neuroinflammation, neurodegeneration and progressive symptoms. Due to the limited causal treatment options they represent a big challenge.
OBJECTIVE
Overview of disease-modifying strategies in neurodegenerative diseases and outlook regarding future treatment development.
MATERIAL AND METHODS
Literature search regarding treatment development in neurodegenerative diseases and integration of the results. Additionally, consideration of expert opinions.
RESULTS
The development of biomarkers and genetic parameters for the detection of causal pathologies of neurodegenerative diseases as an indispensable basis for the development of disease-modifying treatment is rapidly advancing. Targets for causal interventions are all steps in the pathophysiological cascade of neurodegenerative diseases. Therapeutic antibodies are most advanced in the development and are able to remove protein deposits from the brain and to reduce the clinical progression in Alzheimer's disease. A combination of biomarkers, genetic characteristics and clinical parameters could enable an individualized treatment.
CONCLUSION
The future of the treatment of neurodegenerative diseases focuses on disease modification using molecular-based approaches. Targeted interventions against protein aggregation, inflammation and genetic factors as well as a personalized stratification of treatment hold promise for more effective forms of treatment. Although challenges still remain, current research and clinical studies give optimism for the development of disease-modifying treatment for neurodegenerative diseases.
Topics: Humans; Alzheimer Disease; Neurodegenerative Diseases; Parkinson Disease; Brain; Biomarkers
PubMed: 37801166
DOI: 10.1007/s00115-023-01544-x -
Journal of Parkinson's Disease 2024Several dietary patterns and nutritional supplements have been linked to the development, progression, and symptomatic treatment of Parkinson's disease (PD). Most of the... (Review)
Review
Several dietary patterns and nutritional supplements have been linked to the development, progression, and symptomatic treatment of Parkinson's disease (PD). Most of the evidence, at this point, is preliminary and based largely on observational studies. Interventional studies are scarce, so the evidence on effectiveness remains inconclusive. Dietary interventions could, analogous to exercise, potentially have a beneficial effect on disease symptoms as well as on the progression of the disease and should therefore be researched in high quality studies. Further work is also needed to study whether dietary interventions, when applied to an at-risk population, have any potential to postpone the onset of manifest PD. In this paper, we summarize all ongoing clinical trials on dietary interventions in PD. We found 10 ongoing studies, all aimed at a different intervention. These studies are mostly exploratory in nature or represent phase I or phase II trials focusing on safety, biological responses, and symptomatic effects. Taken together, we conclude that research on dietary interventions in persons with PD is still in its early days. The results of the various ongoing trials are expected to generate new hypotheses and will help to shape the agenda for future research on this important topic.
Topics: Humans; Parkinson Disease
PubMed: 38277304
DOI: 10.3233/JPD-230366 -
Current Neurology and Neuroscience... Sep 2023To critically review recent research in the development of non-pharmacological interventions to improve cognitive functioning in individuals with Alzheimer's disease... (Review)
Review
PURPOSE OF REVIEW
To critically review recent research in the development of non-pharmacological interventions to improve cognitive functioning in individuals with Alzheimer's disease (AD) or Parkinson's disease (PD).
RECENT FINDINGS
Cognitive interventions can be grouped into three categories: cognitive stimulation (CS), cognitive training (CT), and cognitive rehabilitation (CR). CS confers temporary, nonspecific benefits and might slightly reduce dementia risk for neurologically healthy individuals. CT can improve discrete cognitive functions, but durability is limited and real-world utility is unclear. CR treatments are holistic and flexible and, therefore, most promising but are difficult to simulate and study under rigorous experimental conditions. Optimally effective CR is unlikely to be found in a single approach or treatment paradigm. Clinicians must be competent in a variety of interventions and select those interventions best tolerated by the patient and most relevant to their needs and goals. The progressive nature of neurodegenerative disease necessitates that treatment be consistent, open-ended in duration, and sufficiently dynamic to meet the patient's changing needs as their disease progresses.
Topics: Humans; Neurodegenerative Diseases; Alzheimer Disease; Parkinson Disease; Cognition; Cognitive Behavioral Therapy
PubMed: 37428401
DOI: 10.1007/s11910-023-01283-1 -
Communications Biology Jan 2024The subthalamic nucleus (STN) is a major neuromodulation target for the alleviation of neurological and neuropsychiatric symptoms using deep brain stimulation (DBS).... (Review)
Review
The subthalamic nucleus (STN) is a major neuromodulation target for the alleviation of neurological and neuropsychiatric symptoms using deep brain stimulation (DBS). STN-DBS is today applied as treatment in Parkinson´s disease, dystonia, essential tremor, and obsessive-compulsive disorder (OCD). STN-DBS also shows promise as a treatment for refractory Tourette syndrome. However, the internal organization of the STN has remained elusive and challenges researchers and clinicians: How can this small brain structure engage in the multitude of functions that renders it a key hub for therapeutic intervention of a variety of brain disorders ranging from motor to affective to cognitive? Based on recent gene expression studies of the STN, a comprehensive view of the anatomical and cellular organization, including revelations of spatio-molecular heterogeneity, is now possible to outline. In this review, we focus attention to the neurobiological architecture of the STN with specific emphasis on molecular patterns discovered within this complex brain area. Studies from human, non-human primate, and rodent brains now reveal anatomically defined distribution of specific molecular markers. Together their spatial patterns indicate a heterogeneous molecular architecture within the STN. Considering the translational capacity of targeting the STN in severe brain disorders, the addition of molecular profiling of the STN will allow for advancement in precision of clinical STN-based interventions.
Topics: Animals; Humans; Subthalamic Nucleus; Brain; Parkinson Disease; Research Personnel
PubMed: 38200143
DOI: 10.1038/s42003-023-05691-4