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Genes Mar 2022Parkinson's disease may be caused by a single pathogenic variant (monogenic) in 5-10% of cases, but investigation of these disorders provides valuable pathophysiological... (Review)
Review
Parkinson's disease may be caused by a single pathogenic variant (monogenic) in 5-10% of cases, but investigation of these disorders provides valuable pathophysiological insights. In this review, we discuss each genetic form with a focus on genotype, phenotype, pathophysiology, and the geographic and ethnic distribution. Well-established Parkinson's disease genes include autosomal dominant forms (, , and ) and autosomal recessive forms (, and ). Furthermore, mutations in the gene are a key risk factor for Parkinson's disease, and there have been major developments for X-linked dystonia parkinsonism. Moreover, atypical or complex parkinsonism may be due to mutations in genes such as , , , , , and . Furthermore, numerous genes have recently been implicated in Parkinson's disease, such as , , , , and . Additionally, we discuss the role of heterozygous mutations in autosomal recessive genes, the effect of having mutations in two Parkinson's disease genes, the outcome of deep brain stimulation, and the role of genetic testing. We highlight that monogenic Parkinson's disease is influenced by ethnicity and geographical differences, reinforcing the need for global efforts to pool large numbers of patients and identify novel candidate genes.
Topics: DNA-Binding Proteins; Genetic Testing; Genotype; Humans; Membrane Proteins; Parkinson Disease; Parkinsonian Disorders; Phenotype; Transcription Factors
PubMed: 35328025
DOI: 10.3390/genes13030471 -
Journal of Neurochemistry Nov 2021Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Two hallmarks of PD are the accumulation of alpha-synuclein and the... (Review)
Review
Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Two hallmarks of PD are the accumulation of alpha-synuclein and the loss of dopaminergic neurons in the brain. There is no cure for PD, and all existing treatments focus on alleviating the symptoms. PD diagnosis is also based on the symptoms, such as abnormalities of movement, mood, and cognition observed in the patients. Molecular imaging methods such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) can detect objective alterations in the neurochemical machinery of the brain and help diagnose and study neurodegenerative diseases. This review addresses the application of functional MRI, PET, and SPECT in PD patients. We provide an overview of the imaging targets, discuss the rationale behind target selection, the agents (tracers) with which the imaging can be performed, and the main findings regarding each target's state in PD. Molecular imaging has proven itself effective in supporting clinical diagnosis of PD and has helped reveal that PD is a heterogeneous disorder, which has important implications for the development of future therapies. However, the application of molecular imaging for early diagnosis of PD or for differentiation between PD and atypical parkinsonisms has remained challenging. The final section of the review is dedicated to new imaging targets with which one can detect the PD-related pathological changes upstream from dopaminergic degeneration. The foremost of those targets is alpha-synuclein. We discuss the progress of tracer development achieved so far and challenges on the path toward alpha-synuclein imaging in humans.
Topics: Humans; Neuroimaging; Parkinson Disease; Positron-Emission Tomography; Tomography, Emission-Computed, Single-Photon; alpha-Synuclein
PubMed: 34532856
DOI: 10.1111/jnc.15516 -
Journal of Neurology Nov 2020Disturbances of balance, gait and posture are a hallmark of parkinsonian syndromes. Recognition of these axial features can provide important and often early clues to... (Review)
Review
Disturbances of balance, gait and posture are a hallmark of parkinsonian syndromes. Recognition of these axial features can provide important and often early clues to the nature of the underlying disorder, and, therefore, help to disentangle Parkinson's disease from vascular parkinsonism and various forms of atypical parkinsonism, including multiple system atrophy, progressive supranuclear palsy, and corticobasal syndrome. Careful assessment of axial features is also essential for initiating appropriate treatment strategies and for documenting the outcome of such interventions. In this article, we provide an overview of balance, gait and postural impairment in parkinsonian disorders, focusing on differential diagnostic aspects.
Topics: Gait; Humans; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders; Supranuclear Palsy, Progressive
PubMed: 31119450
DOI: 10.1007/s00415-019-09382-1 -
Journal of Parkinson's Disease 2021Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson's disease (PD). Initially originating from... (Review)
Review
Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson's disease (PD). Initially originating from the observation that mitochondrial toxins cause PD, findings from genetic PD supported a contribution of mitochondrial dysfunction to the disease. Here, proteins encoded by the autosomal recessively inherited PD genes Parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 are involved in mitochondrial pathways. Additional evidence for mitochondrial dysfunction stems from models of autosomal-dominant PD due to mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2). Moreover, patients harboring alterations in mitochondrial polymerase gamma (POLG) often exhibit signs of parkinsonism. While some molecular studies suggest that mitochondrial dysfunction is a primary event in PD, others speculate that it is the result of impaired mitochondrial clearance. Most recent research even implicated damage-associated molecular patterns released from non-degraded mitochondria in neuroinflammatory processes in PD. Here, we summarize the manifold literature dealing with mitochondria in the context of PD. Moreover, in light of recent advances in the field of personalized medicine, patient stratification according to the degree of mitochondrial impairment followed by mitochondrial enhancement therapy may hold potential for at least a subset of genetic and idiopathic PD cases. Thus, in the second part of this review, we discuss therapeutic approaches targeting mitochondrial dysfunction with the aim to prevent or delay neurodegeneration in PD.
Topics: Animals; Humans; Mitochondrial Diseases; Parkinson Disease
PubMed: 33074190
DOI: 10.3233/JPD-201981 -
Journal of Neural Transmission (Vienna,... Sep 2022The question whether life style may impair the advent or course of the disease in patients with Parkinsonism is of great importance for patients and physicians alike. We... (Review)
Review
The question whether life style may impair the advent or course of the disease in patients with Parkinsonism is of great importance for patients and physicians alike. We present here comprehensive information on the influence of the environment, diet (especially caffeine, nicotine, alcohol, chocolate and dairy products), physical activity and sleep on risk and course of Parkinson's disease.
Topics: Caffeine; Exercise; Humans; Life Style; Parkinson Disease; Parkinsonian Disorders
PubMed: 35606622
DOI: 10.1007/s00702-022-02509-1 -
Journal of Parkinson's Disease 2018Recent epidemiological observations have drawn attention to the rapid rise in the burden caused by Parkinson's disease over the past years, emphasizing that Parkinson's...
Recent epidemiological observations have drawn attention to the rapid rise in the burden caused by Parkinson's disease over the past years, emphasizing that Parkinson's disease is a matter of serious concern for our future generations. A recent report by Public Health England corroborates this message, by providing new insight on trends in deaths associated with neurological diseases in England between 2001 to 2014. The report indicates that mortality associated with Parkinson's disease and related disorders increased substantially between 2001 and 2014. This trend is partially explained by increased longevity in the population. However, it is possible that changes in exposure to risk factors, recent improvements in multidisciplinary care (leading to prolonged survival), and improved diagnostic awareness or improved registration also influenced the observed trend. Furthermore, patients with Parkinson's disease and related disorders were found to die at an advanced age, and the majority die in a care home or hospital, despite a preponderant preference for many patients and their families to spend their last days at home. To combat these concerning observations, future efforts should be focused on providing resources for vulnerable elderly Parkinson patients, avoiding unplanned hospital admissions and out-of-home deaths as much as possible. Possible solutions include a community-based network of specifically trained allied health therapists, personal case managers for Parkinson patients, dedicated Parkinson nursing homes, and improved centralised support services from university clinics to regional community hospitals aimed at facilitating optimal wide-scale care delivery.
Topics: Cause of Death; Delivery of Health Care; Humans; Parkinson Disease; Parkinsonian Disorders; Risk; Survival Rate
PubMed: 30149463
DOI: 10.3233/JPD-181374 -
Journal of Parkinson's Disease 2017The identification of MPTP, a relatively simple compound which causes selective degeneration of the substantia nigra after systemic administration, has had an a... (Review)
Review
The identification of MPTP, a relatively simple compound which causes selective degeneration of the substantia nigra after systemic administration, has had an a significant impact on the understanding and treatment of Parkinson’s disease (PD) over the last 30 years. This article is prefaced by the intriguing “medical detective story” that lead to the discovery of the biological effects of MPTP in humans. The steps that lead to the unraveling its mechanism of action and their impact on research into pathways underlying nigrostriatal degeneration are reviewed. The impact of the animal models that have been developed utilizing MPTP is also described with a focus on the translational implications of MPTP-related research. These include use of MAO-B inhibitors aimed at neuroprotection in PD and the importance of a stable primate model for PD which was utilized to better understand the circuitry of the basal ganglia, and the identification of the subthalamic nucleus as a target for deep brain stimulation. Finally, the results of a broad range of epidemiologic studies aimed as assessing the impact of environmental factors in PD that have been inspired by MPTP are summarized, including the discovery of other neurotoxicants (rotenone and paraquat) with parkinsonogenic effects. Overall, this article attempts to describe how the discovery of this nigral neurotoxicant began, where it is currently, and what the future may hold.
Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Disease Models, Animal; History, 20th Century; Humans; Parkinson Disease; Parkinsonian Disorders; Substantia Nigra; Translational Research, Biomedical
PubMed: 28282815
DOI: 10.3233/JPD-179006 -
Tidsskrift For Den Norske Laegeforening... Feb 2017
Topics: Humans; Parkinson Disease; Parkinsonian Disorders; Terminology as Topic
PubMed: 28225240
DOI: 10.4045/tidsskr.16.0915 -
Parkinsonism & Related Disorders Aug 2014Drug-induced parkinsonism is the second most common cause of parkinsonism after Parkinson's disease and their distinction has crucial implications in terms of management... (Review)
Review
Drug-induced parkinsonism is the second most common cause of parkinsonism after Parkinson's disease and their distinction has crucial implications in terms of management and prognosis. However, differentiating between these conditions can be challenging on a clinical ground, especially in the early stages. We therefore performed a review to ascertain whether assessment of non-motor symptoms, or use of ancillary investigations, namely dopamine transporter imaging, transcranial sonography of the substantia nigra, and scintigraphy for myocardial sympathetic innervation, can be recommended to distinguish between these conditions. Among non-motor symptoms, there is evidence that hyposmia can differentiate between patients with "pure" drug-induced parkinsonism and those with degenerative parkinsonism unmasked by an anti-dopaminergic drug. However, several issues, including smoking history and cognitive functions, can influence smell function assessment. Higher diagnostic accuracy has been demonstrated for dopamine transporter imaging. Finally, preliminary evidence exists for sympathetic cardiac scintigraphy to predict dopaminergic pathway abnormalities and to differentiate between drug-induced parkinsonism and Parkinson's disease. Imaging of the dopaminergic pathway seems to be the only, reasonably available, technique to aid the differential diagnosis between drug-induced parkinsonism and Parkinson's disease.
Topics: Diagnosis, Differential; Humans; Parkinson Disease; Parkinsonian Disorders
PubMed: 24935237
DOI: 10.1016/j.parkreldis.2014.05.011 -
Current Neurology and Neuroscience... Sep 2017This article reviews was to review genes where putative or confirmed pathogenic mutations causing Parkinson's disease or Parkinsonism have been identified since 2012,... (Review)
Review
PURPOSE OF REVIEW
This article reviews was to review genes where putative or confirmed pathogenic mutations causing Parkinson's disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes.
RECENT FINDINGS
Newly reported genes for dominant Parkinson's disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted. RIC3 mutations have been reported from one family but not yet encountered in other patients. New genes for autosomal recessive disease include SYNJ1, DNAJC6, VPS13C, and PTRHD1. Deletions of a region on chromosome 22 (22q11.2del) are also associated with early-onset PD, but the mode of inheritance and the underlying causative gene remain unclear. PODXL mutations were reported in autosomal recessive PD, but their roles remain to be confirmed. Mutations in RAB39B cause an X-linked Parkinsonian disorder. Mutations in the new dominant PD genes have generally been found in medium- to late-onset Parkinson's disease. Many mutations in the new recessive and X-chromosomal genes cause severe atypical juvenile Parkinsonism, but less devastating mutations in these genes may cause PD.
Topics: DNA-Binding Proteins; Genetic Association Studies; Humans; Intracellular Signaling Peptides and Proteins; Mitochondrial Proteins; Mutation; Parkinson Disease; Parkinsonian Disorders; Transcription Factors; Ubiquitin-Protein Ligases
PubMed: 28733970
DOI: 10.1007/s11910-017-0780-8