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Annual Review of Pathology Jan 2023Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected... (Review)
Review
Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops a virtually unique form of Parkinson's syndrome. Clinical manifestations consist of variable motor and nonmotor features, and myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central and peripheral nervous systems, the distribution varies and other pathologies commonly modify PD or trigger similar manifestations. Nearly all PD is genetically influenced. More than 100 genes or genetic loci have been identified, and most cases likely arise from interactions among many common and rare genetic variants. Despite its complex architecture, insights from experimental genetic dissection coalesce to reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms of pathogenesis. This emerging understanding of Parkinson's syndrome, coupled with advances in biomarkers and targeted therapies, presages successful precision medicine strategies.
Topics: Humans; Parkinson Disease; Mitochondria; Mutation
PubMed: 36100231
DOI: 10.1146/annurev-pathmechdis-031521-034145 -
Journal of Parkinson's Disease 2019Increasing evidence points to biological sex as an important factor in the development and phenotypical expression of Parkinson's disease (PD). Risk of developing PD is... (Review)
Review
Increasing evidence points to biological sex as an important factor in the development and phenotypical expression of Parkinson's disease (PD). Risk of developing PD is twice as high in men than women, but women have a higher mortality rate and faster progression of the disease. Moreover, motor and nonmotor symptoms, response to treatments and disease risk factors differ between women and men. Altogether, sex-related differences in PD support the idea that disease development might involve distinct pathogenic mechanisms (or the same mechanism but in a different way) in male and female patients. This review summarizes the most recent knowledge concerning differences between women and men in PD clinical features, risk factors, response to treatments and mechanisms underlying the disease pathophysiology. Unraveling how the pathology differently affect the two sexes might allow the development of tailored interventions and the design of innovative programs that meet the distinct needs of men and women, improving patient care.
Topics: Female; Humans; Inflammation; Male; Oxidative Stress; Parkinson Disease; Sex Characteristics
PubMed: 31282427
DOI: 10.3233/JPD-191683 -
Acta Medica Portuguesa Oct 2019Parkinson's disease is the second most common neurodegenerative disorder, and a significant increase in its prevalence in the past three decades has been documented.... (Review)
Review
Parkinson's disease is the second most common neurodegenerative disorder, and a significant increase in its prevalence in the past three decades has been documented. Environmental and genetic factors contribute to the pathophysiology of this disease, and 5% - 10% of cases have a monogenic cause. The diagnosis relies on clinical findings, supported by adequate testing. There is no absolute method to diagnose Parkinson's disease in vivo, except for genetic testing in specific circumstances, whose usefulness is limited to a minority of cases. New diagnostic criteria have been recently proposed with the aim of improving diagnostic accuracy, emphasizing findings that might point to other causes of parkinsonism. The available therapeutic options are clinically useful, as they improve the symptoms as well as the quality of life of patients. After the introduction of levodopa, deep brain stimulation emerged as the second therapy with an important symptomatic impact in the treatment of Parkinson's disease. Non-motor symptoms and motor complications are responsible for a large proportion of disability, so these should be identified and treated. Current scientific research is focused on the identification of disease biomarkers allowing correct and timely diagnosis, and on creating more effective therapies, thus fulfilling current clinical unmet needs. This paper presents an updated review on Parkinson's disease, guiding the readership through current concepts, and allowing their application to daily clinical practice.
Topics: Antiparkinson Agents; Biomarkers; Deep Brain Stimulation; Diagnosis, Differential; Humans; Levodopa; Parkinson Disease; Symptom Assessment
PubMed: 31625879
DOI: 10.20344/amp.11978 -
Journal of Parkinson's Disease 2018Neurological disorders are now the leading source of disability globally, and the fastest growing neurological disorder in the world is Parkinson disease. From 1990 to... (Review)
Review
Neurological disorders are now the leading source of disability globally, and the fastest growing neurological disorder in the world is Parkinson disease. From 1990 to 2015, the number of people with Parkinson disease doubled to over 6 million. Driven principally by aging, this number is projected to double again to over 12 million by 2040. Additional factors, including increasing longevity, declining smoking rates, and increasing industrialization, could raise the burden to over 17 million. For most of human history, Parkinson has been a rare disorder. However, demography and the by-products of industrialization have now created a Parkinson pandemic that will require heightened activism, focused planning, and novel approaches.
Topics: Aging; Global Health; Humans; Pandemics; Parkinson Disease; Parkinsonian Disorders; Survival Rate
PubMed: 30584159
DOI: 10.3233/JPD-181474 -
RoFo : Fortschritte Auf Dem Gebiete Der... Dec 2021Diagnosis of Parkinson's disease and atypical parkinsonism is based on clinical evaluation of the patient's symptoms and on magnetic resonance imaging (MRI) of the... (Review)
Review
BACKGROUND
Diagnosis of Parkinson's disease and atypical parkinsonism is based on clinical evaluation of the patient's symptoms and on magnetic resonance imaging (MRI) of the brain, which can be supplemented by nuclear medicine techniques. MRI plays a leading role in the differentiation between Parkinson's disease and atypical parkinsonism. While atypical parkinsonism is characterized by relatively specific MRI signs, imaging of Parkinson's disease previously lacked such signs. However, high-field MRI and new optimized MRI sequences now make it possible to define specific MRI signs of Parkinson's disease and have significant potential regarding differentiated imaging, early diagnosis, and imaging of disease progression.
METHODS
PubMed was selectively searched for literature regarding the definition and discussion of specific MRI signs of Parkinson's disease, as well as the most common types of atypical parkinsonism with a leading motor component. No time frame was set, but the search was particularly focused on current literature.
RESULTS
This review article discusses the different MRI signs of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. The pathogenesis of the MRI signs is described, and imaging examples are given. The technical aspects of image acquisition are briefly defined, and the different signs are discussed and compared with regard to their diagnostic significance according to current literature.
CONCLUSION
The MRI signs of Parkinson's disease, which can be defined with high-field MRI and new optimized MRI sequences, enable differentiated structural image interpretation and consecutive diagnostic workup. Despite the fact that the signs are in need of further validation by bigger studies, they have the potential to achieve significant diagnostic relevance regarding the imaging of Parkinson's disease and atypical parkinsonism.
KEY POINTS
· High-field MRI and specialized sequences make it possible to define specific MRI signs for neurodegenerative disorders. · Cerebral alterations can be detected in prodromal stages of Parkinson's disease. · The combination of specific MRI signs makes it possible to differentiate between Parkinson's disease and atypical parkinsonism.
CITATION FORMAT
· Aludin S, Schmill LA. MRI Signs of Parkinson's Disease and Atypical Parkinsonism. Fortschr Röntgenstr 2021; 193: 1403 - 1410.
Topics: Humans; Magnetic Resonance Imaging; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders; Supranuclear Palsy, Progressive
PubMed: 34034347
DOI: 10.1055/a-1460-8795 -
Journal of Parkinson's Disease 2022Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety... (Review)
Review
Early-onset parkinsonism (EO parkinsonism), defined as subjects with disease onset before the age of 40 or 50 years, can be the main clinical presentation of a variety of conditions that are important to differentiate. Although rarer than classical late-onset Parkinson's disease (PD) and not infrequently overlapping with forms of juvenile onset PD, a correct diagnosis of the specific cause of EO parkinsonism is critical for offering appropriate counseling to patients, for family and work planning, and to select the most appropriate symptomatic or etiopathogenic treatments. Clinical features, radiological and laboratory findings are crucial for guiding the differential diagnosis. Here we summarize the most important conditions associated with primary and secondary EO parkinsonism. We also proposed a practical approach based on the current literature and expert opinion to help movement disorders specialists and neurologists navigate this complex and challenging landscape.
Topics: Diagnosis, Differential; Humans; Middle Aged; Neurologists; Parkinson Disease; Parkinsonian Disorders
PubMed: 34569973
DOI: 10.3233/JPD-212815 -
Neuron Jan 2015Understanding the function of genes mutated in hereditary forms of Parkinson's disease yields insight into disease etiology and reveals new pathways in cell biology.... (Review)
Review
Understanding the function of genes mutated in hereditary forms of Parkinson's disease yields insight into disease etiology and reveals new pathways in cell biology. Although mutations or variants in many genes increase the susceptibility to Parkinson's disease, only a handful of monogenic causes of parkinsonism have been identified. Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease. PINK1 accumulates on the outer membrane of damaged mitochondria, activates Parkin's E3 ubiquitin ligase activity, and recruits Parkin to the dysfunctional mitochondrion. Then, Parkin ubiquitinates outer mitochondrial membrane proteins to trigger selective autophagy. This review covers the normal functions that PINK1 and Parkin play within cells, their molecular mechanisms of action, and the pathophysiological consequences of their loss.
Topics: Humans; Mitochondria; Mitophagy; Parkinson Disease; Parkinsonian Disorders; Protein Kinases; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 25611507
DOI: 10.1016/j.neuron.2014.12.007 -
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 -
Clinical Medicine (London, England) Aug 2016The clinical presentation of Parkinson's disease (PD) is heterogeneous and overlaps with other conditions, including the parkinsonian variant of multiple system atrophy... (Review)
Review
The clinical presentation of Parkinson's disease (PD) is heterogeneous and overlaps with other conditions, including the parkinsonian variant of multiple system atrophy (MSA-P), progressive supranuclear palsy (PSP) and essential tremor. Imaging of the brain in patients with parkinsonism has the ability to increase the accuracy of differential diagnosis. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) and positron emission tomography (PET) allow brain imaging of structural, functional and molecular changes in vivo in patients with PD. Structural MRI is useful to differentiate PD from secondary and atypical forms of parkinsonism. 123I-ioflupane (DaTSCAN(TM)) SPECT is a valid tool in the differential diagnosis between PD and non-degenerative tremors, while cardiac 123I-metaiodobenzylguanidine SPECT and 18F-fluorodeoxyglucose PET are valid in the differential diagnosis between PD and atypical parkinsonism (MSA-P, PSP). However, despite significant evidence for the utility of neuroimaging in assessing parkinsonian patients, none of the neuroimaging techniques are specifically recommended for routine use in clinical practice. Hopefully, future larger trials will help to demonstrate additional evidence for the clinical utility of neuroimaging and will include an analysis of the financial benefits for the NHS in the longer term management of the patients.
Topics: Brain; Humans; Molecular Imaging; Neuroimaging; Parkinson Disease
PubMed: 27481384
DOI: 10.7861/clinmedicine.16-4-371 -
Deutsches Arzteblatt International Feb 2016Aside from idiopathic Parkinson syndrome (Parkinson's disease), there are a number of other, so-called atypical parkinsonian syndromes: dementia with Lewy bodies (DLB),... (Review)
Review
BACKGROUND
Aside from idiopathic Parkinson syndrome (Parkinson's disease), there are a number of other, so-called atypical parkinsonian syndromes: dementia with Lewy bodies (DLB), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). DLB is a common disease, with a prevalence of 0.4% (400 cases per 100 000 persons) in the elderly; MSA and PSP both have a prevalence of 5 to 10 per 100 000 persons, while the prevalence of CBD is about 1 per 100 000.
METHODS
This review is based on pertinent publications retrieved by a selective literature search.
RESULTS
The atypical parkinsonian syndromes are synucleinopathies and tauopathies, i.e., disorders characterized by the abnormal deposition of the proteins α-synuclein and tau. The site of deposition is correlated with the clinical features. In DLB, synuclein is mainly deposited in neocortical neurons, with some brain stem involvement as well. The main clinical features are dementia and, later on, parkinsonism. In MSA, synuclein is deposited in oligodendrocytes, mainly in the cerebellum but also in the brain stem; the main clinical feature is autonomic dysfunction combined with parkinsonism or cerebellar ataxia. Synucleinopathies often impair REM (rapid eye movement) sleep. PSP and CBD, on the other hand, are primary tauopathies. PSP usually causes predominantly supranuclear vertical gaze palsy and early postural instability with falls, less commonly parkinsonism (PSP-P) or frontotemporal dementia (PSP-FTD) as its most prominent feature. CBD typically manifests itself as markedly asymmetrical parkinsonism with apraxia or cortical sensory disturbance. At present, there is no accepted causal treatment for any of these disorders; the available symptomatic treatments are of limited efficacy and are supported only by low-level evidence.
CONCLUSION
Causal treatments for neurodegenerative diseases are now being developed and tested, and thus a molecular diagnosis is desirable. This will require the cooperation of primary care physicians with specialized centers.
Topics: Diagnosis, Differential; Evidence-Based Medicine; Humans; Parkinson Disease; Parkinsonian Disorders; Treatment Outcome
PubMed: 26900156
DOI: 10.3238/arztebl.2016.0061