Parkinson’s disease: etiopathogenesis and treatment

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2020, Volume and Issue: 91(8), P. 795 - 808

Published: June 23, 2020

The concept of ‘idiopathic’ Parkinson’s disease (PD) as a single entity has been challenged with the identification several clinical subtypes, pathogenic genes and putative causative environmental agents. In addition to classic motor symptoms, non-motor manifestations (such rapid eye movement sleep disorder, anosmia, constipation depression) appear at prodromic/premotor stage evolve, along cognitive impairment dysautonomia, progresses, often dominating advanced stages disease. key molecular mechanisms include α-synuclein misfolding aggregation, mitochondrial dysfunction, protein clearance (associated deficient ubiquitin-proteasome autophagy-lysosomal systems), neuroinflammation oxidative stress. involvement dopaminergic well noradrenergic, glutamatergic, serotonergic adenosine pathways provide insights into rich variable phenomenology associated PD possibility alternative therapeutic approaches beyond traditional dopamine replacement therapies. One biggest challenges in development potential neuroprotective therapies lack reliable sensitive biomarkers progression. Immunotherapies such use vaccination or monoclonal antibodies directed against aggregated, toxic α-synuclein.as anti-aggregation strategies are currently investigated trials. application glucagon-like peptide one receptor agonists, specific gene target agents GBA LRRK2 modifiers) other modifying drugs cautious optimism that more effective on horizon. Emerging therapies, new symptomatic drugs, innovative drug delivery systems novel surgical interventions give hope patients about their future outcomes prognosis.

Language: Английский

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Parkinson’s Disease

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: 391(5), P. 442 - 452

Published: July 31, 2024

Parkinson's disease is a multisystem neurodegenerative disorder with motor and prominent, sometimes premonitory, nonmotor symptoms. Detection of gene variants may inform prognosis and, potentially, treatment.

Language: Английский

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Disease modification and biomarker development in Parkinson disease

Neurology, Journal Year: 2020, Volume and Issue: 94(11), P. 481 - 494

Published: Feb. 27, 2020

A fundamental question in advancing Parkinson disease (PD) research is whether it represents one disorder or many. Does each genetic PD inform a common pathobiology represent unique entity? Do the similarities between and idiopathic forms of outweigh differences? If aggregates α-synuclein Lewy bodies neurites are present most (α-synucleinopathies), they also etiopathogenically significant (α-synuclein pathogenesis)? matter that postmortem studies have demonstrated mixed protein-aggregate pathology rule pure α-synucleinopathy exception? Should we continue to pursue convergent biomarkers representative diverse whole subtype-specific, divergent biomarkers, some but absent most? Have clinical trials failed demonstrate efficacy putative disease-modifying interventions been true failures (shortcomings hypotheses, which should be rejected) false trials; hypotheses preserved)? Each these questions reflects nosologic struggle lumper's clinicopathologic model embraces heterogeneity splitter's focus on pathobiology-specific set diseases. Most important, even if not single disorder, can advances modification revised concentrate pathologic commonalities large, clinically defined populations? Or our efforts reconstructed smaller subgroups patients, distinguished by well-defined molecular characteristics, regardless their phenotypic classification? Will trial constructs target larger earlier, possibly prodromal, cohorts? molecularly presymptomatic postsymptomatic At Krembil Knowledge Gaps Parkinson's Disease Symposium, tentative answers were discussed, informed successes fields breast cancer cystic fibrosis.

Language: Английский

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Two distinct trajectories of clinical and neurodegeneration events in Parkinson’s disease

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: July 13, 2023

Abstract Increasing evidence suggests that Parkinson’s disease (PD) exhibits disparate spatial and temporal patterns of progression. Here we used a machine-learning technique—Subtype Stage Inference (SuStaIn) — to uncover PD subtypes with distinct trajectories clinical neurodegeneration events. We enrolled 228 patients 119 healthy controls comprehensive assessments olfactory, autonomic, cognitive, sleep, emotional function. The integrity substantia nigra (SN), locus coeruleus (LC), amygdala, hippocampus, entorhinal cortex, basal forebrain were assessed using diffusion neuromelanin-sensitive MRI. SuStaIn model above neuroimaging variables as input was conducted identify subtypes. An independent dataset consisting 153 67 utilized validate our findings. identified two subtypes: subtype 1 rapid eye movement sleep behavior disorder (RBD), autonomic dysfunction, degeneration the SN LC early manifestations, cognitive impairment limbic advanced while 2 hyposmia, impairment, followed later by RBD in disease. Similar shown validation dataset. Moreover, found had weaker levodopa response, more GBA mutations, poorer prognosis than 2. These findings provide new insights into underlying biology might be useful for personalized treatment based on their subtype.

Language: Английский

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Defining the Riddle in Order to Solve It: There Is More Than One “Parkinson's Disease”

Movement Disorders, Journal Year: 2023, Volume and Issue: 38(7), P. 1127 - 1142

Published: May 8, 2023

Abstract Background More than 200 years after James Parkinsondescribed a clinical syndrome based on his astute observations, Parkinson's disease (PD) has evolved into complex entity, akin to the heterogeneity of other human syndromes central nervous system such as dementia, motor neuron disease, multiple sclerosis, and epilepsy. Clinicians, pathologists, basic science researchers arrange concepts andcriteria for clinical, genetic, mechanistic, neuropathological characterization what, in their best judgment, constitutes PD. However, these specialists have generated used criteria that are not necessarily aligned between different operational definitions, which may hinder progress solving riddle distinct forms PD ultimately how treat them. Objective This task force identified current consistencies definitions its diverse variants domains: criteria, classification, genetic subtyping, biomarker signatures, mechanisms disease. initial effort “defining riddle” will lay foundation future attempts better define range variants, been done implemented heterogeneous neurological syndromes, stroke peripheral neuropathy. We strongly advocate more systematic evidence‐based integration our disciplines by looking at well‐defined Conclusion Accuracy defining endophenotypes “typical PD” across but interrelated enable definition stratification therapeutic trials, prerequisite breakthroughs era precision medicine. © 2023 The Authors. Movement Disorders published Wiley Periodicals LLC behalf International Parkinson Disorder Society.

Language: Английский

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Two-year clinical progression in focal and diffuse subtypes of Parkinson’s disease

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: Feb. 17, 2023

Heterogeneity in Parkinson's disease (PD) presents a barrier to understanding mechanisms and developing new treatments. This challenge may be partially overcome by stratifying patients into clinically meaningful subtypes. A recent subtyping scheme classifies de novo PD three subtypes: mild-motor predominant, intermediate, or diffuse-malignant, based on motor impairment, cognitive function, rapid eye movement sleep behavior disorder (RBD) symptoms, autonomic symptoms. We aimed validate this approach large longitudinal cohort of early-to-moderate (n = 499) assessing the influence clinical characteristics at baseline two-year progression. Compared predominant (42%), diffuse-malignant (12%) showed involvement more domains, diffuse hypokinetic-rigid symptoms (decreased lateralization hand/foot focality), faster These findings extend classification subtypes suggest that different pathophysiological (focal versus cerebral propagation) underlie distinct subtype classifications.

Language: Английский

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Defining Parkinson’s Disease: Past and Future

Journal of Parkinson s Disease, Journal Year: 2024, Volume and Issue: 14(s2), P. S257 - S271

Published: March 15, 2024

Parkinson’s disease (PD) is the second most common still relentlessly progressive neurodegenerative disorder with a long period in which pathophysiological process already spreading but cardinal motor symptoms are not present. This review outlines major developments and milestones our understanding of PD that have shaped way we define this disorder. Past criteria definitions been based on clinical manifestations enabling diagnosis only later symptomatic stages. Nevertheless, advancing knowledge pathophysiology aim early detection, shift diagnostic paradigm being advocated towards biological definition similar to other disorders including Alzheimer’s Huntington’s disease, ultimate goal an earlier, course modifying therapy. We summarize pillars possible approach vivo detection neuronal α-synuclein aggregation, neurodegeneration genetics outline their application different contexts use frame definition.

Language: Английский

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Therapy of Parkinson’s Disease Subtypes

Neurotherapeutics, Journal Year: 2020, Volume and Issue: 17(4), P. 1366 - 1377

Published: Aug. 4, 2020

Early descriptions of subtypes Parkinson's disease (PD) are dominated by the approach predetermined groups. Experts defined, from clinical observation, groups based on or demographic features that appeared to divide PD into clinically distinct subsets. Common bases which define have been motor phenotype (tremor dominant vs akinetic-rigid postural instability gait disorder types), age, nonmotor symptoms, and genetic forms. Recently, data-driven approaches used subtypes, taking an unbiased statistical identification subgroups. The vast majority subtyping has done features. Biomarker-based is emerging but still quite undeveloped field. Not all methods established therapeutic implications. This may not be surprising given they were born largely observations in regarding treatment response biological hypotheses. next frontier for research as it applies personalized medicine development genotype-specific therapies. Therapies GBA-PD LRRK2-PD already under development. review discusses each major systems/methods terms its applicability therapy PD, opportunities challenges designing trials develop evidence base subtypes.

Language: Английский

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Subtyping of Parkinson’s Disease - Where Are We Up To?

Aging and Disease, Journal Year: 2019, Volume and Issue: 10(5), P. 1130 - 1130

Published: Jan. 1, 2019

Heterogenous clinical presentations of Parkinson’s disease have aroused several attempts in its subtyping for the purpose strategic implementation treatment order to maximise therapeutic effects. Apart from a priori classifications based purely on motor features, cluster analysis studies achieved little success receiving widespread adoption. A demonstrate that their chosen factors, whether it be age or certain symptoms, do an influence subtypes. However, approach is able integrate these factors and other features produce Differences inclusion criteria datasets, variable selection methodology between made difficult compare This has impeded such subtypes applications. review analysed existing disease, suggested future research should aim discover are robustly replicable across multiple datasets rather than focussing one dataset at a time. Hopefully, through applicable would lead translation into use.

Language: Английский

Citations

60

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Progressive brain atrophy and clinical evolution in Parkinson’s disease

Massimo Filippi, Elisabetta Sarasso, Noemi Piramide

et al.

NeuroImage Clinical, Journal Year: 2020, Volume and Issue: 28, P. 102374 - 102374

Published: Jan. 1, 2020

Clinical manifestations and evolution are very heterogeneous among individuals with Parkinson's disease (PD). The aims of this study were to investigate the pattern progressive brain atrophy in PD according stage elucidate what extent cortical thinning subcortical related clinical motor non-motor evolution. 154 patients at different stages assessed over time using motor, structural MRI evaluations for a maximum 4 years. Cluster analysis defined subtypes. Cortical baseline relative 60 healthy controls. Longitudinal trends progression compared between clusters. contribution predicting non-motor, cognitive mood deterioration was explored. Two main clusters defined: mild (N = 87) moderate-to-severe 67). subtypes further identified: motor-predominant 43) mild-diffuse 44), latter group being older having more severe symptoms. initial PD. Over time, had greatest accumulation cortex left hippocampus, while less distributed observed patients. Baseline 1-year associated long-term cognitive, is accelerated early after onset becomes prominent later development dysfunctions. Structural may be useful monitoring

Language: Английский

Citations

59

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