<i>GBA</i>-Associated Parkinson’s Disease: Progression in a Deep Brain Stimulation Cohort

Lythe, Vanessa; Athauda, Dilan; Foley, Jennifer A.; Mencacci, Niccolò E.; Jahanshahi, Marjan; Cipolotti, Lisa; Hyam, Jonathan A.; Zrinzo, Ludvic; Hariz, Marwan; Hardy, John; Limousin, Patricia; Foltynie, Tom

doi:10.3233/jpd-171172

Cited by 48 publications

(85 citation statements)

References 41 publications

(49 reference statements)

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“…Conversely, in those receiving DBS, GBA1 status is associated with worse long-term outcomes, predominantly because of a higher incidence and severity of cognitive impairment and other nonmotor symptoms. 98 Moreover, it is worth noting that PD carriers of GBA1 mutations display poorer dual-task performance, supporting the presence of enhanced motor and cognitive dysfunction compared with noncarriers. 99 Non-levodopa-responsive.…”

Section: Motor Featuresmentioning

confidence: 95%

“…As the principle indications for DBS are levodopa responsiveness with dyskinesia/fluctuations that are poorly controlled by medication alone, this suggests that, in terms of these 3 criteria, the presentation of PD in mutation carriers is similar to that of those with sporadic PD. Conversely, in those receiving DBS, GBA1 status is associated with worse long‐term outcomes, predominantly because of a higher incidence and severity of cognitive impairment and other nonmotor symptoms . Moreover, it is worth noting that PD carriers of GBA1 mutations display poorer dual‐task performance, supporting the presence of enhanced motor and cognitive dysfunction compared with noncarriers …”

Section: Clinical and Neuroimaging Features Of Gba‐related Synucleinomentioning

confidence: 99%

See 1 more Smart Citation

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Blandini¹,

Cilia

Cerri³

et al. 2018

Movement Disorders

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Glucocerebrosidase is a lysosomal enzyme. The characterization of a direct link between mutations in the gene coding for glucocerebrosidase (GBA1) with the development of Parkinson's disease and dementia with Lewy bodies has heightened interest in this enzyme. Although the mechanisms through which glucocerebrosidase regulates the homeostasis of α‐synuclein remains poorly understood, the identification of reduced glucocerebrosidase activity in the brains of patients with PD and dementia with Lewy bodies has paved the way for the development of novel therapeutic strategies directed at enhancing glucocerebrosidase activity and reducing α‐synuclein burden, thereby slowing down or even preventing neuronal death. Here we reviewed the current literature relating to the mechanisms underlying the cross talk between glucocerebrosidase and α‐synuclein, the GBA1 mutation‐associated clinical phenotypes, and ongoing therapeutic approaches targeting glucocerebrosidase. © 2018 International Parkinson and Movement Disorder Society

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Section: Motor Featuresmentioning

confidence: 95%

Section: Clinical and Neuroimaging Features Of Gba‐related Synucleinomentioning

confidence: 99%

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Blandini¹,

Cilia

Cerri³

et al. 2018

Movement Disorders

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“…Motor complications, such as swallowing disorders, dysarthria, and freezing of gait, are observed more frequently in GBA-PD patients (Jesús et al, 2016). The risk of developing motor fluctuations and dyskinesia seems to be higher in GBA-PD subjects carrying a severe mutation (Cilia et al, 2016;Jesús et al, 2016;Lythe et al, 2017).…”

Section: Motor Featuresmentioning

confidence: 98%

“…A recent article investigating the outcomes of treatment with deep brain stimulation in a cohort of GBA-PD patients after a 7.5-year follow-up demonstrated similar outcomes compared to iPD in terms of motor symptoms, whereas cognitive deterioration and non-motor features were more represented among GBA-PD patients (Lythe et al, 2017). However, because of the positive effects on motor impairment, deep brain stimulation should also be considered as a suitable therapeutic option for these patients.…”

Section: Therapeutic Strategy For Gba-pd Patientsmentioning

confidence: 99%

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

Avenali

Blandini

Cerri³

2020

Front. Aging Neurosci.

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Heterozygous mutations of the GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), occur in a considerable percentage of all patients with sporadic Parkinson's disease (PD), varying between 8% and 12% across the world. Genome wide association studies have confirmed the strong correlation between PD and GBA1 mutations, pointing to this element as a major risk factor for PD, possibly the most important one after age. The pathobiological mechanisms underlying the link between a defective function of GCase and the development of PD are still unknown and are currently the focus of intense investigation in the community of pre-clinical and clinical researchers in the PD field. A major controversy regards the fact that, despite the unequivocal correlation between the presence of GBA1 mutations and the risk of developing PD, only a minority of asymptomatic carriers with GBA1 mutations convert to PD in their lifetime. GBA1 mutations reduce the enzymatic function of GCase, impairing lysosomal efficiency and the cellular ability to dispose of pathological alpha-synuclein. Changes in the cellular lipidic content resulting from the accumulation of glycosphingolipids, triggered by lysosomal dysfunction, may contribute to the pathological modification of alpha-synuclein, due to its ability to interact with cell membrane lipids. Mutant GCase can impair mitochondrial function and cause endoplasmic reticulum stress, thereby impacting on cellular energy production and proteostasis. Importantly, reduced GCase activity is associated with clear activation of microglia, a major mediator of neuroinflammatory response within the brain parenchyma, which points to neuroinflammation as a major consequence of GCase dysfunction. In this present review article, we summarize the current knowledge on the role of GBA1 mutations in PD development and their phenotypic correlations. We also discuss the potential role of the GCase pathway in the search for PD biomarkers that may enable the development of disease modifying therapies. Answering these questions will aid clinicians in offering more appropriate counseling to the patients and their caregivers and provide future directions for PD preclinical research.

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“…For example, the effects of specific genetic risk factors for PD on the long-term outcomes of patients who undergo DBS are the focus of ongoing studies. [Au: The trial on the clinicaltrials.gov website can be cited -I will add this to the references when I receive manuscript back from you] There are some data to suggest that patients with mutations in GBA1 have more aggressive disease 59,60 and that, consequently, their disability progresses to a greater extent after DBS than in those with other forms of PD. Whether this effect simply reflects a more aggressive underlying disease process in these individuals or indicates an interaction between genotype and the surgical intervention requires further study, ideally in a randomized study.…”

Section: [H1] Current and Future Clinical Implicationsmentioning

confidence: 99%

Long-term outcomes of deep brain stimulation in Parkinson disease

2019

Self Cite

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| The efficacy of deep brain stimulation (DBS) for Parkinson disease (PD) is well established for up to 1 or 2 years, but long-term outcome data are still limited. In this Review, we critically discuss the evidence on the long-term outcomes of DBS and consider the clinical implications. Although many patients are lost to follow-up, the evidence indicates that subthalamic nucleus DBS improves motor function for up to 10 years, although the magnitude of improvement tends to decline over time. Functional scores recorded during onmedication periods worsen faster than those recorded in off periods, consistent with the degeneration of non-dopaminergic pathways. Dyskinesia, motor fluctuations and activities of daily living in off periods remain improved at 5 years, but quality of life scores have usually fallen below pre-operative levels.The incidence and severity of dementia among patients receiving DBS are comparable to those among patients who receive medical treatment. Severe adverse events are rare, but adverse events such as dysarthria are common and probably under-reported. Long-term data on the outcomes of globus pallidus interna DBS are limited and mostly confirm the efficacy for dyskinesia. A trend towards offering DBS in the earlier stages of PD creates a need to identify factors that predict long-term outcomes and to discuss realistic expectations with patients pre-operatively.

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GBA-Associated Parkinson’s Disease: Progression in a Deep Brain Stimulation Cohort

Abstract: GBA status appears to be an important predictor for non-motor symptom disease progression, after deep brain stimulation surgery.

Cited by 48 publications

References 41 publications

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Glucocerebrosidase mutations and synucleinopathies: Toward a model of precision medicine

Glucocerebrosidase Defects as a Major Risk Factor for Parkinson’s Disease

Long-term outcomes of deep brain stimulation in Parkinson disease

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