Genotype and phenotype in Parkinson's disease: Lessons in heterogeneity from deep brain stimulation

Angeli, A.; Mencacci, Niccolò E.; Durán, Raquel; Avilés-Olmos, Icíar; Kefalopoulou, Zinovia; Candelario, Joseph; Rusbridge, Sarah; Foley, Jennifer A.; Pradhan, Priyanka; Jahanshahi, Marjan; Zrinzo, Ludvic; Hariz, Marwan; Wood, Nicholas W.; Hardy, John; Limousin, Patricia; Foltynie, Tom

doi:10.1002/mds.25535

Cited by 78 publications

(121 citation statements)

References 24 publications

Supporting

Mentioning

116

Contrasting

Unclassified

Order By: Relevance

“…Patients who carry GBA1 mutations present a higher prevalence and severity of bradykinesia, motor complications, hyposmia, autonomic impairment, sexual dysfunction, hallucinations, cognitive decline, depression and anxiety (Alcalay et al, 2012;Beavan and Schapira, 2013;Brockmann et al, 2011;Lesage et al, 2010;Li et al, 2014;McNeill et al, 2012;Wang et al, 2014;Winder-Rhodes et al, 2013;Zokaei et al, 2014). Because of the increased rate of clinical decline, patients with GBA1 mutations often initiate therapies earlier compared with non-mutation carriers (Angeli et al, 2013;Barrett et al, 2014).…”

Section: Clinical Features Of Gaucher-related Pdmentioning

confidence: 99%

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

Sardi¹,

Cheng²,

Shihabuddin³

2015

Progress in Neurobiology

View full text Add to dashboard Cite

Gaucher disease, the most common lysosomal storage disease, is caused by a recessively inherited deficiency in glucocerebrosidase and subsequent accumulation of toxic lipid substrates. Heterozygous mutations in the lysosomal glucocerebrosidase gene (GBA1) have recently been recognized as the highest genetic risk factor for the development of α-synuclein aggregation disorders ("synucleinopathies"), including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Despite the wealth of experimental, clinical and genetic evidence that supports the association between mutant genotypes and synucleinopathy risk, the precise mechanisms by which GBA1 mutations lead to PD and DLB remain unclear. Decreased glucocerebrosidase activity has been demonstrated to promote α-synuclein misprocessing. Furthermore, aberrant α-synuclein species have been reported to downregulate glucocerebrosidase activity, which further contributes to disease progression. In this review, we summarize the recent findings that highlight the complexity of this pathogenetic link and how several pathways that connect glucocerebrosidase insufficiency with α-synuclein misprocessing have emerged as potential therapeutic targets. From a translational perspective, we discuss how various therapeutic approaches to lysosomal dysfunction have been explored for the treatment of GBA1-related synucleinopathies, and potentially, for non-GBA1-associated neurodegenerative diseases. In summary, the link between GBA1 and synucleinopathies has become the paradigm of how the study of a rare lysosomal disease can transform the understanding of the etiopathology, and hopefully the treatment, of a more prevalent and multifactorial disorder.

show abstract

Section: Clinical Features Of Gaucher-related Pdmentioning

confidence: 99%

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

Sardi¹,

Cheng²,

Shihabuddin³

2015

Progress in Neurobiology

View full text Add to dashboard Cite

show abstract

“…1 Up to 29% of patients who have PD and receive deep brain stimulation (DBS) have a mutation in 1 of 3 genes: glucocerebrosidase ( GBA ), leucine-rich repeat kinase 2 ( LRRK2 ), and parkin ( PRKN ). 2 The reason for this may be that patients with PD who receive DBS tend to have a younger age at onset (AAO) than the general PD population, which leads to an over-representation of genetic forms of PD in this population. 2 Specific mutations, like those in GBA , may be associated with more rapid disease progression 3 ; whereas other mutations, like those in LRRK2 , may be associated with slower disease progression.…”

mentioning

confidence: 99%

Genetic and Clinical Predictors of Deep Brain Stimulation in Young‐Onset Parkinson's Disease

Pal

Hall

Ouyang

et al. 2016

Movement Disord Clin Pract

View full text Add to dashboard Cite

Objective In a cohort of patients with young-onset Parkinson's disease (PD), the authors assessed (1) the prevalence of genetic mutations in those who enrolled in deep brain stimulation (DBS) programs compared with those who did not enroll DBS programs and (2) specific genetic and clinical predictors of DBS enrollment. Methods Subjects were participants from 3 sites (Columbia University, Rush University, and the University of Pennsylvania) in the Consortium on Risk for Early Onset Parkinson's Disease (CORE-PD) who had an age at onset < 51 years. The analyses presented here focus on glucocerebrosidase (GBA), leucine-rich repeat kinase 2 (LRRK2), and parkin (PRKN) mutation carriers. Mutation carrier status, demographic data, and disease characteristics in individuals who did and did not enroll in DBS were analyzed. The association between mutation status and DBS placement was assessed in logistic regression models. Results Patients who had PD with either GBA, LRRK2, or PRKN mutations were more common in the DBS group (n = 99) compared with the non-DBS group (n = 684; 26.5% vs. 16.8%, respectively; P = 0.02). In a multivariate logistic regression model, GBA mutation status (odds ratio, 2.1; 95% confidence interval, 1.0–4.3; P = 0.05) was associated with DBS surgery enrollment. However, when dyskinesia was included in the multivariate logistic regression model, dyskinesia had a strong association with DBS placement (odds ratio, 3.8; 95% confidence interval, 1.9–7.3; P < 0.0001), whereas the association between GBA mutation status and DBS placement did not persist (P = 0.25). Conclusions DBS populations are enriched with genetic mutation carriers. The effect of genetic mutation carriers on DBS outcomes warrants further exploration.

show abstract

“…On therapy, the medication group (MedON) and the DBS group (StimON) exhibited similar motor ON scores (P = 0.44) indicating similar treatment response of both groups. This is important to account for comparability of the medication and DBS group given the substantial endophenotypic variability in PD including patients treated with DBS (Brockmann et al 2011;Weiss et al 2012;Angeli et al 2013). …”

Section: Resultsmentioning

confidence: 99%

The subthalamic nucleus modulates the early phase of probabilistic classification learning

et al. 2014

View full text Add to dashboard Cite

Previous models proposed that the subthalamic nucleus (STN) is critical in the early phase of skill acquisition. We hypothesized that subthalamic deep brain stimulation modulates the learning curve in early classification learning. Thirteen idiopathic Parkinson's disease patients (iPD) with subthalamic deep brain stimulation (STN-DBS), 9 medically treated iPD, and 21 age-matched healthy controls were tested with a probabilistic classification task. STN-DBS patients were tested with stimulation OFF and ON, and medically treated patients with medication OFF and ON, respectively. Performance and reaction time were analyzed on the first 100 consecutive trials as early learning phase. Moreover, data were separated for low and high-probability patterns, and more differentiated strategy analyses were used. The major finding was a significant modulation of the learning curve in DBS patients with stimulation ON: although overall learning was similar to healthy controls, only the stimulation ON group showed a transient significant performance dip from trials '41-60' that rapidly recovered. Further analysis indicated that this might be paralleled by a modulation of the learning strategy, particularly on the high-probability patterns. The reaction time was unchanged during the dip. Our study supports that the STN serves as a relay in early classification learning and directs attention toward unacquainted content. The STN might play a role in balancing the short-term success against strategy optimization for improved long-term outcome. AbstractPrevious models proposed that the subthalamic nucleus (STN) is critical in the early phase of skill acquisition. We hypothesized that subthalamic deep brain stimulation modulates the learning curve in early classification learning. 13 idiopathic Parkinson's disease patients (iPD) with subthalamic deep brain stimulation (STN-DBS), 9 medically treated iPD, and 21 age-matched healthy controls were tested with a probabilistic classification task. STN-DBS patients were tested with stimulation OFF and ON, medically treated patients with medication OFF and ON, respectively. Performance and reaction time were analyzed on the first 100 consecutive trials as early learning phase. Moreover, data were separated for low and high probability patterns, and more differentiated strategy analyses were used.The major finding was a significant modulation of the learning curve in DBS patients with stimulation ON: although overall learning was similar to healthy controls, only the stimulation ON group showed a transient significant performance dip from trials '41-60' that rapidly recovered. Further analysis indicated that this might be paralleled by a modulation of the learning strategy, particularly on the high probability patterns. The reaction time was unchanged during the dip. Our study supports that the STN serves as a relay in early classification learning and directs attention towards unacquainted content.The STN might play a role in balancing the short-term success against strategy optimi...

show abstract

Genotype and phenotype in Parkinson's disease: Lessons in heterogeneity from deep brain stimulation

Cited by 78 publications

References 24 publications

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

Gaucher-related synucleinopathies: The examination of sporadic neurodegeneration from a rare (disease) angle

Genetic and Clinical Predictors of Deep Brain Stimulation in Young‐Onset Parkinson's Disease

The subthalamic nucleus modulates the early phase of probabilistic classification learning

Contact Info

Product

Resources

About