Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

McNeill, Alisdair; Wu, Ruey‐Meei; Tzen, Kai-Yuan; Aguiar, Patricia C.; Arbelo, José Matías; Barone, Paolo; Bhatia, Kailash P.; Barsottini, Orlando Graziani Póvoas; Bonifati, Vincenzo; Bostantjopoulou, Sevasti; Bressan, Rodrigo A.; Cossu, Giovanni; Cortelli, Pietro; Felı́cio, André Carvalho; Ferraz, Henrique B.; Herrera, Joanna; Houlden, Henry; Hoexter, Marcelo Q.; Isla, Concepción; Lees, Andrew J.; Lorenzo‐Betancor, Oswaldo; Mencacci, Niccolò E.; Pástor, Pau; Pappatà, Sabina; Pellecchia, Maria Teresa; Silveria-Moriyama, Laura; Varrone, Andrea; Foltynie, Tom; Schapira, Anthony H.V.

doi:10.1371/journal.pone.0069190

Cited by 56 publications

(54 citation statements)

References 33 publications

(63 reference statements)

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“…Dopamine imaging by single photon emission tomography (SPECT) of the dopamine transporter and positron emission tomography (PET) are abnormal in patients with PD and GBA mutations, in a pattern that is similar to sporadic PD (McNeill et al, 2013a). In a PET study to investigate underlying dopaminergic dysfunction in GBA mutation carriers with and without parkinsonism, Kono et al demonstrated presynaptic dopaminergic dysfunction characteristic of sporadic PD in both a patient with GD and PD, and three subjects with heterozygous GBA mutations and PD (Böttcher et al, 2013).…”

Section: Neuroimagingmentioning

confidence: 99%

“…Neuroimaging in GBA-PD with positron emission tomography or single photon emission computed tomography for the visualisation of radioactive dopamine transporter ligands demonstrates an asymmetry of radioligand uptake indistinguishable from idiopathic PD (Goker-Alpan et al, 2012;; McNeill et al, 2013a).…”

Section: Gba Mutation Escalates the Onset Of Parkinson's Diseasementioning

confidence: 99%

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Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Beavan

Schapira

2013

Annals of Medicine

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Section: Neuroimagingmentioning

confidence: 99%

Section: Gba Mutation Escalates the Onset Of Parkinson's Diseasementioning

confidence: 99%

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Beavan

Schapira

2013

Annals of Medicine

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“…There are more subtle features associated with GBA PD, which may be elicited in research settings and are discussed in the clinical section of this review. No differences are observed in imaging, pharmacological response or pathology between idiopathic and GBA mutation linked PD [15].…”

Section: G O'regan Et Al / Gba In Parkinson Diseasementioning

confidence: 87%

Glucocerebrosidase Mutations in Parkinson Disease

O’Regan

deSouza

Balestrino

et al. 2017

JPD

104

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Abstract.Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

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“…Young onset age, more symmetric involvement, dystonia at presentation, brisk deep tendon reflexes, a good response to levodopa therapy (Lohmann et al., 2003; Lucking et al., 2000), and more symmetric and more marked reduction of dopamine uptake on 123I FP‐CIT SPECT scan (DaTSCAN) were found in Parkin ‐related disease (McNeill et al., 2013). Parkin mutation carriers (homozygotes or compound heterozygotes) also showed better cognitive and motor performance than noncarriers, suggesting a slower disease progression (Alcalay et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

Olfaction in Parkin carriers in Chinese patients with Parkinson disease

Wang

Liu

et al. 2017

Brain and Behavior

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BackgroundOlfactory identification was reported to be better among PD (Parkinson disease) patients with Parkin mutations, but previous studies didn't eliminate the interference of other PD related genes on olfaction, and whether olfaction of Parkin mutations patients was better in Chinese population was still unknown.ObjectiveTo assess olfaction function among PD patients with Parkin mutations in Chinese population.Materials and MethodsA total of 226 PD patients with a positive family history or an early‐onset age (<50 years) were enrolled for genetic testing of PD related genes by target sequencing and multiple ligation‐dependent probe amplification. The clinical data including olfactory function test were investigated. Linear regression was performed to adjust for the covariates between all groups.ResultsThere were 68 patients found having a negative result in PD genetic testing and 43 patients carrying homozygous or compound heterozygous Parkin mutations. Among them, 49 PD panel negative patients and 33 PD‐Parkin patients had results of olfactory assessment. PD ‐Parkin patients performed significantly better on the Sniffin’ Sticks tests than panel negative patients (8.0 ± 1.7 vs. 5.7 ± 1.9, p < .001), but still worse compared to healthy controls (9.4 ± 1.5, p = .003). These differences persisted after adjusting for confounders.ConclusionsAmong Chinese population, PD ‐Parkin patients had relatively preserved olfaction compared to PD panel negative patients after eliminating the interference of other PD related genes, but were still worse than healthy controls.

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Dopaminergic Neuronal Imaging in Genetic Parkinson's Disease: Insights into Pathogenesis

Cited by 56 publications

References 33 publications

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Glucocerebrosidase Mutations in Parkinson Disease

Olfaction in Parkin carriers in Chinese patients with Parkinson disease

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