The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow

Abstract

Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with (18)F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H(2)(15)O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the pattern of dopamine loss in patients with both Parkinson and Gaucher disease was similar to sporadic Parkinson disease, indicating comparable damage in midbrain neurons. However, H(2)(15)O positron emission tomography studies indicated that these subjects have decreased resting activity in a pattern characteristic of diffuse Lewy body disease. These findings provide insight into the pathophysiology of GBA-associated parkinsonism.

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

“…Nevertheless, SN hyperechogenicity has also been a reported feature of PD associated with GBA mutations, and there is a comparable degree of SN hyper-echogenicity and common features regarding SN pathology . Recent evidence suggests, however, that this is a frequent finding in GD patients, irrespective of whether they had developed PD or not, and could be related to disturbances of iron metabolism in GD (Goker-Alpan et al, 2012).…”

“…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).…”

Glucocerebrosidase Mutations in Parkinson Disease

“…Recent evidence shows significant reductions in regional cerebral blood flow associated with GBA PD compared with idiopathic cases, particularly in the parietal cortices and precuneus [54,77]. This pattern of cerebral blood flow alternation seen in Lewy body dementia and contributes to neurobiological explanation for early cognitive decline in GBA PD.…”

Imaging of genetic and degenerative disorders primarily causing Parkinsonism

“…This is true for both idiopathic late-onset PD and dominant genetic causes of the disorder such as LRRK2 (Adams et al, 2005) and GBA mutations (Goker-Alpan et al, 2012). Recessive causes of PD tend to show severe loss of striatal dopamine terminal function compared with the degree of disability present and the loss is more symmetric, involving the head of caudate to a greater degree (Khan et al, 2001).…”