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

Ozlem Goker-Alpan, Joseph C. Masdeu, Philip D. Kohn, Angela Ianni, Grisel Lopez, Catherine Groden, Molly C. Chapman, Brett Cropp, Daniel P. Eisenberg, Emerson D. Maniwang, Joie Davis, Edythe Wiggs, Ellen Sidransky, Karen F. Berman

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

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 18F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H2 15O 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, H2 15O 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.

Original languageEnglish (US)
Pages (from-to)2440-2448
Number of pages9
JournalBrain
Volume135
Issue number8
DOIs
StatePublished - Aug 2012

Keywords

  • brain imaging
  • genetic risk
  • lysosomal storage disorders
  • Parkinson disease
  • positron emission tomography (PET)

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Fingerprint

Dive into the research topics of 'The neurobiology of glucocerebrosidase-associated parkinsonism: A positron emission tomography study of dopamine synthesis and regional cerebral blood flow'. Together they form a unique fingerprint.

Cite this