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|Title:||Brain Imaging of PD Genes|
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University of British Columbia, Department of Physics and Astronomy, BC, Canada
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|Content:||Functional imaging of subjects genetically at risk of developing Parkinsonís disease is of great interest for at least two reasons: (i) the detection of preclinical abnormalities in individuals genetically at risk may help to localize and identify previously unidentified genes while also providing a characterization of the neurochemical profile of the mutation-specific dopaminergic dysfunction (ii) it provides a tool for investigation of preclinical and early disease-induced regulatory and compensatory changes at a time where such changes occur most rapidly. Positron emission tomography (PET) imaging provides several possible and complementary approaches to the investigation of dopaminergic function, three of which assess the integrity of the dopamine neuron Ė the density of vesicular monoamine (VMAT2, investigated with [11C]dihydrotetrabenazine; [11C]DTBZ), the density of the dopamine transporter (DAT, investigated with a variety of [11C] or [18F] ligands) and the capacity to take up radiolabeled levodopa (6-[18F]fluoro-L-dopa; FD), convert it to dopamine and store it in synaptic vesicles. The other approaches are indirect and include the use of a low affinity ligand for the dopamine D2 receptor such as [11C] raclopride to detect changes in dopamine release, or to study changes in the profile of metabolic activity or cerebral blood flow. |
PET imaging has been used to study the most common form of dominantly inherited PD due to the mutation of the LRRK2 gene and recessive forms of inherited PD; several differences in their neurochemical profiles have been found. Adams et al. studied two kindreds with LRRK2 mutations, Families A and D, with Y1699C and R1441C substitutions, respectively, using a combination of [11C]DTBZ, [11C]d-threo-methylphenidate (MP; a DAT ligand) and FD(1). In affected members of both families, the pattern of tracer uptake was identical to that seen in sporadic PD, with asymmetry and a rostrocaudal gradient. VMAT2 and DAT binding were affected more than FD uptake, in keeping with earlier report of compensatory changes in early sporadic PD(2). In the original study, there was one asymptomatic individual who had abnormal DAT and VMAT2 binding but FD uptake within normal limits. This individual was studied 4 years later, by which time he had gone on to develop early clinical signs of PD and FD uptake was reduced. In followup studies conducted in these and other kindreds, several individuals who had normal PET values at the time of original study were found to have developed asymptomatic abnormalities on imaging within 4 years of the original study(3). Interestingly in all cases, DAT (and in some cases VMAT2) binding was reduced to a greater extent than FD uptake and in no case clinical abnormalities were present unless FD uptake was reduced below the control range. In addition to showing that the in-vivo neurochemical phenotype of LRKK2 mutations is indistinguishable from that of sporadic PD, these studies have confirmed earlier evidence suggesting that compensatory upregulation of decarboxylase activity may be responsible for the delay of clinical symptoms and that these develop once this compensation becomes inadequate. It would also appear based on these studies that DAT binding is reduced to a greater extent than VMAT2 binding, also in keeping with compensatory downregulation of the DAT (2). Preliminary findings also show a large increase in dopamine turnover in the presymptomatic stage in keeping with earlier findings for sporadic PD (4).
In recessively inherited PD, findings are somewhat different. In subjects with established disease, there is less sparing of the caudate nucleus compared to sporadic PD, in contrast to dominantly inherited PD(5,6). An interesting observation is the consistent finding that carriers of single heterozygous mutations in either the parkin or PINK1 genes show evidence of impaired nigrostriatal function as determined by FD PET(7,8). The interpretation of this intriguing finding is as yet unresolved.
These studies have provided invaluable insights not only into the inherited, but also into the sporadic forms of PD, into mechanisms associated with disease progression and compensatory changes. Combining genetic studies with imaging at various stages of the disease provides a set of investigative tools that are uniquely powerful and will contribute to providing explanations to the many unanswered questions associated with PD.
1. Adams JR, van Netten H, Schulzer M, Mak E, McKenzie J, Strongosky A et al. PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. Brain 2005; 128(Pt 12):2777-2785.
2. Lee CS, Samii A, Sossi V, Ruth TJ, Schulzer M, Holden JE et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson's disease. Ann Neurol 2000; 47(4):493-503
3. Nandhagopal R, Mak E, Schulzer M, McKenzie J, McCormick SE, Ruth TJ et al. Multitracer Positron Emission Tomographic analysis of progression of presynaptic dopaminergic dysfunction in a LRRK2 kindred. Neurology 2007; 68(12 (Suppl. 1)):A325.
4. Sossi V, de la Fuente-FernŠndez R, Holden JE, Doudet DJ, McKenzie J, Stoessl AJ, Ruth TJ, Increase in dopamine turnover occurs early in Parkinsonís disease: evidence from a new modeling approach to PET 18F-fluorodopa data, J Cereb Blood Flow and Metab.2002 22: 232-239
5. Khan NL, Valente EM, Bentivoglio AR, Wood NW, Albanese A, Brooks DJ et al. Clinical and subclinical dopaminergic dysfunction in PARK6-linked parkinsonism: an 18F-dopa PET study. Ann Neurol 2002; 52(6):849-853.
6. Scherfler C, Khan NL, Pavese N, Eunson L, Graham E, Lees AJ et al. Striatal and cortical pre- and postsynaptic dopaminergic dysfunction in sporadic parkin-linked parkinsonism. Brain 2004; 127(Pt 6):1332-1342.
7. Scherfler C, Khan NL, Pavese N, Lees AJ, Quinn NP, Brooks DJ et al. Upregulation of dopamine D2 receptors in dopaminergic drug-naive patients with Parkin gene mutations. Mov Disord 2006; 21(6):783-788.
8. Khan NL, Scherfler C, Graham E, Bhatia KP, Quinn N, Lees AJ et al. Dopaminergic dysfunction in unrelated, asymptomatic carriers of a single parkin mutation. Neurology 2005; 64(1):134-136.
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