Imaging Neurodegeneration in Parkinson's Disease

Table 1.

Differential Imaging Findings in Parkinsonian Syndromes

Table 2.

Differential Imaging Findings in Dementias

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Feigin A et al. (2001) Metabolic correlates of levodopa response in Parkinson’s disease. Neurology 57: 2083-2088
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Detection of Preclinical Parkinson's Disease

For every patient who presents with clinical PD there might be 10-15 subclinical cases with incidental brainstem Lewy body disease in the community, according to estimates from postmortem studies.^[43] Individuals at risk of developing PD include carriers of genes known to be associated with parkinsonism, relatives of patients with PD, elderly individuals with idiopathic hyposmia, and patients with rapid eye movement sleep behavior disorder (RBD).

Subclinical midbrain hyperechogenicity detected with TCS has been reported in around 10% of healthy elderly individuals.^[44] This raised echogenicity correlated with the presence of ‘soft’ signs of parkinsonism, such as increased muscle tone and reduced arm swing. In another study, increased midbrain echogenicity was reported in four out of seven asymptomatic carriers of PDassociated mutations in the Parkin gene. Only two of the seven carriers, however, were found to have reduced striatal ¹⁸F-dopa uptake.^[45] In a third series, the same group used TCS to investigate patients with hyposmia. Out of 30 patients with idiopathic olfactory loss, 11 showed midbrain hyperechogenicity, and 5 of these 11 had reduced ¹²³I-FP-CIT binding in the striatum.^[46] Increased nigral echogenicity can be detected in about a third of individuals at risk for PD, but this finding correlates with reduced dopaminergic function in fewer than 50% of patients.^[44-46]

Ponsen and colleagues collected data on 40 elderly relatives of patients with PD who had no overt parkinsonism but who manifested hyposmia on olfactory screening, and they found that seven of these relatives showed reduced ¹²³I β-carbomethoxy-3β-(4 iodophenyl)tropane (¹²³I-β-CIT) uptake in the striatum.47 Four of these seven individuals subsequently converted to clinical PD over a 2-year period.

¹⁸F-dopa PET has been used to study asymptomatic adult relatives in familial PD kindreds.^[48] In all, 25% of the asymptomatic adult rela tives who were scanned showed reduced levels of ¹⁸F-dopa uptake in the putamen and a third of these subsequently developed clinical parkinsonism over a 5-year follow-up period. Parkin disease has also been investigated with ¹⁸F-dopa PET. Compound heterozygous gene carriers who are symptomatic show more-severe reductions of striatal ¹⁸F-dopa uptake than would be expected for their degree of dis ability, which suggests that adaptive processes might be compensating for the dopamine deficiency.^[49,50] The pattern of dopaminergic deficit in patients with symptomatic Parkin disease can mimic that of PD, in that the putamen is targeted, but the caudate nucleus and midbrain seem to be more involved in Parkin disease.^[51] Interestingly, heterozygous Parkin mutation carriers who are asymptomatic show a mild reduction in putamen ¹⁸F-dopa uptake, but this feature does not seem to progress significantly over a 10-year period.^[52] The question of whether carrying a single Parkin mutation makes an individual more susceptible to late-onset PD is still being debated.

The most common known cause of dominantly inherited PD has emerged to be mutations in the leucine-rich repeat kinase 2 (LRRK2) gene—also known as PARK8. In a recent series, 15 family members of an LRRK2 kindred underwent ¹⁸F-dopa, ¹¹C-DTBZ and ¹¹Cd-threo-methylphenidate (¹¹C-MP) PET to assess dopamine storage, vesicle monoamine transporter density and DAT binding, respectively.^[53] Four clinically affected LRRK2 family members showed similar results to those found in PD, two asymptomatic mutation carriers had abnormal DAT binding, and another two asymptomatic mutation carriers initially had normal levels of ¹¹C-MP uptake but experienced reductions in these levels over 4 years of follow-up. Interestingly, ¹⁸F-dopa uptake remained normal in the asymptomatic individuals, although two of them had reduced ¹¹C-DTBZ binding. The authors concluded that the in vivo neurochemical phenotype of LRRK2 mutations was indistinguishable from that of sporadic PD, and that compensatory changes, including downregulation of DAT binding and upregulation of decarboxylase activity, might act to delay the onset of parkinsonian symptoms.

RBD is a common feature of PD, and 30 patients with isolated RBD were investigated with ¹²³I-FP-CIT SPECT for the presence of dopamine deficiency.^[54] Out of 11 patients with RBD who agreed to undergo SPECT, three showed reduced striatal DAT binding, and one of these had clinical parkinsonism. These proportions are considerably higher than would be expected in the general population.