Estimates based on postmortem studies suggest that for every patient who presents with PD, there may be up to 15 cases of preclinical PD (development of Lewy body pathology without clinical signs of PD) (111). Neuroreceptor imaging studies provide a window into this preclinical period of PD, the time during which neurodegeneration has begun, but symptoms have not yet become manifest. Preclinical identification of affected subjects is particularly important if intervention exists, which may prevent progression of disease. The most extensive preclinical imaging data is from studies imaging patients with hemi-PD. In several imaging studies, there is a significant reduction in putamen DAT or 18F-DOPA uptake of about 25% to 30% in the "presymptomatic" striatum in these patients who are known to progress to bilateral disease (11,66,67).
Progression studies also elucidate the preclinical period of PD. For example, given the assumption that progression is linear, it is possible to back extrapolate from sequential imaging data and reported symptom duration to estimate the level of reduction in dopaminergic activity at symptom onset and the duration of the pre-clinical phase of PD (Fig. 2). Data from longitudinal imaging studies using both
FIGURE 2 Presymptomatic loss of 18F-Dopa in the asymptomatic co-twin of a PD patient. Note that the asymptomatic co-twin shows mild reduction in 18F-Dopa at baseline, which has worsened abnormality at five-year follow-up associated with onset of symptoms. Source: Courtesy of D Brooks, London, U.K.
MZ co-twin Asymptomatic at baseline
MZ co-twin symptomatic 5 years later
MZ co-twin Asymptomatic at baseline
18F-DOPA and DAT imaging have been remarkably consistent with estimated disease onset at 70% to 75% of normal dopaminergic activity and a preclinical phase of four to eight years (102,112). Interestingly, these data are consistent with estimates of duration of the preclinical phase from pathology studies of 4.7 years derived from cross-sectional data (111). Although the data available to calculate estimates of preclinical phase must be viewed as preliminary, data acquired using different imaging methods measuring different components of the dopaminergic system and data from an independent pathology study suggest a relatively brief preclinical phase of less than a decade for PD. These data influence our understanding of disease etiology and developing strategies for disease screening and treatment. For example, if preclinical disease is relatively short, repetitive screening might be required to identify affected individuals in an at risk population. Furthermore, as potential preventive or restorative therapies are developed, these treatments might be directed to the time period from onset of degeneration to onset of symptoms.
Most studies of the preclinical period have focused on potential "at risk" individuals for PD, such as family members or unaffected twins of PD patients. In a study of hyposmic first-degree relatives of PD patients, it was shown that four of 40 (10%) hyposmic relatives with no parkinsonian signs converted to PD over a two-year period (113). Of the 40 subjects, seven showed a reduction in [123I] P-CIT uptake and the four with the lowest uptake were those converting to PD. Findings from this study suggest that [123I] P-CIT and SPECT have the capacity to detect changes in DAT prior to the onset of symptoms.
In studies of familial PD in several well-characterized kindreds, 11 of 32 asymptomatic relatives were found to have reduced 18F-DOPA uptake and three of these subjects have subsequently developed symptomatic PD (114). Several asymptomatic cotwins who also showed a reduction in 18F-DOPA activity later developed symptoms of PD (Fig. 2), although the concordance rate for monozygotic and dyzygotic twins remains uncertain (115). Sporadic cases also have been reported of individuals imaged as presumed healthy subjects with mildly abnormal 18F-DOPA uptake, who later developed definite PD (116). Preclinical identification of subjects with PD forces us to reexamine our clinical definitions of disease. The recent identification of genes, which confer the PD phenotype in familial PD, will provide an opportunity to evaluate an "at risk" population both clinically and with sequential imaging studies (117,118). As additional genetic markers are discovered, imaging will play an essential role in assessing neurodegeneration and possibly in redefining clinical disease onset.
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