The baseline PET findings in family D subjects 1–6, 8, 9, 10, and 13, including clinically affected subjects 1 and 2, were described earlier.4
In this communication, we present the PET findings of three additional subjects, 7, 11, and 12, and progression of neurochemical changes in subjects 3, 5, 8, 9, and 13. The subjects in whom follow-up data are presented here are different from those previously reported.4
The current work documents for the first time the progression of dopaminergic dysfunction in family D kindred, at both clinical and subclinical (PET) levels. PET revealed dopaminergic abnormalities in mutation carriers even in the absence of clinically evident parkinsonism. In subjects 8, 9, and 10 even at the initial visit, and 13 at the time of second scan, significantly reduced MP binding with normal or borderline decline in FD uptake and reduced or normal DTBZ binding were in keeping with downregulated DAT expression and upregulated dopa decarboxylase activity in early PD.6
However, although subject 13 was genealogically at risk, the genotype of subject 13 is not known and findings in this subject must be interpreted with caution.
In subjects 8, 9 (mutation carriers), and 13 (genealogically at risk subject), there was a decline in PET markers over the course of the study that was significantly greater than the expected rate of change in healthy controls. During the study period, VMAT 2 density in subject 8 changed from being normal at baseline scan to abnormal reduction relative to healthy controls at follow-up. Interestingly, the repeated measurements of FD uptake were within normal range, while the annual rate of decline in Kocc was significantly abnormal. In subject 9, we have documented the progression from subclinical neurochemical change to clinical disease. In the presymptomatic phase, this subject had abnormal VMAT 2 and DAT binding in the putamen along with borderline decline in FD uptake (in the left putamen only) cross-sectionally. FD uptake became abnormally (bilaterally and asymmetrically) low in the symptomatic stage. The previously abnormal DAT binding in subjects 8 and 9 did not reveal further decline during the study period. On the other hand, in subject 13, there was marked longitudinal reduction in DAT binding over the course of study. This subject also demonstrated abnormality in the other facets of DA processing (from normal VMAT 2 binding and FD uptake at baseline to abnormal reduction at follow-up), although the rates of decline in BPDTBZ
and Kocc were not significant. Our findings indicate that PET abnormalities can identify asymptomatic subjects early in the illness who might then go on to develop subtle disease on follow-up. In families with unknown genotype, such characterization in vivo may allow reclassification of subject thought to be normal on clinical grounds, but who have a high probability of carrying the as yet unidentified mutation. Recruitment of such subjects with subclinical dopaminergic dysfunction would be expected to improve the power of multiplex pedigrees and the value of linkage statistics in disease gene identification. PET endophenotype has also been explored and found to be useful under simulated phenoconversion in genetic linkage studies.11
Our study, despite the limitation of small sample size, provides further credence to the utility of PET in this regard. Indeed, the identification of asymptomatic subjects with dopaminergic dysfunction on PET imaging provided much assistance in subsequent tracking of the genetic mutation in this kindred.
Reduced DAT binding was the earliest indication of dopaminergic dysfunction in these individuals, implying that DAT imaging is more sensitive in detecting subclinical deficits in the nigrostriatal pathway. Motor function appeared to be preserved until the capacity to synthesize and store dopamine, as assessed by FD uptake, was impaired. The possible exception to this was subject 8, who had abnormal DTBZ and MP binding, but normal FD uptake over the study course. Subject 8 had prior polio which might have affected the clinical findings. As noted above, FD uptake in this subject did decline significantly between the two visits. However, study of a much larger sample of subjects is required to ascertain the relationship between the evolution of motor dysfunction and changes in PET markers. As the subjects were not taking antiparkinsonian medication because of asymptomatic status or very early disease, there was no lingering drug effect on tracer binding/uptake. The mutation negative subjects were included and followed up with PET, as the investigators were blinded as to the mutation status of the kindred during the study period. These subjects served as internal controls with similar genetic and environmental background.
The neurochemical abnormalities as assessed with PET and the clinical expression of PD are both age dependent. In a clinical study of LRRK2
R1441C mutation carriers (including family D members) from three continents, more than 90% of carriers became symptomatic by the eighth decade, whereas fewer than 20% manifested with PD before age 50.12
Asymptomatic individuals older than 80 years and heterozygous for G2019S mutation have been described.13–15
PET findings in these subjects are not known. Subject 11 (asymptomatic mutation carrier), who demonstrated normal tracer binding on PET imaging, was at least 10 years younger than the mean age at onset of motor symptoms in family D. Hence, continued follow-up of the presently asymptomatic subjects is essential to ascertain the progression to subclinical dopaminergic dysfunction and later development of clinical disease, and for the purpose of genetic counseling. Longitudinal follow-up of more of these subjects should ultimately permit a more precise estimation of the preclinical period. Further, such in vivo assessment will be useful in characterizing the progression of early disease. Familial subjects represent an ideal group in which to study potential neuroprotective strategies aimed at arresting or delaying the clinical onset of PD. Potential reasons for the failure of past neuroprotective studies include application of rescue or restorative measures late in the cellular neurodegeneration (i.e., in early symptomatic subjects) in pathogenetically heterogeneous disorders (such as sporadic PD). In contrast to the marked heterogeneity observed in sporadic PD, LRRK2
families provide a more powerful, homogeneous population and multitracer PET imaging, by identifying subclinical dopamine dysfunction, might permit selection of individuals during the window of maximum potential benefit. Such considerations have relevance for other neurodegenerative disorders.