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Brain Advance Access originally published online on August 4, 2005
Brain 2005 128(12):2777-2785; doi:10.1093/brain/awh607

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PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation

John R. Adams¹, Hinke van Netten¹, Michael Schulzer¹, Edwin Mak¹, Jessamyn Mckenzie¹, Audrey Strongosky⁴, Vesna Sossi², Thomas J. Ruth³, Chong S. Lee¹, Matthew Farrer⁴, Thomas Gasser⁵, Ryan J. Uitti⁴, Donald B. Calne¹, Zbigniew K. Wszolek^4,* and A. Jon Stoessl^1,*

¹ Pacific Parkinson's Research Centre and ² Department of Physics and Astronomy, University of British Columbia, ³ TRIUMF, Vancouver, BC, Canada, ⁴ Mayo Clinic, Jacksonville, FL, USA and ⁵ Department of Neurodegenerative disorders, Hertie Institute for Clinical Brain Research, Center of Neurology, University of Tubingen, Tubingen, Germany

Correspondence to: Dr A. J. Stoessl, Pacific Parkinson's Research Centre, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5 E-mail: jstoessl{at}interchange.ubc.ca

	Summary

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Parkinson's disease may arise from multiple aetiologies, including genetic mutations that are for the most part uncommon. We describe here the positron emission tomography (PET) findings in clinically affected and asymptomatic, high-risk members of two autosomal dominantly inherited Parkinson's disease kindreds with recently described mutations at the PARK8 locus, in a novel gene encoding a leucine-rich repeat kinase (LRRK2). Affected family members have L-dopa-responsive parkinsonism with loss of dopaminergic nigral neurons and pleomorphic subcellular pathology. Fifteen family members underwent PET using: ¹⁸F-6-fluoro-L-dopa (¹⁸F-dopa) to assess dopamine (DA) synthesis and storage, ¹¹C-(±)-dihydrotetrabenazine (¹¹C-DTBZ) for the vesicular monoamine transporter, and ¹¹C-d-threo-methylphenidate (¹¹C-MP) for the membrane dopamine transporter (DAT). Measurements were compared with normal (n = 33) and sporadic Parkinson's disease (sPD) (n = 67) control groups. Four clinically affected members had findings similar to sPD, with impaired presynaptic DA function affecting the putamen more than the caudate. In two affected members, D2 dopamine receptor binding was intact. Two asymptomatic mutation carriers had abnormal DAT binding with another two developing such abnormalities over 4 years of follow-up. In these individuals, ¹⁸F-dopa uptake remained normal, although two of them also displayed abnormal ¹¹C-DTBZ binding. Our study demonstrates that the in vivo neurochemical phenotype of LRRK2 mutations is indistinguishable from that of sPD, despite the pathological heterogeneity of the condition. Furthermore, we suggest that compensatory changes including downregulation of the DAT and upregulation of decarboxylase activity may delay the onset of parkinsonian symptoms.

Key Words: genetics; Parkinson's disease; pathophysiology; positron emission tomography

Abbreviations: ¹¹C-DTBZ = ¹¹C-(±)-dihydrotetrabenazine; ¹¹C-MP = ¹¹C-d-threo-methylphenidate; ¹¹C-RAC = ¹¹C-raclopride; ¹⁸F-dopa = ¹⁸F-6-fluoro-L-dopa; BP = binding potential; DAT = dopamine transporter; LRRK2 = leucine-rich repeat kinase 2; PET = positron emission tomography; sPD = sporadic Parkinson's disease; UPDRS = Unified Parkinson's Disease Rating Scale; VMAT2 = vesicular monoamine transporter

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Received February 10, 2005. Revised May 30, 2005. Accepted July 4, 2005.

	Introduction

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Parkinson's disease is one of the most common neurodegenerative disorders with a prevalence of 1–2 in 100 for the 65 years and older population (de Rijk et al., 2000). Parkinson's disease is characterized by tremor, rigidity, bradykinesia/akinesia and postural instability, resulting from the loss of dopaminergic neurons within the substantia nigra pars compacta (SNc). Although most Parkinson's disease is sporadic, several mutations resulting in parkinsonism have been identified in recent years (Vila and Przedborski, 2004). The clinical expression in some of these disorders differs from that of sporadic Parkinson's disease (sPD) in features such as age of onset, rate of progression, associated neurological features and the incidence of complications. Neuropathological and neurochemical characterization of most of these forms of parkinsonism has been limited, and thus their relationship to sPD has for the most part remained unresolved.

The most recent addition to dominantly-inherited causes of Parkinson's disease involves a gene encoding a newly described large, multifunctional protein, leucine-rich repeat kinase LRRK2 (leucine-rich repeat kinase 2) in which eight mutations have been described (Paisan-Ruiz et al., 2004; Zimprich et al., 2004a; Di Fonzo et al., 2005; Kachergus et al., 2005). Gly2019Ser mutations in this gene may account for between 1–2 and 5–7% of sporadic and familial Parkinson's disease, respectively (Aasly et al., 2005; Gilks et al., 2005; Nichols et al., 2005). Patients with mutations in this gene have L-dopa-responsive parkinsonism with typical complications of therapy, but while loss of dopamine-producing neurons of the SNc is seen in all, the ultrastructural pathology is highly pleomorphic, with Lewy bodies seen in some but not others, while some subjects display abnormal tau and even amyloid deposition.

Positron emission tomography (PET), by providing quantitative information on dopaminergic function, is useful for the in vivo investigation of Parkinson's disease. ¹⁸F-6-fluoro-L-dopa (¹⁸F-dopa) uptake correlates with the number of nigral dopamine (DA) neurons in humans (Snow et al., 1993) and in animal models of Parkinson's disease (Pate et al., 1993). PET or SPECT studies with ¹⁸F-dopa, ¹¹C-(±)-dihydrotetrabenazine (¹¹C-DTBZ) or a variety of dopamine transporter (DAT) markers have consistently demonstrated a rostrocaudal gradient of striatal presynaptic DA dysfunction in sPD with the putamen more affected than the caudate (Garnett et al., 1983; Brooks et al., 1990; Frey et al., 1996; Guttman et al., 1997; Lee et al., 2000). Subclinical nigrostriatal DA dysfunction has been previously demonstrated in subjects exposed to MPTP (Calne et al., 1985), and in subjects with a high genetic risk of Parkinson's disease (Piccini et al., 1999).

In the present PET study, we sought to characterize the neurochemical phenotype of clinically affected and asymptomatic, high-risk individuals from two dominantly-inherited Parkinson's disease families with mutations in LRRK2. Presynaptic striatal dopaminergic function was evaluated using ¹⁸F-dopa to assess dopa uptake, decarboxylation via L-aromatic amino acid decarboxylase (L-AADC) and storage as ¹⁸F-dopamine; whereas, ¹¹C-d-threo-methylphenidate (¹¹C-MP) assessed the DAT and ¹¹C-DTBZ provided a more effective marker of nerve terminal integrity due to the reduced susceptibility of vesicular monoamine transporter (VMAT2) to pharmaceutical and compensatory mechanisms (Vander Borght et al., 1995; Kilbourn et al., 1996). In two affected subjects, post-synaptic striatal D2 receptor function was assessed using ¹¹C-raclopride (¹¹C-RAC).

	Methods

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Study population
Fifteen members from two well-documented families with autosomal dominantly inherited Parkinson's disease (families A and D) were investigated with PET. The Family A (German-Canadian) pedigree consists of 208 members, spanning six generations with at least 15 affected members. Family D (Western Nebraska) consists of 190 members with 22 affected members spanning six generations. Affected members from both families demonstrate L-dopa-responsive parkinsonism with typical therapy-related complications. Amyotrophy, dementia, dystonia, tremor and generalized epilepsy have occurred in some members from Family A. Previously reported PET studies with ¹⁸F-dopa in one affected member from each family and ¹¹C-RAC in one affected member from Family A demonstrated findings similar to sPD (Wszolek et al., 1995, 1997). Pathological findings include nigral neuronal loss with gliosis in all. Variable subcellular findings have included diffuse or brainstem-restricted Lewy bodies, non-specific eosinophilic granules, mild anterior horn cell loss, senile plaques and neurofibrillary tangles. One case demonstrated neither tangles nor Lewy bodies (Wszolek et al., 1995, 1997, 2004). Linkage to the PARK 8 locus on chromosome 12 has been demonstrated for both families (Zimprich et al., 2004b). In Family A, there is a Y1699C mutation and in family D there is a R1441C substitution in the gene encoding LRRK2 (Zimprich et al., 2004a). PET data from 33 healthy volunteers and 67 patients with clinically definite sPD (Calne et al., 1992), obtained with identical imaging and data analysis protocols, were included for comparison. At the time of investigation four family members, all carrying mutations in LRRK2, had clinically definite Parkinson's disease. Of these subjects, one was receiving L-dopa/carbidopa (350 mg/day), another pramipexole (3 mg/day) and a third selegiline (5 mg/day). The fourth subject, diagnosed at the time of study, was receiving no antiparkinsonian therapy. The remaining subjects were asymptomatic. Table 1 summarizes the characteristics of the subjects and controls. As a part of an ongoing follow-up study, several family members have been rescanned using the same protocol. All subjects gave written informed consent. This study was approved by the Clinical Research Ethics Board of the University of British Columbia.

View this table: [in this window] [in a new window]   Table 1 Family A (German-Canadian) and Family D (Western Nebraska) subject and control characteristics at the time of the first scans

 
Tracer chemistry
¹¹C-DTBZ was synthesized using a modification of the method of Kilbourn et al. (1995). ¹¹C-d-threo-MP was synthesized by modification of the procedure of Ding et al. (1994). The chemical synthesis for ¹⁸F-dopa has been described elsewhere (Adam and Ruth, 1988). ¹⁸F was produced as F₂ via the double shoot method making use of the ¹⁸O(p,n)¹⁸F reaction to produce the radioactivity and a second irradiation using F₂/Ar gas mixture for the recovery of ¹⁸F-F₂ (Nickles et al., 1984). The enriched ¹⁸O-O₂-target gas was recovered using a system similar to that described in the literature (Ruth et al., 2001). ¹¹C-RAC was synthesized as previously described (Ehrin et al., 1987).

PET studies and image analysis
All antiparkinsonian medications were stopped at least 12 h before each assessment. (18 h for controlled release L-dopa/carbidopa and dopamine agonists). Subjects fasted overnight and received a standard low-protein breakfast the morning of scanning. Subjects underwent brief clinical examination including videotaped motor Unified Parkinson's Disease Rating Scale (UPDRS) (Fahn et al., 1987). PET scans were performed consecutively in the order of ¹¹C-DTBZ, ¹¹C-MP and ¹⁸F-dopa, in a single day for most cases. If included, ¹¹C-RAC scans were performed the following day. All scans were performed in three-dimensional mode with an ECAT 953B/31 tomograph (CTI/Siemens, Knoxville, TN). Data processing and reconstruction are described in detail elsewhere (Sossi et al., 1998). Subjects were positioned supine with the gantry parallel to the orbitomeatal line and the head centred in the field of view. A thermoplastic mask was used to minimize movement and for repositioning in subsequent scans.

A transmission scan with ⁶⁸Ge rods for attenuation correction was obtained 10 min prior to injection of each radioligand. Using a Harvard infusion pump, ¹¹C-DTBZ (185 MBq in 10 ml of saline) was injected intravenously over 60 s. A series of sequential emission scans was obtained (4 x 1-min, 3 x 2-min, 8 x 5-min, 1 x 10-min) starting at tracer injection, for a total acquisition time of 60 min. Following an interval of 2.5 h (i.e. >7 half-lives for ¹¹C) to allow for radioactive decay, subjects were re-positioned and ¹¹C-MP (185 MBq in 10 ml of saline) was injected. Scans were acquired over 60 min as above. Following an additional interval of at least 2.5 h subjects received ¹⁸F-dopa (185–260 MBq in 10 ml of saline). One hour prior to ¹⁸F-dopa injection subjects received 200 mg of carbidopa orally. Nine sequential emission scans, each lasting 10 min, were obtained over 90 min. For subjects receiving ¹¹C-RAC, 185 MBq in 10 ml of saline were injected and data were acquired as for ¹¹C-DTBZ and ¹¹C-MP.

The methods of image analysis have been described in detail elsewhere (Lee et al., 2000). In brief, for all tracers regions of interest (ROIs) were placed on the summed images from the last 30 min of scanning in the five adjacent slices which best demonstrated the striatum. One circular ROI (area 61.2 mm², diameter 8.8 mm) was placed on each caudate head. Three additional ROIs of identical dimension were placed sequentially along the rostrocaudal axis of each putamen without overlap. For ¹⁸F-dopa, ¹¹C-DTBZ and ¹¹C-MP larger, circular ROIs (area 297 mm², diameter 19.4 mm) were positioned 3 per side over the cortex of the temporo-occipital lobe. For ¹¹C-RAC, a single large ROI (area 2107 mm²) was placed over the cerebellum. The ROIs were then replicated on each acquired time frame to obtain a time activity curve for each sampled region.

Binding potentials (BP) for ¹¹C-MP, ¹¹C-DTBZ and ¹¹C-RAC data were obtained using a multiple time graphical method (Logan et al., 1996) with an occipital lobe input function (cerebellar for ¹¹C-RAC). ¹⁸F-dopa uptake rate constant (K_occ) was obtained using a graphical method for unidirectional transport (Patlak and Blasberg, 1985; Martin et al., 1989) with an occipital cortex input function.

Statistical analysis
Left and right mean putaminal K_occ and BP values were obtained by averaging the three putaminal ROIs. Mean caudate and putaminal values (K_occ or BP) were obtained by averaging the corresponding left and right values. Using simple and multiple regression techniques for each ligand, it was determined that correction was required for age when comparing mean caudate or putaminal MP BP values to the normal control group and for age and disease duration (symptom onset to time of imaging) when comparisons of mean caudate MP BP values were made to the sPD control group. For each subject, results were determined as percentile values of the normal or sPD groups with significance derived from the corresponding confidence intervals. The results were ultimately expressed as percent values of normal controls. Statistical significance was set at P < 0.05.

	Results

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To protect the anonymity of the subjects, members from both families have been grouped together and labelled as subjects 1–15. Four subjects demonstrated clinically definite Parkinson's disease (subjects 1–4) with symptom duration 1 year and UPDRS motor scores ranging from 6 to 30 (Table 1). The remaining subjects were asymptomatic at the time of scanning; those with abnormal PET scans are listed after the clinically affected subjects with the remainder in random order.

The mean age of normal and sPD controls was 54.76 ± 14.15 and 61.04 ± 9.44 years, respectively. Mean symptom duration for the sPD group was 8.02 ± 6.17 years with a mean UPDRS motor score of 30.2 ± 11.7 (Table 1). The mean age for all mutation carriers was 48.9 ± 19.6 years, 58.0 ± 14.3 for those with clinical disease and 42.3 ± 21.3 years for those who remained asymptomatic. The mean age of non-mutation carriers was 59.0 ± 13.8 years. Previous reports have documented mean age of symptom onset at 53 and 65 years for Family A and D, respectively (Wszolek et al., 1997, 2004). In the current analysis, symptom onset was at a mean age of 46.5 ± 4.9 (n = 2) and 67.5 ± 12.0 (n = 2) years for affected Family A and D members, respectively. PET measurements for all subjects as well as normal and sPD controls are summarized in Table 2. For subjects with abnormal scans, individual ROI values are presented in Table 4. For each ligand, comparison to the normal control group is presented as a percentage (Table 3) with ¹¹C-MP binding potential values corrected for age. LRRK2 gene mutation status is presented in Tables 1–3.

View this table: [in this window] [in a new window]   Table 2 Striatal PET measurements (first scans) for familial subjects and controls*

 

View this table: [in this window] [in a new window]   Table 3 Percent values: comparison to normal controls for putamen*

 
¹⁸F-dopa
The mean putaminal uptake constant (K_occ) for ¹⁸F-dopa was 0.0104 ± 0.0011 min^–1 and 0.0046 ± 0.0017 min^–1 for the normal and sPD control groups, respectively. For each of the clinically affected subjects, ¹⁸F-dopa uptake was significantly reduced when compared to the normal control group and demonstrated asymmetry and a rostrocaudal gradient of severity, similar to that reported in sPD (Garnett et al., 1983; Martin et al., 1989; Brooks et al., 1990), with the putamen more severely affected (Table 4). There was no significant difference between putaminal values of affected family members and sPD controls. Subject 11 was unable to complete the ¹⁸F-dopa component of the protocol.

View this table: [in this window] [in a new window]   Table 4 PET values of individual ROIs for subjects with abnormal PET findings

 
¹¹C-DTBZ
The mean putaminal BP for ¹¹C-DTBZ was 0.98 ± 0.009 and 0.35 ± 0.15 for the normal and sPD control groups, respectively. Significantly reduced BP values for ¹¹C-DTBZ were demonstrated for all clinically affected subjects when compared to normal controls. As for ¹⁸F-dopa uptake, asymmetry and a rostrocaudal gradient were observed (Table 4). Subject 1 did not complete either the ¹¹C-DTBZ or ¹¹C-MP protocol. No difference was detected between clinically affected subjects and sPD controls. One asymptomatic mutation carrier (Subject 5) demonstrated significantly reduced ¹¹C-DTBZ BP (54% of normal) when compared to normal controls. For this individual, ¹⁸F-dopa uptake remained within normal limits, whereas age-adjusted ¹¹C-MP binding was also reduced to 51% of normal.

¹¹C-MP
The mean putaminal BP for ¹¹C-MP was 1.32 ± 0.002 and 0.41 ± 0.20 (0.49 ± 0.24, age-adjusted) for the normal and sPD control groups, respectively. As for ¹⁸F-dopa K_occ and ¹¹C-DTBZ BP, age-adjusted values for ¹¹C-MP BP in clinically affected members were significantly reduced compared to normal, with asymmetry and a rostrocaudal gradient (Table 4). In addition, two asymptomatic subjects (Subjects 5 and 6, both mutation carriers) also demonstrated significant reductions in putaminal age-adjusted ¹¹C-MP BP. As noted above, Subject 5 demonstrated reduced putaminal values for ¹¹C-DTBZ binding as well as age-adjusted ¹¹C-MP binding, but ¹⁸F-dopa uptake was normal. Whereas Subject 6 demonstrated significantly reduced age-adjusted ¹¹C-MP binding at 71% of normal, ¹⁸F-dopa and ¹¹C-DTBZ values for this individual were normal. Adjusted ¹¹C-MP binding in clinically affected members and asymptomatic Subject 5 was not significantly different from the sPD comparison group, but the putaminal age-adjusted ¹¹C-MP BP for asymptomatic Subject 6 was significantly increased compared to sPD controls.

¹¹C-RAC
¹¹C-RAC PET was performed on two clinically affected family members (Subjects 1 and 4). BP values for both subjects were within the range of normal and consistent with sPD (2.34 and 2.23 for putamen and 2.71 and 2.19 for caudate, respectively).

Follow-up scans
As part of an ongoing study, returning subjects underwent repeat scanning, using an identical protocol, on average 4 years after the original scans. Of those returning to date, two asymptomatic mutation carriers (Subjects 12 and 14) with previously normal scans had abnormalities. One demonstrated significantly reduced ¹¹C-DTBZ binding (putamen only) at 81% of normal and age-adjusted ¹¹C-MP binding at 69% of normal. These findings represent reductions of 13 and 14% (age-adjusted) from original scan results, respectively. ¹⁸F-dopa uptake remained normal with only a 2.4% reduction. A second asymptomatic member demonstrated significantly reduced age-adjusted ¹¹C-MP at 76% of normal, a reduction of 15% (age-adjusted) from the original scan. Reductions of 5% and 12% were seen for ¹⁸F-dopa uptake and ¹¹C-DTBZ binding, respectively, but levels were still within normal limits. At follow-up, both subjects were a minimum of 10 years younger than the average age of onset of parkinsonism in their respective families and motor examination revealed no evidence of parkinsonism (motor UPDRS scores of 1 and 2, respectively).

	Discussion

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We have shown that in affected members from two families with autosomal dominantly inherited parkinsonism linked to PARK8, the neurochemical profile of dopaminergic dysfunction as assessed by PET is indistinguishable from that of sPD. Thus, affected individuals have reductions in ¹⁸F-dopa uptake and in binding of ¹¹C-MP and ¹¹C-DTBZ to the DAT and VMAT2, respectively, while in both individuals so studied, post-synaptic dopamine D2 receptors were intact. Our findings are consistent with recent studies of ¹⁸F-dopa PET in six patients with a Gly2019Ser mutation of LRRK2 (Hernandez et al., 2005) and one additional subject with linkage to the PARK8 locus (Paisan-Ruiz et al., 2005). The pattern of DA dysfunction is typical of that seen in sPD, with relative sparing of the caudate nucleus and more severe impairment of the putamen. Affected subjects from both families showed asymmetric reduction of tracer uptake typical of sPD, and in contrast to some forms of inherited parkinsonism, PET values were in keeping with clinical severity when compared to sPD. The families described here have dominantly inherited, L-dopa-responsive parkinsonism associated with typical complications of long-term treatment. In both families, neurological disease arises from mutations in a newly described gene, designated LRRK2. LRRK2 is a member of the recently defined ROCO family of proteins that have five conserved domains, including a leucine-rich repeat. The fact that at least eight mutations in LRRK2 have been described in numerous families suggests that mutations in this gene are a much more common cause of inherited Parkinson's disease than other dominantly inherited mutations described to date and may account for up to 7% of familial Parkinson's disease and between 1 and 2% of sPD (Aasly et al., 2005; Gilks et al., 2005; Nichols et al., 2005). Importantly, the pathology described in seven individuals from these two families is heterogeneous. While all affected members have shown loss of DA neurons in the SNc and associated gliosis, only one individual from Family D had Lewy bodies restricted to the brainstem, and another had diffuse Lewy bodies. Three individuals from both kindreds showed neurofibrillary tangles and abnormal tau deposits, with senile plaques seen in three other individuals from both families. In affected members of Family A, there is additionally anterior horn cell loss associated with axonal spheroids.

This striking heterogeneity raises issues of fundamental importance. First, it is clear that multiple pathological expressions can arise from the same disease. Indeed, all of the described subjects had Parkinson's disease based on clinical criteria, even though only a single individual showed typical Lewy body pathology restricted to the substantia nigra. Other causes for Parkinson's disease include conditions in which there is nigral cell loss in the absence of Lewy bodies (e.g. parkin mutations), whereas nigral Lewy bodies have also been described in other neurodegenerative conditions (e.g. Hallervorden Spatz disease) (Arawaka et al., 1998) and in the absence of parkinsonism (Fearnley and Lees, 1991). Thus, the demonstration of PET findings typical of sPD in PARK 8 parkinsonism supports the view that the single most important pathological feature shared by the various forms of Parkinson's disease is the regional distribution of nigral neuronal loss, rather than the subcellular changes, which, as seen in this disorder, can be highly variable despite a single, well-defined aetiology. Other less common causes of inherited Parkinson's disease such as mutations in the gene encoding -synuclein also result in PET profiles typical of sPD (Samii et al., 1999), although that condition has a clinical course which is somewhat more aggressive than typical Parkinson's disease (Golbe et al., 1990). In contrast, in subjects with parkin-related parkinsonism, presynaptic DA dysfunction may range from mild to severe, with the caudate and putamen similarly affected, or a rostrocaudal gradient may be seen as in sPD (Broussolle et al., 2000; Hilker et al., 2001; Portman et al., 2001; Scherfler et al., 2004). Furthermore, post-synaptic dysfunction in the form of reduced D2 receptor binding has been reported (Hilker et al., 2001; Scherfler et al., 2004). Similarly, patients with PARK 6 parkinsonism also display more severe involvement of the anterior striatum than do patients with sPD (Khan et al., 2002).

Four of the asymptomatic mutation carriers reported here had reduced DAT binding. In two, DTBZ binding was significantly lower than normal, but reduced to a lesser degree than symptomatic sPD, suggesting very early nerve terminal loss. In all of the asymptomatic mutation carriers, ¹⁸F-dopa uptake was normal, despite the other evidence for impaired DA function, suggesting that L-AADC activity in these subjects was sufficient to maintain DA levels and avoid symptoms. Taken together, these findings are in keeping with other evidence for differential involvement of L-AADC, VMAT2 and DAT in Parkinson's disease (Wilson et al., 1996; Lee et al., 2000), possibly reflecting compensatory changes that serve to maintain extracellular levels of DA.

In summary, clinically affected and unaffected mutation carriers of these families demonstrate PET changes indistinguishable from those of sPD, in which there is dysfunction of presynaptic DA function affecting the putamen more than the caudate nucleus. The greater reduction of DAT than changes in VMAT2 and L-AADC in preclinical disease is in keeping with compensatory mechanisms that have been described in sPD, but could alternatively reflect a disease process that preferentially targets the DAT in early disease. The ability to reliably detect nigrostriatal dysfunction at an early preclinical stage may ultimately allow the use of neuroprotective therapies designed to halt or slow disease progress prior to symptom development in subjects at high risk.

	Notes

 
^* These authors contributed equally to this work

	Acknowledgements

 
We gratefully acknowledge the participation of the subjects and their family members. The work was funded in part by the Canadian Institutes for Health Research, Canada Research Chairs (A.J.S.), James and Donna Mae Moore endowment of the Michael Smith Foundation for Health Research, Parkinson Society Canada (J.R.A.), Michael Smith Foundation for Health Research (V.S.), Natural Sciences and Engineering Research Council of Canada (V.S.), National Institutes of Health, the National Institute of Neurologic Disorders and Stroke, the Morris K. Udall Parkinson's Disease Research Center of Excellence and the Life Sciences program at TRIUMF, Canada's National Laboratory for Nuclear and Particle Physics.

	References

Top Summary Introduction Methods Results Discussion References

 
Aasly JO, Toft M, Fernandez-Mata I, Kachergus J, Hulihan M, White LR, et al. Clinical features of LRRK2-associated Parkinson's disease in central Norway. Ann Neurol 2005; 57: 762–5.[CrossRef][Web of Science][Medline]

Adam MJ, Ruth TJ. Synthesis and purification of L-6-[¹⁸F]fluorodopa. Appl Radiat Isot 1988; 39: 1203–6.

Arawaka S, Saito Y, Murayama S, Mori H. Lewy body in neurodegeneration with brain iron accumulation type 1 is immunoreactive for alpha-synuclein. Neurology 1998; 51: 887–9.[Abstract/Free Full Text]

Brooks DJ, Ibanez V, Sawle GV, Quinn N, Lees AJ, Mathias CJ, et al. Differing patterns of striatal ¹⁸F-dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Ann Neurol 1990; 28: 547–55.[CrossRef][Web of Science][Medline]

Broussolle E, Lucking CB, Ginovart N, Pollak P, Remy P, Durr A. [¹⁸F]-dopa PET study in patients with juvenile-onset PD and parkin gene mutations. Neurology 2000; 55: 877–9.[Abstract/Free Full Text]

Calne DB, Langston JW, Martin WR, Stoessl AJ, Ruth TJ, Adam MJ, et al. Positron emission tomography after MPTP: observations relating to the cause of Parkinson's disease. Nature 1985; 317: 246–8.[CrossRef][Medline]

Calne DB, Snow BJ, Lee C. Criteria for diagnosing Parkinson's disease. Ann Neurol 1992; 32 (Suppl): S125–7.

de Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, et al. Prevalence of Parkinson's disease in Europe: a collaborative study of population-based cohorts. Neurologic diseases in the elderly research group. Neurology 2000; 54 (Suppl. 5): S21–3.[Web of Science][Medline]

Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, et al. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 2005; 365: 412–5.[Web of Science][Medline]

Ding YS, Sugano Y, Fowler JS, Salata C. Synthesis of the racemate and individual enantiomers of [¹¹C]methylphenidate for studying presynaptic dopaminergic neuron with positron emission tomography. J Labelled Comp Radiopharm 1994; 34: 989–97.[CrossRef][Web of Science]

Ehrin E, Gawell L, Hogberg T, de Paulis T, Strom P. Synthesis of [methoxy-H-3]- and [methoxy-C-11]-labeled raclopride—specific dopamine-D2 receptor ligands. J Labelled Comp Radiopharm 1987; 24: 931–40.[CrossRef][Web of Science]

Fahn S, Elton R, Members of the UPDRS Development Committee. Unified Parkinson's Disease Rating Scale. In: Fahn S, Marsden CD, Calne DB, Goldstein M, editors. Recent developments in Parkinson's disease. Florham Park, N.J: Macmillan Health Care; 1987. p. 153–63.

Fearnley JM and Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 1991; 114: 2283–301.[Abstract/Free Full Text]

Frey KA, Koeppe RA, Kilbourn MR, Vander Borght TM, Albin RL, Gilman S, et al. Presynaptic monoaminergic vesicles in Parkinson's disease and normal aging. Ann Neurol 1996; 40: 873–84.[CrossRef][Web of Science][Medline]

Garnett ES, Firnau G, Nahmias C. Dopamine visualized in the basal ganglia of living man. Nature 1983; 305: 137–8.[CrossRef][Medline]

Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, et al. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 2005; 365: 415–6.[Web of Science][Medline]

Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC. A large kindred with autosomal dominant Parkinson's disease. Ann Neurol 1990; 27: 276–82.[CrossRef][Web of Science][Medline]

Guttman M, Burkholder J, Kish SJ, Hussey D, Wilson A, DaSilva J, et al. [¹¹C]RTI-32 PET studies of the dopamine transporter in early dopa-naive Parkinson's disease: implications for the symptomatic threshold. Neurology 1997; 48: 1578–83.[Abstract/Free Full Text]

Hernandez DG, Paisan-Ruiz C, McInerney-Leo A, Jain S, Meyer-Lindenberg A, Evans EW, et al. Clinical and positron emission tomography of Parkinson's disease caused by LRRK2. Ann Neurol 2005; 57: 453–6.[CrossRef][Web of Science][Medline]

Hilker R, Klein C, Ghaemi M, Kis B, Strotmann T, Ozelius LJ, et al. Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol 2001; 49: 367–76.[CrossRef][Web of Science][Medline]

Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005; 76: 672–80.[CrossRef][Web of Science][Medline]

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: 849–53.[CrossRef][Web of Science][Medline]

Kilbourn M, Lee L, Vander BT, Jewett D, Frey K. Binding of alpha-dihydrotetrabenazine to the vesicular monoamine transporter is stereospecific. Eur J Pharmacol 1995; 278: 249–52.[CrossRef][Web of Science][Medline]

Kilbourn MR, Frey KA, Vander BT, Sherman PS. Effects of dopaminergic drug treatments on in vivo radioligand binding to brain vesicular monoamine transporters. Nucl Med Biol 1996; 23: 467–71.[CrossRef][Web of Science][Medline]

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: 493–503.[CrossRef][Web of Science][Medline]

Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 1996; 16: 834–40.[CrossRef][Web of Science][Medline]

Martin WR, Palmer MR, Patlak CS, Calne DB. Nigrostriatal function in humans studied with positron emission tomography. Ann Neurol 1989; 26: 535–42.[CrossRef][Web of Science][Medline]

Nichols WC, Pankratz N, Hernandez D, Paisan-Ruiz C, Jain S, Halter CA, et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 2005; 365: 410–2.[Web of Science][Medline]

Nickles RJ, Davis MR, Ruth TJ. An ¹⁸O₂ target for the production of ¹⁸F–F₂. Int J Appl Radiat Isot 1984; 35: 117–22.[CrossRef]

Paisan-Ruiz C, Jain S, Evans EW, Gilks WP, Simon J, van der BM, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004; 44: 595–600.[CrossRef][Web of Science][Medline]

Paisan-Ruiz C, Saenz A, de Munain AL, Marti I, Martinez GA, Marti-Masso JF, et al. Familial Parkinson's disease: clinical and genetic analysis of four Basque families. Ann Neurol 2005; 57: 365–72.[CrossRef][Web of Science][Medline]

Pate BD, Kawamata T, Yamada T, McGeer EG, Hewitt KA, Snow BJ, et al. Correlation of striatal fluorodopa uptake in the MPTP monkey with dopaminergic indices. Ann Neurol 1993; 34: 331–8.[CrossRef][Web of Science][Medline]

Patlak CS, Blasberg RG. Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 1985; 5: 584–90.[Web of Science][Medline]

Piccini P, Burn DJ, Ceravolo R, Maraganore D, Brooks DJ. The role of inheritance in sporadic Parkinson's disease: evidence from a longitudinal study of dopaminergic function in twins. Ann Neurol 1999; 45: 577–82.[CrossRef][Web of Science][Medline]

Portman AT, Giladi N, Leenders KL, Maguire P, Veenma-van der Duin L, Swart J, et al. The nigrostriatal dopaminergic system in familial early onset parkinsonism with parkin mutations. Neurology 2001; 56: 1759–62.[Abstract/Free Full Text]

Ruth TJ, Buckle KR, Chun KS, Hurtado ET, Jivan S, Zeisler S. A proof of principle for targetry to produce ultra high quantities of 18F-fluoride. Appl Radiat Isot 2001; 55: 457–61.[CrossRef][Web of Science][Medline]

Samii A, Markopoulou K, Wszolek ZK, Sossi V, Dobko T, Mak E, et al. PET studies of parkinsonism associated with mutation in the alpha-synuclein gene. Neurology 1999; 53: 2097–102.[Abstract/Free Full Text]

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: 1332–42.[Abstract/Free Full Text]

Snow BJ, Tooyama I, McGeer EG, Yamada T, Calne DB, Takahashi H, et al. Human positron emission tomographic [18F]fluorodopa studies correlate with dopamine cell counts and levels. Ann Neurol 1993; 34: 324–30.[CrossRef][Web of Science][Medline]

Sossi V, Oakes TR, Chan GL, Schulzer M, Ruth TJ. Quantitative comparison of three- and two-dimensional PET with human brain studies. J Nucl Med 1998; 39: 1714–9.[Abstract/Free Full Text]

Vander Borght TM, Kilbourn M, Desmond T, Kuhl D, Frey K. The vesicular monoamine transporter is not regulated by dopaminergic drug treatments. Eur J Pharmacol 1995; 294: 577–83.[CrossRef][Web of Science][Medline]

Vila M, Przedborski S. Genetic clues to the pathogenesis of Parkinson's disease. Nat Med 2004; 10 (Suppl): S58–62.

Wilson JM, Levey AI, Rajput A, Ang L, Guttman M, Shannak K, et al. Differential changes in neurochemical markers of striatal dopamine nerve terminals in idiopathic Parkinson's disease. Neurology 1996; 47: 718–26.[Abstract/Free Full Text]

Wszolek ZK, Pfeiffer B, Fulgham JR, Parisi JE, Thompson BM, Uitti RJ, et al. Western Nebraska family (family D) with autosomal dominant parkinsonism. Neurology 1995; 45: 502–5.[Abstract/Free Full Text]

Wszolek ZK, Vieregge P, Uitti R, Gasser T, Yasuhara O, Mcgeer P, et al. German-Canadian family (family A) with parkinsonism, amyotrophy, and dementia—longitudinal observations. Parkinsonism Relat Disord 1997; 3: 125–39.

Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, McComb RD, Stoessl AJ, et al. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 2004; 62: 1619–22.[Abstract/Free Full Text]

Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004a; 44: 601–7.[CrossRef][Web of Science][Medline]

Zimprich A, Muller-Myhsok B, Farrer M, Leitner P, Sharma M, Hulihan M, et al. The PARK8 locus in autosomal dominant parkinsonism: confirmation of linkage and further delineation of the disease-containing interval. Am J Hum Genet 2004b; 74: 11–9.[CrossRef][Web of Science][Medline]

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