Sage Journals: Discover world-class research

Abstract

Smoking is associated with a lower incidence of Parkinson's disease (PD), which might be related to a neuroprotective action of nicotine. Postmortem studies have shown a decrease of cerebral nicotinic acetylcholine receptors (nAChRs) in PD. In this study, we evaluated the decrease of nAChRs in PD in vivo using positron emission tomography (PET), and we explored the relationship between nAChRs density and PD severity using both clinical scores and the measurement of striatal dopaminergic function. Thirteen nondemented patients with PD underwent two PET scans, one with 6-[¹⁸F]fluoro-3,4-dihydroxy-l-phenylalanine (6-[¹⁸F]fluoro-l-DOPA) to measure the dopaminergic function and another with 2-[¹⁸F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-[¹⁸F]fluoro-A-85380), a radiotracer with high affinity for the nAChRs. Distribution volumes (DVs) of 2-[¹⁸F]fluoro-A-85380 measured in the PD group were compared with those obtained from six nonsmoking healthy controls, with regions-of-interest and voxel-based approaches. Both analyses showed a significant (P<0.05) decrease of 2-[¹⁸F]fluoro-A-85380 DV in the striatum (10%) and substantia nigra (14.9%) in PD patients. Despite the wide range of PD stages, no correlation was found between DV and the clinical and PET markers of PD severity.

Keywords

nicotinic receptors Parkinson's disease PET

Introduction

Parkinson's disease (PD) is a neurodegenerative movement disorder that is characterized by a progressive loss of the nigrostriatal dopaminergic neurons leading to a severe dopamine depletion state. In addition to the decline of the dopaminergic function, other neurotransmitter systems are involved in PD, including the nicotinic cholinergic system (Jellinger, 1991). There is now accumulating evidence that there are significant declines in nicotinic acetylcholine receptors (nAChRs) in the postmortem brains of both demented and nondemented patients with PD (Aubert et al, 1992; Rinne et al, 1991; Quik, 2004). Moreover, converging evidence suggests that nAChRs could be potential targets for PD therapy and neuroprotective strategies. For example, numerous studies have shown that the stimulation of the nicotinic receptors located on presynaptic dopaminergic neurons by nicotine increases dopamine release in the striatum (McCallum et al, 2006; Salminen et al, 2004). In parallel, smoking markedly reduces the risk of developing PD (Allam et al, 2004). Finally, nicotine protects against neuronal insults in experimental models of PD (Jeyarasasingam et al, 2002; Parain et al, 2003; Quik et al, 2006). Hence, a deeper knowledge with regard to the nAChRs located in the basal ganglia and the changes related to PD is necessary.

Neuronal nAChRs are pentameric ligand-gated ion channels composed of α-subunits (homomeric receptors) or of α- (α2 to α7) and β-subunits (β2 to β4) (heteromeric receptors). The α4β2 nAChRs are the prominent subtype in the human brain (Gotti and Clementi, 2004). Nontoxic and selective ligands of nicotinic receptors have been recently developed and validated in humans for the assessment of cerebral nAChRs with SPECT (single photon emission computed tomography) or positron emission tomography (PET) imaging. Among those, the derivatives of 3-[2(S)-2-azetidinylmethoxy]pyridine (A-85380) are ligands with a high affinity for the β2* nAChR subtype (Gao et al, 2008; Pimlott et al, 2004; Quik et al, 2004; Schmaljohann et al, 2006). Recent SPECT studies (Fujita et al 2006; Oishi et al, 2007) using 5-[¹²³I]iodo-A-85380 have found a decrease of nAChRs in both the cortical and subcortical regions in the brain of PD patients.

A-85380 has also been radiolabeled with fluorine-18 and characterized for PET imaging of nicotinic receptors in the human brain (Dollé et al, 1999; Koren et al, 1998; Valette et al, 1999a, b ; Bottlaender et al, 2003). Among these compounds, 2-[¹⁸F]fluoro-A-85380 has a high affinity for the α4β2* subtype (Gao et al, 2008) and is the most studied PET radioligand.

This study aimed at measuring the in vivo cerebral loss of nAChRs in 13 nondemented PD patients using 2-[¹⁸F]fluoro-A-85380 and high-resolution imaging with PET. We also investigated the relationship between nAChRs cerebral distributions and PD severity using the clinical variables of PD patients and the measurement of striatal dopaminergic function with PET and 6-[¹⁸F]fluoro-3,4-dihydroxy-l-phenylalanine (6-[¹⁸F] fluoro-l-DOPA) reflecting dopamine synthesis and vesicular storage capacity (Brooks et al, 2003).

Materials and methods

Subjects

Thirteen nondemented PD patients, aged 61.2 ± 10.8 years (mean ± s.d.) were enrolled (Table 1). All subjects satisfied the United Kingdom Parkinson's Disease Society Brain Bank Diagnostic criteria for the clinical diagnosis of idiopathic PD (Hughes et al, 1992). Symptoms duration ranged from 0.75 to 19 years and the Hoehn and Yahr stage varied from I to IV, when off medication. All but one, were on anti-Parkinsonian medication. None of them had been treated with drugs interacting with the cholinergic system in the 2 months before the study. None of the PD patients had dementia according to the MMSE (Mini-Mental State Examination) score; they all scored higher than 26/30, except patient no. 4 who scored 25. However, this Polish patient had trouble with the French language, which explained most of his mistakes. Five patients had never smoked. Eight patients had quit 7 to 26 years earlier.

Table 1

Characteristics of the PD patients

Patients	MMSE	Disease	L-DOPA (mg)	Clinical scores in ‘off’						6-[¹⁸F]fluoro-L-DOPA Ki (per min)

No./age/sex	Score/30	duration (years)	equivalents	H&Y	UPDRS-3	Purdue Pegboard		Hand-arm		Caudate		Putamen

						Right	Left	Right	Left	Right	Left	Right	Left
1/59/M	26	15.0	1,490	4	35.0	9.0	7.0	26.0	27.5	0.0070	0.0078	0.0036	0.0038
2/36/M	28	9.0	1,460	1.5	22.0	6.0	10.5	58.0	27.0	0.0102	0.0091	0.0068	0.0057
3/71/M	27	0.8	632	1	5.0	12.5	11.0	19.5	21.5	0.0093	0.0139	0.0072	0.0063
4/72/F	25	4.2	411	2.5	18.0	10.0	10.0	30.0	31.0	0.0072	0.0066	0.0057	0.0049
5/57/F	26	5.0	472	2	21.5	12.0	8.5	27.0	28.0	0.0097	0.0104	0.0064	0.0072
6/53/M	30	1.6	357	1.5	13.5	9.0	10.0	24.0	20.0	0.0115	0.0068	0.0097	0.0052
7/69/M	29	19.0	1,400	3	45.5	3.5	7.5	25.5	26.5	0.0090	0.0094	0.0060	0.0051
8/70/M	26	13.0	880	3	15.5	10.0	10.0	33.0	37.0	0.0070	0.0075	0.0046	0.0047
9/71/M	28	10.0	765	2	31.0	9.0	8.5	40.0	35.5	0.0071	0.0044	0.0045	0.0037
10/57/F	26	7.0	1,581	3	53.0	6.0	7.0	122.0	138.0	0.0096	0.0110	0.0059	0.0056
11/64/F	26	8.0	550	3	21.0	10.0	11.0	21.5	19.0	0.0075	0.0077	0.0034	0.0042
12/68/F	28	3.2	0	1	11.0	8.0	12.0	34.0	31.0	0.0106	0.0099	0.0085	0.0065
13/49/F	27	5.0	1,110	4	29.0	11.0	9.0	30.0	37.5	0.0069	0.0074	0.0055	0.0066
Mean	27.3	7.8	855	2.4	24.7	8.9	9.4	37.7	36.9	0.0087	0.0086	0.0060	0.0053
(s.d.)	(1.4)	(5.4)	(511)	(1.0)	(13.7)	(2.5)	(1.6)	(27.2)	(31.0)	(0.0016)	(0.0024)	(0.0018)	(0.0011)

F, female; H&Y, Hoehn and Yahr; M, male; MMSE, Mini-Mental State Examination; PD, Parkinson's disease; UPDRS, Unified Parkinson's Disease Rating Scale.

L-DOPA equivalents have been calculated according to Thobois (2006); H&Y. Purdue Pegboard = number of digits in 30 secs. Hand-arm = time to perform 20 movements. Global cognitive efficiency was evaluated using the MMSE according to Folstein et al (1975).

The control group consisted of six nonsmoking healthy volunteers, aged 61.2 ± 13.9 years (range 37 to 74, three men and three women) without any psychiatric or neurologic illness or cholinergic medication. All of them had a negative plasma cotinine determination and a normal brain magnetic resonance imaging (MRI). There was no significant difference in age (t-test, P=0.8) or gender (χ², P = 0.88) between the two groups. This study was approved by the local ethical committee. Written informed consent was obtained from all participants.

Study Design

The severity of PD was measured using the UPDRS (Unified Parkinson's Disease Rating Scale) motor score and timed motor tests (Purdue Pegboard, hand-arm tests) in the defined ‘off’ condition (i.e., at least 12 h after the last anti-Parkinsonian medications) (Defer et al, 1999). This evaluation was performed by one neurologist, an expert in movement disorders. He was blinded to the PET results.

All subjects underwent a T₁-weighted MR scan and a 2-[¹⁸F]fluoro-A-85380 PET scan on the same day. The reduction of striatal dopaminergic function was assessed in PD patients using 6-[¹⁸F]fluoro-l-DOPA PET on a separate day. All PET studies were carried out using an ECAT, EXACT HR+ tomograph (Siemens Medical Solutions, Knoxville, TN, USA), which collected 63 simultaneous 2.4-mm-thick axial slices in a three-dimensional mode, with an isotropic intrinsic resolution of 4.5 mm. A thermolabile plastic face mask ensured a stable position of the head. Before the tracer injection, a transmission scan ([⁶⁸Ge] rods; 15 mins) was recorded in each individual to correct for γ-ray attenuation.

Magnetic Resonance Imaging and Anatomic Volumes-of-Interest

Magnetic resonance imaging scans were performed on a 1.5 T imager (Signa, General Electric, Milwaukee, WI, USA). A T₁-weighted inversion-recovery sequence in a three-dimensional mode was used to generate anatomic images and anatomic volumes-of-interest (VOIs). Magnetic resonance imaging parameters included 124 axial slices of 1.2-mm thickness, a field of view of 24 cm, and an acquisition matrix of 256 times 256, with a voxel size of 0.93 times 0.93 times 1.2 mm³.

Volumes-of-interest were drawn manually on each patient's T₁-weighted MRI using the BrainVisa software (http://brainvisa.info). It was performed by the same physician blinded to subject information. The same method was used to delineate VOIs in all subjects. Frontal (8.5 ± 0.6 mL), parietal (6.5 ± 0.7 mL), occipital (12.5 ± 1.0 mL), and temporal (6.6 ± 0.6 mL) cortical VOIs were outlined following the gray matter ribbon with the identification of key sulci. Others VOIs included the cerebellum (23.9 ± 1.8 mL), corpus callosum (9.0 ± 1.3 mL), caudate (2.7 ± 0.2 mL), putamen (3.7 ± 0.3 mL), thalamus (5.7 ± 0.6 mL), substantia nigra (2.3 ± 0.2 mL), pons (8.1 ± 0.8 mL), hippocampus (3.1 ± 0.5 mL), and amygdala (1.2 ± 0.2 mL). All VOIs were automatically one-voxel thickness eroded. We verified that there was no significant difference in cortical and subcortical volumes between patients and age-matched controls (t-test, all P>0.05).

6-[¹⁸F]fluoro-l-DOPA Positron Emission Tomography Acquisition and Analysis

All dopaminergic medications were stopped at least 12 h before the scan (Brooks et al, 2003; Ribeiro et al, 2002). All patients received 100 mg of carbidopa, a peripheral decarboxylase inhibitor, 1 h before tracer injection. Nine frames were acquired over 90 mins, after tracer intravenous injection (159.7 ± 31.2 MBq). Positron emission tomography scans were reconstructed with filtered back projection with a ramp filter producing images with a resolution of 6.8 mm full-width at half-maximum. Positron emission tomography images were corrected for scatter, γ-ray attenuation, and fluorine-18 decay. The voxel size was 2.4 times 2.4 times 2.4 mm³.

A parametric image of 6-[¹⁸F]fluoro-l-DOPA influx constant (K_i, measured per min) was generated using the Patlak graphical analysis and occipital radioactivity as a nonspecific function (Patlak and Blasberg, 1985; Ribeiro et al, 2002). The parametric image was coregistered with the individual MRI using a mutual information algorithm and a PET image obtained after staggered summation of dynamic images over 90 mins. K_i values were measured in the striatum using the anatomic VOIs described above.

2-[¹⁸F]fluoro-A-85380 Positron Emission Tomography Acquisition and Analysis

A-85380 was labeled with fluorine-18 by a no-carrier-added nucleophilic aromatic substitution (Dollé et al, 1999). 2-[¹⁸F]fluoro-A-85380 (188 ± 22 MBq; 2 to 3 nmol) was injected intravenously as a 1-min bolus. Positron emission tomography acquisition started 90 mins later and lasted for 2 h, a period in which the apparent steady state of 2-[¹⁸F]fluoro-A-85380 was reached as shown by Gallezot et al (2005) and Mitkovski et al (2005). Fifteen sequential frames were acquired with the acquisition duration ranging from 5 to 10 mins. Twenty venous blood samples were collected, initially every 5 mins during the first hour after injection, and then subsequently every 10 mins until the end of the PET emission (Picard et al, 2006). Plasma radioactivity was measured in a γ-counter (Cobra Quantum D5003, Perkin-Elmer, France). On the basis of the fact that the metabolites of 2-[¹⁸F]fluoro-A-85380 do not cross the blood—brain barrier (unpublished data), we applied a metabolite correction only for the plasma as previously described (Gallezot et al, 2005). Positron emission tomography emissions were reconstructed using the same procedure as that of the 6-[¹⁸F]fluoro-l-DOPA PET. Correction for partial volume effects was not performed on PET data, considering that brain atrophy is not common in nondemented PD patients (Burton et al, 2004). Moreover, there was no significant difference in cortical and subcortical volumes measured in PD patients and controls.

The distribution volume (DV) of 2-[¹⁸F]fluoro-A-85380 was determined using a simplified method based on the ratio of brain tissue concentration to unchanged 2-[¹⁸F]fluoro-A-85380 plasma concentration at equilibrium as defined by Mitkovski et al (2005). However, venous plasma was used instead of arterial plasma in our series. This simplified approach has been previously validated in 10 subjects (5 PD patients and 5 controls) of our study. These subjects had dynamic PET scan acquisition, and arterial and venous blood collections started with the bolus administration of 2-[¹⁸F]fluoro-A-85380, which enabled the calculation of DV with a two-tissue compartmental model analysis as described in Gallezot et al (2005). We found that the DV values defined by the region-to-venous plasma ratio were strongly correlated with those obtained from a two-tissue compartmental model analysis (data not shown). It showed that the venous blood sampling was an acceptable choice for input function and that 2-[¹⁸F]fluoro-A-85380 DV values expressed by this ratio can be used to quantify cerebral nAChRs concentration.

Parametric images of 2-[¹⁸F]fluoro-A-85380 DV were created using the BrainVisa software. For each frame collected during the last 30 mins of the emission scan, the radioactivity in each voxel was divided by the value of individually metabolite-corrected 2-[¹⁸F]fluoro-A-85380 concentration in venous plasma measured at the same time point.

Statistical Analysis

The 2-[¹⁸F]fluoro-A-85380 DV images were analyzed by combining an individual analysis using VOIs and a voxel-based approach using the Statistical Parametric Mapping software (SPM2, Wellcome Department of Cognitive Neurology, London, UK), which enables exploratory analysis of the entire brain volume without requiring an a priori hypothesis.

Distribution volume values in the VOIs were measured from the PET parametric image, after coregistration with the MRI. The DV values of the patients and controls were compared by an analysis of variance with post hoc t-tests. Spearman's rank test was used to study the relationship between DV values and the mean caudate and putamen K_i, and between DV values and disease duration, the daily dose of levodopa and dopamine agonist and motor scores. Statistical tests were performed using StatView (SAS, Cary, NC, USA) and were considered significant at P<0.05.

The SPM2 software implemented in Matlab 6.5 (MathWorks, Natick, MA, USA) was also used to localize mean group differences in 2-[¹⁸F]fluoro-A-85380 DV between PD patients and controls throughout the entire brain volume. The DV images were spatially normalized to a standard anatomic orientation (Montreal Neurological Institute space) using an appropriate gray matter template; first, individual parametric images were registered to individual T₁-weighted MRI, thereafter gray matter segmented MRI were normalized to the template, and finally the corresponding normalization coordinates were applied to DV images. Normalized images were smoothed using an isotropic Gaussian kernel of 8 mm to remove high-frequency noise from the images and to take into account anatomic differences between subjects. As each voxel contains a quantified DV value, no global normalization was applied. The SPM comparisons between patients and controls were performed using a two-sample t-test. The entire brain volume was initially assessed at a height threshold of uncorrected P < 0.001. Thereafter, a small volume correction was performed using a mask, including the midbrain and the basal ganglia, at a level of P < 0.05 corrected for multiple comparisons. This analysis was based on the hypothesis that a change in nAChRs density might appear in these regions according to postmortem findings in PD. Anatomic locations were obtained using the Anatomical Automatic Labeling software (http://www.cyceron.fr/freeware).

Results

2-[¹⁸F]fluoro-A-85380 Volume Of Interest Analysis

In controls, the greatest DV value was found in the thalamus. High-to-intermediate levels were observed in other regions, and the lowest DV values were found in the occipital cortex and corpus callosum (Table 2, Figure 1).

Figure 1

Axial, sagittal, and coronal mean PET images obtained from one control between 90 and 120 mins, after the injection of 2-[¹⁸F]fluoro-A-85380. PET images are coregistered with MR images.

Table 2

2-[¹⁸F]fluoro-A-85380 DV values: mean ± s.d.

DV	Controls (n = 6, mean ± s.d.)	PD patients (n = 13, mean ± s.d.)
Thalamus	11.2 ± 1.9	10.0 ± 1.0
Caudate^†	6.0 ± 0.4	5.4 ± 0.4
Putamen^*	6.5 ± 0.4	5.9 ± 0.6
Substantia nigra^*	7.5 ± 1.1	6.4 ± 0.8
Hippocampus	5.4 ± 0.3	5.1 ± 0.5
Pons	6.4 ± 1.0	6.2 ± 0.8
Frontal cortex	5.4 ± 0.4	5.2 ± 0.6
Parietal cortex	4.8 ± 0.3	4.6 ± 0.6
Temporal cortex	5.1 ± 0.4	4.8 ± 0.5
Occipital cortex	4.3 ± 0.2	4.3 ± 0.5
Cerebellum	5.7 ± 0.6	5.4 ± 0.6
Corpus callosum	3.9 ± 0.5	3.6 ± 0.5

DV, distribution volume; PD, Parkinson's disease.

†

P < 0.005,

P < 0.05 (corrected).

In PD patients, there was no right-to-left asymmetry of DV values despite the asymmetry of motor symptoms. Accordingly, statistical tests were performed using DV values averaged over both hemispheres. Compared with controls, we found a widespread decrease of DV values in the PD patients, ranging from −.4% in the occipital cortex to a −.9% loss in the substantia nigra (Table 2). After Bonferroni correction, the decrease remained significant only in the substantia nigra (−.9%, P=0.02), putamen (−.6%, P=0.03), and caudate (−.7%, P=0.004). There was no significant difference between putamen and caudate DV values in PD patients.

2-[¹⁸F]fluoro-A-85380 SPM Analysis

We found a significant bilateral decrease of DV in the striatum in the PD group (Table 3). The analysis performed with a small volume correction (P<0.05, corrected) showed a significant decrease of DV values in the substantia nigra (Figure 2). Conversely, whole-brain analysis showed no significant decrease of 2-[¹⁸F]fluoro-A-85380 DV in the cerebral cortex of PD patients.

Figure 2

SPM analysis: Brain areas with a significant decrease of 2-[¹⁸F]fluoro-A-85380 DV in the striatum and the substantia nigra, in the PD patients compared with that in controls. Colors reflect Z-scores. R: right; L: left.

Table 3

Decrease of 2-[¹⁸F]fluoro-A-85380 DV in PD patients: SPM results

Location	Local maxima MNI coordinates			Z-scores	Cluster size	P_corrected

	x (mm)	y (mm)	z (mm)		(voxels)	(voxel level)
Left caudate	−18	18	2	3.49	2,230	0.035
Left putamen	−26	−18	−4	3.18		0.035
Left putamen	−26	−4	10	3.00		0.035
Right caudate	16	12	10	3.45	1,884	0.035
Right putamen	22	20	−2	3.28		0.035
Right caudate	18	2	18	3.16		0.035
Left substantia nigra	−8	−24	−14	2.56	61	0.037

DV, distribution volume; MNI, Montreal Neurological Institute; PD, Parkinson's disease.

The cluster coordinates refer to the MNI neuroanatomical space.

SPM, statistical parametric mapping.

Correlations

No significant correlation was observed using both VOI (Spearman rank correlation test, all P> 0.05) and voxel-based analyses between regional DV values in the PD group and the markers of disease severity, namely the UPDRS motor score, the timed motor tests (Purdue Pegboard, hand-arm tests), the disease duration, and the daily dose of levodopa and dopamine agonists. In addition, there was no correlation between 6-[¹⁸F]fluoro-lDOPA K_i values measured in the putamen and in the caudate nucleus (details in Table 1) and the density of nAChRs measured with 2-[¹⁸F]fluoro-A-85380.

Discussion

Using 2-[¹⁸F]fluoro-A-85380 and PET, we found a mild but significant reduction of the density of nAChRs in the striatum and substantia nigra of 13 nondemented PD patients. Despite the wide range of disease severity in these patients, we found no correlation between the different measures of PD severity and the reduction of nAChRs density.

The cerebral distribution of nAChRs in our group of elderly healthy subjects is in agreement with previous studies in nonsmoking healthy volunteers (Gallezot et al, 2005; Kimes et al, 2003; Mitkovski et al, 2005; Picard et al, 2006) and is consistent with data obtained in vitro (Schmaljohann et al, 2006). In PD patients, there is a trend toward a mild and widespread decrease of nAChRs density. However, both regional and voxel-based analyses showed that this reduction was significant only in the substantia nigra and striatum, i.e., the main structures involved in the neurodegenerative process in this disease. Interestingly, this result is in agreement with postmortem data. Although most of the latter studies did not distinguish between the different nAChRs subtypes, they consistently reported a reduction of nAChRs in the striatum of deceased PD patients (Aubert et al, 1992; Court et al, 2000; Perry et al, 1995; Rinne et al, 1991). In addition, the substantia nigra was examined once (Perry et al, 1995) and a significant decrease of nAChRs was also reported. More recent postmortem studies (Pimlott et al, 2004; Quik et al, 2004; Schmaljohann et al, 2006) using more specific ligands, confirmed the previous studies showing a significant decrease of 5-[¹²⁵I]iodo-A-85380 and 2-[¹⁸F]fluoro-A-85380 binding in the striatum of PD patients. The amplitude of this reduction (−30 to −50%) is greater than what we found in vivo. This might be related to methodological reasons; e.g., as there is no region devoid of nAChRs, we could not measure accurately NSB (nonspecific binding) and calculate a SB (specific binding) of 2-[¹⁸F]fluoro-A-85380. As the PET tissue concentration is (NSB + SB), the SB decrease may have been underestimated. Alternatively, it is unclear whether postmortem studies have included PD patients with cognitive impairment. Demented patients have a more severe decrease of nAChRs than nondemented PD patients (Court et al, 2000; Rinne et al, 1991). As only nondemented patients were enrolled in our study, this might have affected the amplitude of the reduction of nAChRs.

Although most studies converge to show a reduction of nAChRs density in the nigrostriatal system in PD, an emerging question is whether these changes are related to disease progression. We found no correlation between DV values and the different clinical markers of PD progression, including the amount of medication taken by the subjects, nor with the loss of 6-[¹⁸F]fluoro-l-DOPA uptake in the putamen of these patients. Moreover, the reduction of nAChRs density was similar in the caudate and putamen, as well as in the left and right hemispheres, which differs from the gradient of the reduction of 6-[¹⁸F]fluoro-l-DOPA uptake. One possible explanation for this result might be related to the subtypes of nAChRs, which are directly involved in the neurodegenerative process. The decrease of 2-[¹⁸F]fluoro-A-85380 DV reflects a reduction of heteromeric nAChRs as this tracer has a very low affinity for the homomeric α7 subtypes (Deuther-Conrad et al, 2004). Among the heteromeric nAChRs, 2-[¹⁸F]fluoro-A-85380 shows a selectivity for α4β2 over α3β4 receptors (Deuther-Conrad et al, 2004), whereas its affinity for the other less abundant α*-β2 subtypes remains to be established (Gao et al, 2008). As 5-[¹²³I]iodo-A-85380, our tracer might interact with α6β2 subtypes (Kulak et al, 2002). Recent studies have shown that the striatal αβ2-containing nAChRs, especially the α4αβ2β3 subtype, are particularly susceptible to nigrostriatal damage (Bohr et al, 2005; Bordia et al, 2007), suggesting that they are located primarily on striatal dopaminergic terminals. Conversely, Quik et al (2004) found a dissociation between the severity of the loss of dopaminergic neurons and the binding of 5-[¹²⁵I]iodo-A-85380 in the putamen of postmortem Parkinsonian brains. Moreover, several studies suggest that α4β2 nAChRs are not only distributed on dopaminergic neurons but also on other neurons in the striatum, which remain unaffected by the degenerative process (Quik et al, 2004). Taken together, these findings may explain the lack of correlation between the 2-[¹⁸F]fluoro-A-85380 DV values and the 6-[¹⁸F]fluoro-l-DOPA uptake.

Eventually, it has been suggested that nAChRs, especially in the cerebral cortex, might be involved in the cognitive deterioration of PD patients (Rinne et al, 1991; Whitehouse et al, 1988). In our series of 13 nondemented patients, 2-[¹⁸F]fluoro-A-85380 DV was reduced by an average of 5% in the cortical regions, which did not reach statistical significance. In their study of 10 nondemented patients Fujita et al (2006), found a similar reduction (−6% on average) of cortical binding of 5-[¹²³I]iodo-A-85380. In addition, Oishi et al (2007) reported a decrease of 5-[¹²³I]iodo-A-85380 DV in the cerebral cortex of 10 nondemented PD patients that only reached significance in the frontal cortex. These slight discrepancies might be related to methodological reasons, such as the use of two different derivates of A-85380, the blood sampling and the plasma analysis, or differences between PET and SPECT procedures, which do not have the same resolution and accuracy. Alternatively, this might simply show individual variations in three different small groups of patients. It could be hypothesized that some individuals have a more severe reduction of cortical nAChRs, which might be predictive of future dementia. Further longitudinal studies are needed to confirm such a hypothesis. Nevertheless, considering the high affinity of 2-[¹⁸F]fluoro-A-85380 for the α4β2 nAChRs, the most widespread nAChRs population in the cortex, this ligand has a great potential for investigating the relationship between cognitive deficits and nAChRs density in Parkinsonian patients.

Footnotes

Acknowledgements

This work was supported in part by a grant from ‘Les Journées de Neurologie de Langue Française’.

The authors declare no conflict of interest.

References

Allam

Campbell

Del Castillo

Fernandez-Crehuet Navajas

(2004) Parkinson's disease protects against smoking? Behav Neurol 15:65–71

Aubert

Araujo

Cecyre

Robitaille

Gauthier

Quirion

(1992) Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer's and Parkinson's diseases. J Neurochem 58:529–41

Bohr

Ray

McIntosh

Chalon

Guilloteau

McKeith

Perry

Clementi

Perry

Court

Piggott

(2005) Cholinergic nicotinic receptor involvement in movement disorders associated with Lewy body diseases. An autoradiography study using [(125)I]alpha-conotoxinMII in the striatum and thalamus. Exp Neurol 191:292–300

Bordia

Grady

McIntosh

Quik

(2007) Nigrostriatal damage preferentially decreases a subpopulation of alpha6beta2* nAChRs in mouse, monkey, and Parkinson's disease striatum. Mol Pharmacol 72:52–61

Bottlaender

Valette

Roumenov

Dolle

Coulon

Ottaviani

Hinnen

Ricard

(2003) Biodistribution and radiation dosimetry of 18F-fluoro-A-85380 in healthy volunteers. J Nucl Med 44:596–601

Brooks

Frey

Marek

Oakes

Paty

Prentice

Shults

Stoessl

(2003) Assessment of neuroimaging techniques as biomarkers of the progression of Parkinson's disease. Exp Neurol 184(Suppl 1):S68–79

Burton

McKeith

Burn

Williams

O'Brien

(2004) Cerebral atrophy in Parkinson's disease with and without dementia: a comparison with Alzheimer's disease, dementia with Lewy bodies and controls. Brain 127:791–800

Court

Piggott

Lloyd

Cookson

Ballard

McKeith

Perry

(2000) Nicotine binding in human striatum: elevation in schizophrenia and reductions in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease and in relation to neuroleptic medication. Neuroscience 98:79–87

Defer

Widner

Marie

Remy

Levivier

(1999) Core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT-PD). Mov Disord 14:572–84

10.

Deuther-Conrad

Patt

Feuerbach

Wegner

Brust

Steinbach

(2004) Norchloro-fluoro-homoepibatidine: specificity to neuronal nicotinic acetylcholine receptor subtypes in vitro. Farmaco 59:785–92

11.

Dollé

Dolci

Valette

Hinnen

Vaufrey

Guenther

Fuseau

Coulon

Bottlaender

Crouzel

(1999) Synthesis and nicotinic acetylcholine receptor in vivo binding properties of 2-fluoro-3-[2(S)-2-azetidinylmethoxylpyridine: a new positron emission tomography ligand for nicotinic receptors. J Med Chem 42:2251–9

12.

Folstein

McHugh

(1975) ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–98

13.

Fujita

Ichise

Zoghbi

Liow

Ghose

Vines

Sangare

Cropley

Iida

Kim

Cohen

Bara-Jimenez

Ravina

Innis

(2006) Widespread decrease of nicotinic acetylcholine receptors in Parkinson's disease. Ann Neurol 59:174–7

14.

Gallezot

Bottlaender

Gregoire

Roumenov

Deverre

Coulon

Ottaviani

Dolle

Syrota

Valette

(2005) In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET. J Nucl Med 46:240–7

15.

Gao

Kuwabara

Spivak

Xiao

Kellar

Ravert

Kumar

Alexander

Hilton

Wong

Dannals

Horti

(2008) Discovery of (−)-7-methyl-2-exo-[3′-(6-[¹⁸F]fluoropyridin-2-yl)-5′-pyridinyl]-7-azabicy clo[2.2.1] heptane, a radiolabeled antagonist for cerebral nicotinic acetylcholine receptor (alpha4beta2-nAChR) with optimal positron emission tomography imaging properties. J Med Chem 51:4751–64

16.

Gotti

Clementi

(2004) Neuronal nicotinic receptors: from structure to pathology. Prog Neurobiol 74:363–96

17.

Hughes

Daniel

Kilford

Lees

(1992) Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatr 55:181–4

18.

Jellinger

(1991) Pathology of Parkinson's disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 14:153–97

19.

Jeyarasasingam

Tompkins

Quik

(2002) Stimulation of non-alpha7 nicotinic receptors partially protects dopaminergic neurons from 1-methyl-4-phenylpyridinium-induced toxicity in culture. Neuroscience 109:275–85

20.

Kimes

Horti

London

Chefer

Contoreggi

Ernst

Friello

Koren

Kurian

Matochik

Pavlova

Vaupel

Mukhin

(2003) 2-[18F]F-A-85380: PET imaging of brain nicotinic acetylcholine receptors and whole body distribution in humans. FASEB J 17:1331–3

21.

Kulak

Sum

Musachio

McIntosh

Quik

(2002) 5-Iodo-A-85380 binds to alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors (nAChRs) as well as alpha4beta2* subtypes. J Neurochem 81:403–406

22.

Koren

Horti

mukhin

Gundisch

Kimes

Dannais

London

(1998) 2-, 5-, 6-Halo-3-(2(S)-azetidinylmethoxy)pyridines: synthesis, affinity for nicotinic acethylcholine receptors, and molecular modeling. J Med Chem 41:3690–8

23.

McCallum

Parameswaran

Perez

Bao

McIntosh

Grady

Quik

(2006) Compensation in presynaptic dopaminergic function following nigrostriatal damage in primates. J Neurochem 96:960–72

24.

Mitkovski

Villemagne

Novakovic

O'Keefe

Tochon-Danguy

Mulligan

Dickinson

Saunder

Gregoire

Bottlaender

Dolle

Rowe

CC.

(2005) Simplified quantification of nicotinic receptors with 2[18F]F-A-85380 PET. Nucl Med Biol 32:585–91

25.

Oishi

Hashikawa

Yoshida

Ishizu

Ueda

Kawashima

Saji

Fukuyama

(2007) Quantification of nicotinic acetylcholine receptors in Parkinson's disease with (123)I-5IA SPECT. J Neurol Sci 256:52–60

26.

Parain

Hapdey

Rousselet

Marchand

Dumery

Hirsch

(2003) Cigarette smoke and nicotine protect dopaminergic neurons against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinsonian toxin. Brain Res 984:224–32

27.

Patlak

Blasberg

(1985) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 5:584–90

28.

Perry

Morris

Court

Cheng

Fairbairn

McKeith

Irving

Brown

Perry

(1995) Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: possible index of early neuropathology. Neuroscience 64:385–95

29.

Picard

Bruel

Servent

Saba

Fruchart-Gaillard

Schollhorn-Peyronneau

Roumenov

Brodtkorb

Zuberi

Gambardella

Steinborn

Hufnagel

Valette

Bottlaender

(2006) Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study. Brain 129:2047–60

30.

Pimlott

Piggott

Owens

Greally

Court

Jaros

Perry

Wyper

(2004) Nicotinic acetylcholine receptor distribution in Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease, and vascular dementia: in vitro binding study using 5-[(125)i]-a-85380. Neuropsychopharmacology 29:108–16

31.

Quik

Bordia

Forno

McIntosh

(2004) Loss of alpha-conotoxinMII- and A85380-sensitive nicotinic receptors in Parkinson's disease striatum. J Neurochem 88:668–79

32.

Quik

(2004) Smoking, nicotine and Parkinson's disease. Trends Neurosci 27:561–8

33.

Quik

Chen

Parameswaran

Xie

Langston

McCallum

(2006) Chronic oral nicotine normalizes dopaminergic function and synaptic plasticity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates. J Neurosci 26:4681–9

34.

Ribeiro

Vidailhet

Loc'h

Dupel

Nguyen

Ponchant

Dolle

Peschanski

Hantraye

Cesaro

Samson

Remy

(2002) Dopaminergic function and dopamine transporter binding assessed with positron emission tomography in Parkinson disease. Arch Neurol 59:580–6

35.

Rinne

Myllykyla

Lonnberg

Marjamaki

(1991) A postmortem study of brain nicotinic receptors in Parkinson's and Alzheimer's disease. Brain Res 547:167–70

36.

Salminen

Murphy

McIntosh

Drago

Marks

Collins

Grady

(2004) Subunit composition and pharmacology of two classes of striatal presynaptic nicotinic acetylcholine receptors mediating dopamine release in mice. Mol Pharmacol 65:1526–35

37.

Schmaljohann

Gundisch

Minnerop

Bucerius

Joe

Reinhardt

Guhlke

Biersack

Wullner

(2006) In vitro evaluation of nicotinic acetylcholine receptors with 2-[18F]F-A85380 in Parkinson's disease. Nucl Med Biol 33:305–9

38.

Thobois

(2006) Proposed dose equivalence for rapid switch between dopamine receptor agonists in Parkinson's disease: a review of the literature. Clin Ther 28:1–12

39.

Valette

Bottlaender

Dolle

Guenther

Fuseau

Coulon

Ottaviani

Crouzel

(1999a) Imaging central nicotinic acetylcholine receptors in baboons with [¹⁸F]fluoro-A-85380. J Nucl Med 40:1374–80

40.

Valette

Bottlaender

Dolle

Guenther

Coulon

Hinnen

Fuseau

Ottaviani

Crouzel

(1999b) Characterization of the nicotinic ligand 2-[¹⁸F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine in vivo. Life Sci 64:PL93–7

41.

Whitehouse

Martino

Wagster

Price

Mayeux

Atack

Kellar

(1988) Reductions in [3H]nicotinic acetylcholine binding in Alzheimer's disease and Parkinson's disease: an autoradiographic study. Neurology 38:720–3

Decrease of Nicotinic Receptors in the Nigrostriatal System in Parkinson's Disease

Abstract

Keywords

Introduction

Materials and methods

Subjects

Study Design

Magnetic Resonance Imaging and Anatomic Volumes-of-Interest

6-[18F]fluoro-l-DOPA Positron Emission Tomography Acquisition and Analysis

2-[18F]fluoro-A-85380 Positron Emission Tomography Acquisition and Analysis

Statistical Analysis

Results

2-[18F]fluoro-A-85380 Volume Of Interest Analysis

2-[18F]fluoro-A-85380 SPM Analysis

Correlations

Discussion

Footnotes

Acknowledgements

References

6-[¹⁸F]fluoro-l-DOPA Positron Emission Tomography Acquisition and Analysis

2-[¹⁸F]fluoro-A-85380 Positron Emission Tomography Acquisition and Analysis

2-[¹⁸F]fluoro-A-85380 Volume Of Interest Analysis

2-[¹⁸F]fluoro-A-85380 SPM Analysis