Dopamine Transporter Positron Emission Tomography Research Articles

Dopamine transporter positron emission tomography in patients with Alzheimer’s disease with Lewy body disease features

In 36 normal controls (NC), 37 patients with Alzheimer’s disease (AD) without parkinsonism (ADP-), 31 AD with parkinsonism (ADP+), and 40 AD with dementia with Lewy bodies (ADDLB), dual-phase dopamine transporter (DAT) positron emission tomography (PET) were performed to evaluate the diagnostic performance of DAT and early-to-delayed uptake ratios (E/Ds) in the anterior caudate (AC), posterior caudate (PC), anterior putamen (AP), posterior putamen (PP), and substantia nigra (SN) to differentiate ADP+/ADDLB from NC, and their effects on parkinsonism and cognition. DAT-SN and E/D-PP showed higher accuracies to differentiate ADP+/ADDLB from NC than DAT-PP. Among AD patients, lower DAT in the putamen and PC and higher E/Ds in the striatum were associated with severe parkinsonism, while higher E/Ds in the putamen, PC, and SN were associated with executive dysfunction. Our results suggest that decreased DAT-SN and increased E/D-PP could be biomarkers differentiating ADP+/ADDLB from pure AD and controls. Meanwhile, increased E/Ds in the putamen could reflect the severity of DLB presenting with parkinsonism and executive dysfunction among AD patients.

Correlation Between Neuromelanin-Sensitive MRI and 18F-FP-CIT PET in Early-Stage Parkinson's Disease: Utility of a Voxel-Wise Analysis by Using High-Spatial-Resolution MRI.

The correlation between dopamine transporter (DAT) imaging and neuromelanin-sensitive magnetic resonance imaging (NM-MRI) in early-stage Parkinson's disease (PD) has not yet been established. This study aimed to determine the correlation between NM-MRI and DAT positron-emission tomography (PET) in patients with early-stage PD. Fifty drug-naïve patients with early-stage PD who underwent both 0.8-mm isovoxel NM-MRI and DAT PET were enrolled retrospectively. Using four regions of interest (nigrosome 1 and nigrosome 2 [N1 and N2] regions) from a previous study, the contrast ratios (CRs) of 12 regions were measured: N1, N2, flipped N1, flipped N2, combined N1 and N2, and whole substantia nigra pars compacta [SNpc] (all on both sides). The clinically more affected side was separately assessed. The standardized uptake value ratios (SUVRs) were measured in the striatum using DAT PET. A partial correlation analysis was performed between the SUVR and CR measurements. CR of the flipped left N1 region was significantly correlated with SUVR of the right posterior putamen (p=0.047), and CR values of the left N1 region, left N2 region, flipped right N1 region, and combined left N1 and N2 regions were significantly correlated with SUVR of the left posterior putamen (p=0.011, 0.038, 0.020, and 0.010, respectively). SUVR of the left anterior putamen was significantly correlated with CR of the left N2 region (p=0.027). On the clinically more affected side, the CR values of the N1 region, combined N1 and N2 regions, and the whole SNpc were significantly correlated with SUVR of the posterior putamen (p=0.001, 0.024, and 0.021, respectively). There were significant correlations between the SUVR of the anterior putamen and the CR values of the N1 region, combined N1 and N2 regions, and whole SNpc (p=0.027, 0.001, and 0.036, respectively). This study found that there were significant correlations between CR values in the SNpc on NM-MRI and striatal SUVR values on DAT PET on both sides in early-stage PD.

Temporal trajectory model for dopaminergic input to the striatal subregions in Parkinson's disease

IntroductionAlmost half of the nigral neurons are already lost during the preclinical period of Parkinson's disease (PD), and then the speed of neuronal loss is slowly attenuated during the subsequent progression. We sought to establish long-term temporal trajectory models for the dopaminergic input to the striatal subregions and a 4D-temporal trajectory model for the dopamine transporter positron emission tomography (PET). MethodsWe selected 83 patients in PD spectrum who underwent dopamine transporter PET scan twice and 71 age-matched healthy controls. We created temporal trajectories of specific binding ratios of the striatal subregions by integrating function between baseline values and their annual change rates and also created 4D-temporal trajectory model by applying the same method for each striatal voxel. Using the PET data of additional 100 PD patients, we estimated an individual time point in the 4D-temporal trajectory model for the validation. ResultsDegenerative loss of striatal dopaminergic input first appeared in the posterior dorsal putamen in the more affected side at 14.4 years before the clinical onset, and subsequently in the posterior ventral and anterior putamen, and finally in the caudate. The time delay between the initiation of dopaminergic loss in the more and less affected posterior dorsal putamen was 6.1 years. The estimated individual time points within the entire disease course were correlated with the motor severity. ConclusionOur temporal trajectory model demonstrated a sequential loss of dopaminergic input in the striatal subregions in PD and may be beneficial for the evaluation of individual status of disease progression.

The Value of Neuroimaging in Dementia Diagnosis.

This article discusses neuroimaging in dementia diagnosis, with a focus on new applications of MRI and positron emission tomography (PET). Although the historical use of MRI in dementia diagnosis has been supportive to exclude structural etiologies, recent innovations allow for quantification of atrophy patterns that improve sensitivity for supporting the diagnosis of dementia causes. Neuronuclear approaches allow for localization of specific amyloid and tau neuropathology on PET and are available for clinical use, in addition to dopamine transporter scans in dementia with Lewy bodies and metabolic studies with fludeoxyglucose PET (FDG-PET). Using computerized software programs for MRI analysis and cross-sectional and longitudinal evaluations of hippocampal, ventricular, and lobar volumes improves sensitivity in support of the diagnosis of Alzheimer disease and frontotemporal dementia. MRI protocol requirements for such quantification are three-dimensional T1-weighted volumetric imaging protocols, which may need to be specifically requested. Fluid-attenuated inversion recovery (FLAIR) and 3.0T susceptibility-weighted imaging (SWI) sequences are useful for the detection of white matter hyperintensities as well as microhemorrhages in vascular dementia and cerebral amyloid angiopathy. PET studies for amyloid and/or tau pathology can add additional specificity to the diagnosis but currently remain largely inaccessible outside of research settings because of prohibitive cost constraints in most of the world. Dopamine transporter PET scans can help identify Lewy body dementia and are thus of potential clinical value.

Implication of metabolic and dopamine transporter PET in dementia with Lewy bodies

To evaluate the implication of 18F-fluorodeoxyglucose (FDG)- and dopamine transporter (DAT)-positron emission tomography (PET) in the diagnosis and clinical symptoms of dementia with Lewy bodies (DLB), 55 DLB patients and 49 controls underwent neuropsychological evaluation and FDG-, DAT-, and 18F-Florbetaben (FBB) PET. DAT- and FDG-uptake and FDG/DAT ratio were measured in the anterior and posterior striatum. The first principal component (PC1) of FDG subject residual profiles was identified for each subject. Receiver operating characteristic curve analyses for the diagnosis of DLB were performed using FDG- and DAT-PET biomarkers as predictors, and general linear models for motor severity and cognitive scores were performed adding FBB standardized uptake value ratio as a predictor. Increased metabolism in the bilateral putamen, vermis, and somato-motor cortices, which characterized PC1, was observed in the DLB group, compared to the control group. A combination of posterior putamen FDG/DAT ratio and PC1 showed the highest diagnostic accuracy (91.8% sensitivity and 96.4% specificity), which was significantly greater than that obtained by DAT uptake alone. Striatal DAT uptake and PC1 independently contributed to motor severity and language, memory, frontal/executive, and general cognitive dysfunction in DLB patients, while only PC1 contributed to attention and visuospatial dysfunction.

Effect of Alzheimer's Disease and Lewy Body Disease on Metabolic Changes.

The relationship among amyloid-β (Aβ) deposition on amyloid positron emission tomography (PET), cortical metabolism on 18F-fluoro-2-deoxy-D-glucose (FDG)-PET, and clinical diagnosis has not been elucidated for both Alzheimer's disease (AD) and Lewy body disease (LBD). We investigated the patterns of cerebral metabolism according to the presence of AD and LBD. A total of 178 subjects were enrolled including 42 pure AD, 32 pure LBD, 34 Lewy body variant AD (LBVAD), 15 LBD with amyloid, 26 AD with dementia with Lewy bodies (DLB), and 29 control subjects. Pure AD, LBVAD, and AD with DLB groups had biomarker-supported diagnoses of typical AD, while pure LBD, LBD with amyloid, and AD with DLB groups had biomarker-supported diagnoses of typical LBD. Typical AD and LBD with amyloid showed amyloid-positivity on 18F-florbetaben (FBB) PET, while typical LBD and LBVAD had abnormalities on dopamine transporter PET. We measured regional patterns of glucose metabolism using FDG-PET and evaluated their relationship with AD and LBD. Compared with control group, typical AD and typical LBD commonly exhibited hypometabolism in the bilateral temporo-parietal junction, precuneus, and posterior cingulate cortex. Typical AD showed an additional hypometabolism in the entorhinal cortex, while patients with dopamine transporter abnormality-supported diagnosis of LBD showed diffuse hypometabolism that spared the sensory-motor cortex. Although the diffuse hypometabolism in LBD also involved the occipital cortex, prominent occipital hypometabolism was only seen in LBD with amyloid group. Combining clinical and metabolic evaluations may enhance the diagnostic accuracy of AD, LBD, and mixed disease cases.

Effects of APOE4 on Alzheimer’s disease, Lewy body disease, cerebral amyloid deposition and cognitive dysfunction

AbstractBackgroundWe investigated the effects of apolipoprotein E e4 allele (APOE4) on the risk of Alzheimer’s disease (AD) and/or Lewy body disease (LBD), cerebral amyloid deposition, and cognitive dysfunction.MethodWe consecutively recruited 131 control subjects and 208 (110 non‐demented and 98 demented) patients with AD and/or LBD. Patients were categorized into typical AD (pure AD and Lewy body variant of AD), typical LBD (pure LBD and LBD with amyloid deposition), and typical AD with LBD based on clinical features and biomarker evidence from 18F‐Florbetaben (FBB) positron emission tomography (PET) and dopamine transporter PET. Logistic regression analysis was performed to investigate whether APOE4 increased the risk for each disease. General linear models (GLMs) were performed to investigate the independent and interaction effects of APOE4, typical AD and typical LBD on cerebral FBB deposition, cross‐sectional cognition and the rate of longitudinal cognitive decline.Result APOE4 increased the risk of pure AD, AD with DLB, Lewy body variant of AD, and DLB with amyloid deposition, but did not increase the risk of pure LBD. In overall participants, APOE4 increased the risk of typical AD, but not typical LBD. APOE4, typical AD and typical LBD were positively associated with occipital FBB deposition; typical LBD was associated with higher occipital FBB deposition in the absence of typical AD; and APOE4 was associated with higher occipital FBB deposition in the presence of typical LBD. In GLMs for cross‐sectional cognition, APOE4 was associated with lower scores in verbal memory tests and higher clinical dementia rating sum of boxes (CDR‐SOB); it was associated with higher CDR‐SOB in the presence of typical LBD and lower scores in verbal memory tests in the presence of typical AD. APOE4 had no significant effects on the rates of longitudinal cognitive changes.Conclusion APOE4 is associated with increased risks of AD and amyloid deposition but not with LBD. APOE4 and typical LBD are independently and synergistically associated with occipital amyloid deposition. APOE4 interacts with typical AD on poor memory function and interacts with typical LBD on higher CDR‐SOB cross‐sectionally, but did not have significant effects on longitudinal cognitive decline.

Distinguishing between dementia with Lewy bodies and Alzheimer's disease using metabolic patterns

Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the 2 most common causes of dementia. We compared the regional metabolism on 18F-fluorodeoxyglucose positron emission tomography (PET) among 21 control subjects and cognitively impaired patients due to DLB (N = 63) and AD (N = 38). All participants underwent 18F-Florbetaben (FBB) PET, and all DLB patients had abnormality on dopamine transporter PET. Both the FBB-positive DLB (N = 38) and FBB-negative DLB (N = 25) groups had increased metabolism in the bilateral central cerebellum, posterior putamen, and somatomotor cortices compared with the control and AD groups. Compared with the control group, the DLB and AD groups commonly exhibited hypometabolism in the bilateral lateral temporal, temporo-parietal junction, posterior cingulate, and precuneus cortices. Both DLB groups had additional hypometabolism in the bilateral thalami and dorsolateral prefrontal cortices, whereas the AD group did in the bilateral entorhinal cortices and hippocampi. Our results suggest that hypermetabolism in the somatomotor cortex, posterior putamen, or central cerebellum could be a useful imaging biomarker for detecting DLB patients, while entorhinal/hippocampal hypometabolism could be a specific biomarker for AD.

Putaminal dopamine depletion in de novo Parkinson's disease predicts future development of wearing-off

IntroductionThe present study aimed to investigate whether the level of presynaptic dopamine neuronal loss predicts future development of wearing-off in de novo Parkinson's disease. MethodsThis retrospective cohort study included a total of 342 non-demented patients with de novo Parkinson's disease who underwent dopamine transporter positron emission tomography scans at their initial evaluation and received dopaminergic medications for 24 months or longer. Onset of wearing-off was determined based on patients' medical records at their outpatient clinic visits every 3–6 months. Predictive power of dopamine transporter activity in striatal subregions and other clinical factors for the development of wearing-off was evaluated by Cox proportional hazard models. ResultsDuring a median follow-up period of 50.2 ± 18.9 months, 69 patients (20.2%) developed wearing-off. Patients with wearing-off exhibited less dopamine transporter activity in the putamen, particularly the anterior and posterior putamens, compared to those without wearing-off. Multivariate Cox proportional hazard models revealed that dopamine transporter activities of the anterior (hazard ratio 0.556; p = 0.008) and whole putamens (hazard ratio 0.504; p = 0.025) were significant predictors of development of wearing-off. In addition, younger age at onset of Parkinson's disease, lower body weight, and a motor phenotype of postural instability/gait disturbance were also significant predictors for development of wearing-off. ConclusionThe present results provide in vivo evidence to support the hypothesis that presynaptic dopamine neuronal loss, particularly in the anterior putamen, leads to development of wearing-off in Parkinson's disease.

Multi-modality molecular imaging characteristics of dementia with Lewy bodies.

ObjectiveDementia with Lewy bodies (DLB) is a common type of neurodegenerative dementia. Molecular neuroimaging using dopamine transporter (DaT), Pittsburgh compound B (PIB), and fluorodeoxyglucose (FDG) positron emission tomography (PET) has advantages in detecting dopaminergic neuron loss, abnormal amyloid β-protein deposition, and glucose metabolism changes in patients with neurodegenerative disorders. However, the multi-modality molecular imaging features of patients with DLB have rarely been reported.MethodsFive patients with a probable diagnosis of DLB were enrolled. PET/magnetic resonance imaging was performed with three tracers: 11C-β-CFT, 11C-PIB, and 18F-FDG. Clinical and imaging characteristics were analyzed.ResultsAll patients with DLB showed reduced uptake in the bilateral putamen on DaT PET, increased uptake throughout the cerebral cortex on PIB PET, and intact metabolism of the posterior cingulate gyrus on FDG PET.ConclusionMultimodal molecular imaging is helpful for early diagnosis of DLB. Studies with larger sample sizes are needed to confirm the molecular imaging differences between DLB and Alzheimer’s disease and Parkinson’s disease dementia.

18F-FP-CIT dopamine transporter PET findings in cirrhotic patients with parkinsonism

We report the clinical features and imaging findings of presynaptic dopamine transporter (DAT) positron emission tomography (PET) in four of patients with liver cirrhosis and concurrent parkinsonism. We also reviewed previously reported cases of cirrhosis-related parkinsonism using dopaminergic molecular imaging.Our results using 18F-radiolabeled N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT) DAT PET in four patients with cirrhosis and parkinsonism showed two different molecular imaging patterns well related to their neurological symptoms. 18F-FP-CIT PET imaging of two patients showed normal DAT density in the striatum. Their clinical features included symmetric parkinsonism, early gait disturbances and postural instability, and the absence of resting tremor. The other two patients showed reduced striatal DAT uptake asymmetrically with a rostrocaudal gradient similar to idiopathic Parkinson’s disease (IPD). They had clinical findings of hemiparkinsonism, resting tremor, without early gait disturbance or postural instability. They also showed sustained response to levodopa treatment.Based on the structured review of 21 cases with cirrhosis-related parkinsonism in the literature including the present cases, we categorized cirrhotic parkinsonism into three groups. Eleven of the twenty-one cases were categorized into group 1; levodopa-resistant atypical parkinsonism without a dopaminergic deficit in molecular imaging similar to primary manganism. Another 6 cases were categorized into group 2; coincidental IPD with superimposed cirrhosis with sustained good response to levodopa and presynaptic dopaminergic deficit with rostrocaudal gradient typical of IPD. The other undetermined 4 cases were categorized into group 3. They showed symmetric parkinsonism with variable response to levodopa therapy. Their molecular imaging showed a global diffuse dopaminergic deficit in the presynaptic molecular imaging distinct to group 1 (normal uptake) or 2 (asymmetric rostrocaudal deficit). In conclusion, cirrhosis-related parkinsonism is a heterogeneous disorder.

Feasibility of Computed Tomography-Guided Methods for Spatial Normalization of Dopamine Transporter Positron Emission Tomography Image.

BackgroundSpatial normalization is a prerequisite step for analyzing positron emission tomography (PET) images both by using volume-of-interest (VOI) template and voxel-based analysis. Magnetic resonance (MR) or ligand-specific PET templates are currently used for spatial normalization of PET images. We used computed tomography (CT) images acquired with PET/CT scanner for the spatial normalization for [18F]-N-3-fluoropropyl-2-betacarboxymethoxy-3-beta-(4-iodophenyl) nortropane (FP-CIT) PET images and compared target-to-cerebellar standardized uptake value ratio (SUVR) values with those obtained from MR- or PET-guided spatial normalization method in healthy controls and patients with Parkinson’s disease (PD).MethodsWe included 71 healthy controls and 56 patients with PD who underwent [18F]-FP-CIT PET scans with a PET/CT scanner and T1-weighted MR scans. Spatial normalization of MR images was done with a conventional spatial normalization tool (cvMR) and with DARTEL toolbox (dtMR) in statistical parametric mapping software. The CT images were modified in two ways, skull-stripping (ssCT) and intensity transformation (itCT). We normalized PET images with cvMR-, dtMR-, ssCT-, itCT-, and PET-guided methods by using specific templates for each modality and measured striatal SUVR with a VOI template. The SUVR values measured with FreeSurfer-generated VOIs (FSVOI) overlaid on original PET images were also used as a gold standard for comparison.ResultsThe SUVR values derived from all four structure-guided spatial normalization methods were highly correlated with those measured with FSVOI (P < 0.0001). Putaminal SUVR values were highly effective for discriminating PD patients from controls. However, the PET-guided method excessively overestimated striatal SUVR values in the PD patients by more than 30% in caudate and putamen, and thereby spoiled the linearity between the striatal SUVR values in all subjects and showed lower disease discrimination ability. Two CT-guided methods showed comparable capability with the MR-guided methods in separating PD patients from controls and showed better correlation between putaminal SUVR values and the parkinsonian motor severity than the PET-guided method.ConclusionCT-guided spatial normalization methods provided reliable striatal SUVR values comparable to those obtained with MR-guided methods. CT-guided methods can be useful for analyzing dopamine transporter PET images when MR images are unavailable.

Heterogeneity of Monosymptomatic Resting Tremor in a Prospective Study: Clinical Features, Electrophysiological Test, and Dopamine Transporter Positron Emission Tomography.

Background:The relationship between monosymptomatic resting tremor (mRT) and Parkinson's disease (PD) remains controversial. In this study, we aimed to assess the function of presynaptic dopaminergic neurons in patients with mRT by dopamine transporter positron emission tomography (DAT-PET) and to evaluate the utility of clinical features or electrophysiological studies in differential diagnosis.Methods:Thirty-three consecutive patients with mRT were enrolled prospectively. The Unified Parkinson's Disease Rating Scale and electromyography were tested before DAT-PET. Striatal asymmetry index (SAI) was calculated, and a normal DAT-PET was defined as a SAI of <15%. Scans without evidence of dopaminergic deficits (SWEDDs) were diagnosed in patients with a subsequent normal DAT-PET and structural magnetic resonance imaging.Results:Twenty-eight mRT patients with a significant reduction in uptake of DAT binding in the striatum were diagnosed with PD, while the remained 5 with a normal DAT-PET scan were SWEDDs. As for UPRDS, the dressing and hygiene score, walking in motor experiences of daily living (Part II) and motor examination (Part III) were significant different between two groups (P < 0.05 and P < 0.01, respectively). Bilateral tremor was more frequent in the SWEDDs group (P < 0.05). The frequency of resting tremor and the amplitude of postural tremor tend to be higher in the SWEDDs group (P = 0.08 and P = 0.05, respectively).Conclusions:mRT is heterogeneous in presynaptic nigrostriatal dopaminergic degeneration, which can be determined by DAT-PET brain imaging. Clinical and electrophysiological features may provide clues to distinguish PD from SWEDDs.

Dilated Virchow-Robin Space and Dopamine Transporter Imaging in the Striatum of Patients with Parkinsonism.

The radiological and clinical significance of a dilated Virchow-Robin space (dVRS) in the striatum (STR) remains unclear. We investigated the role of dVRS in STR on parkinsonism and dopamine transporter positron emission tomography (DaT-PET) findings. Patients with parkinsonism who underwent both brain magnetic resonance imaging and DaT-PET were included. Clinical status was evaluated by Hoehn and Yahr (HY) stage, Korean-Mini Mental Status Examination (K-MMSE), Montreal Cognitive Assessment Korea (MoCA-K), and Frontal Assessment Battery (FAB). dVRS was assessed by semi-quantitative and quantitative scales in each of the three segments of STR (caudate nuclei, anterior and posterior putamen) and was expressed as a dVRS score. DaT-PET was qualitatively assessed as either normal or abnormal in each segment. The relationship between dVRS and DaT-PET abnormality (ab-DaT-PET) was designated in each segment as either concordant or discordant. A concordant segment was defined by the presence of dVRS with ab-DaT-PET [Concordance rate (CR)=number of concordant segments/number of concordant and discordant segments]. Eleven patients were included. There was no significant correlation between the presence of dVRS and ab-DaT-PET. The mean CR was 0.39. CR was not significantly correlated with any clinical or neuroimaging scales. The dVRS score was significantly correlated with K-MMSE, MoCA-K, and FAB (r=-0.675, -0.847, and -0.868, respectively) but not with HY stage. dVRS in STR played no significant role on dopaminergic innervation revealed by DaT-PET and made little contribution to clinical parkinsonism; however, it was correlated with cognitive impairment.

Striatal dopamine transporter imaging (FMT-PET) in patients with idiopathic rapid eye movement sleep behavior disorder – A cross-sectional study

Introduction It has become clear that Parkinson’s disease (PD) can have a premotor stage such as idiopathic REM sleep behavior disorder (IRBD). Imaging technologies such as dopamine transporter imaging currently offer the highest degree of accuracy for identifying premotor PD. Recent dopamine transporter SPECT and PET studies demonstrated decreased striatal dopaminergic innervations in IRBD patients. Materials and methods Positron emission tomography (PET) with 6-[(18)F](FMT), which can assess the level of the presynaptic dopaminergic nerve, were performed in 44 patients with IRBD, 14 patients with PD and 14 control subjects to assess nigrostriatal function. Results There were significant differences in the group 6-[18F] FMT uptake levels in bilateral putamen between PD patients and both IRBD patients and control subjects. IRBD patients with no signs of parkinsonism had almost intact striatal dopaminergic innervation, similar to the controls. In contrast, PD patients had parkinsonism by definition and had lost striatal dopaminergic innervation, as evidenced by decreased striatal uptake. Conclusion PET imaging seem to be helpful in identifying patients with IRBD potentially at risk to develop PD, dementia of Lewy body (DLB), or multiple system atrophy (MSA). However, more longitudinal follow-up studies are necessary to estimate the ratio of patients with dopaminergic cell loss in the basal ganglia who will develop PD, DLB, or MSA in the future. Acknowledgements This work was supported by Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (Grant No. 24621009 ). The authors thank Junichi Saitou and Toshihiko Satou (PET Center, Ustunomiya Central Clinic) for their technical support in performing FMT/PET.

Tropane‐derived 11C‐labelled and 18F‐labelled DAT ligands

Radiolabelling of cocaine‐derived 3‐phenyltropanes for dopamine transporter positron emission tomography with 18F and 11C is reviewed. Copyright © 2013 John Wiley &amp; Sons, Ltd.

The Influence of Residual Nor-β-CFT in 11C CFT Injection on the Parkinson Disease Diagnosis

Fully automated synthesis of 11C-labeled 2β-carbomethoxy-3β-(4-fluorophenyl)tropane (11C CFT) as a dopamine transporter positron emission tomography (PET) tracer is performed with Sep-Pak purification, which cannot separate 11C CFT from nor-β-CFT and will result in the residual precursor nor-β-CFT in the final 11C CFT injection. The aim of this study is to estimate the influence of the residual precursor nor-β-CFT in the 11C CFT injection on the Parkinson disease (PD) diagnosis results. Automated synthesis of 11C CFT was performed using the different chemical amounts (0.10, 0.20, 0.25, and 0.30 mg) of nor-β-CFT with Sep-Pak purification. According to the given different amounts of nor-β-CFT in the radiosynthesis, clinically suspected 25 PD patients were randomly divided into the following 4 groups: 0.10 mg, 0.20 mg, 0.25 mg, and 0.30 mg, which had 5, 9, 5, and 6 cases, respectively. A normal control group with 0.10 mg of nor-β-CFT included 2 volunteers. After the brain PET images of the subjects were acquired, the regions of interests of striatum and cerebellum were drawn, and the standard uptake values of these regions were calculated. Finally, comparing the 18F FDG PET and clinical diagnosis, the coincidence rates of 11C CFT PET imaging for PD patients were determined. Given 0.25 mg of the precursor nor-β-CFT, high radiochemical yield (59.4%) and high radiochemical purity of 11C CFT were obtained using Sep-Pak purification within a short synthesis time. The 11C CFT standard uptake value ratios of striatum to cerebellum had no statistically significant difference (P > 0.05) between the 4 suspected PD groups. However, there was statistically significant difference (P < 0.05) between the suspected PD groups and the control group. Also, the coincidence rates between the PD diagnosis using 11C CFT PET imaging for different dose groups and the final clinical diagnosis result were greater than 80%, but difference between the coincidence rates was not statistically significant (P = 0.955). A simple, rapid, and efficient automated synthesis of 11C CFT using 0.25 mg of nor-β-CFT with Sep-Pak purification is afforded, providing enough radioactivity for PD PET imaging routinely. The residual nor-β-CFT in the 11C CFT injection is not inhibit 11C CFT binding to dopamine transporter, and also has no influence on PET diagnosis results of PD.

Age-Related Striatal Dopaminergic Denervation and Severity of a Slip Perturbation

Striatal dopamine activity declines with normal aging. Age-related striatal dopaminergic denervation (SDD) has been implicated in standing balance and unperturbed gait. The goal of this study was to analyze the association between the degree of SDD and the magnitude of an unexpected slip perturbation induced during gait. Fifty healthy participants aged 20-86 years old underwent dopamine transporter positron emission tomography to classify SDD severity as mild, moderate, or severe. Participants also walked on a floor that was unexpectedly contaminated with a glycerol solution for gait testing. The magnitude of a slip was quantified using the peak slip velocity (PSV), measured at the slipping foot. Data were analyzed for both fast (greater than 1.2 m/s) and slow walkers as gait speed correlated with slip severity. All data analyses were age adjusted. Greater severity of dopaminergic denervation in the caudate nucleus was correlated with higher PSV (p < .01) but only in the fast speed walking group. The relationship between SDD in the putamen and slip severity was not statistically significant in fast and slow walkers. Age-related SDD may impact the ability to recover from large perturbations during walking in individuals who typically walk fast. This effect, prominent in the caudate nucleus, may implicate a role of cognitive frontostriatal pathways in the executive control of gait when balance is challenged by large perturbations. Finally, a cautious gait behavior present in slow walkers may explain the apparent lack of involvement of striatal dopaminergic pathways in postural responses to slips.

Olfactory loss and nigrostriatal dopaminergic denervation in the elderly

Olfactory dysfunction may precede common neurodegenerative disorders in the elderly, such as Alzheimer (AD) or Parkinson disease (PD). However, pathobiological mechanisms of olfactory loss in the elderly are poorly understood. Although nigrostriatal dopaminergic denervation is a key patholobiological feature of PD, age-associated nigrostriatal denervation (AASDD) occurs also with normal aging and can be more prominent in some elderly. We investigated the relationship between AASDD and olfactory performance in community-dwelling subjects. Community-dwelling subjects ( n = 73, 44 F/29 M, mean age 64.0 ± 16.4, range 20–85) underwent brain dopamine transporter (DAT) [ 11C]2-β-carbomethoxy-3β-(4-fluorophenyl) tropane (β-CFT) positron emission tomography (PET) imaging and olfactory assessment using the 40-odor University of Pennsylvania Smell Identification Test (UPSIT). Subjects with clinical or DAT PET evidence of Parkinson disease (PD) were not eligible for the study. AASDD was defined based on normative data in young and middle-aged subjects. Compared to a mild and general linear decline in odor identification observed in most subjects ( R 2 = 0.18, P = 0.0002), there were 13 subjects who deviated below the 5% confidence interval level in age-predicted UPSIT scores. Analysis limited to elderly subjects 60 years and over demonstrated a significant association between poor smell ( n = 10 out of 49, 20.4%) and AASDD ( χ 2 = 4.4, P < 0.05). There is a significant association between olfactory dysfunction and more prominent nigrostriatal denervation in the elderly. Olfactory assessment may have potential as a screening tool to detect age-accelerated neurodegeneration in the elderly.

Grooved pegboard test as a biomarker of nigrostriatal denervation in Parkinson's disease

Recent pharmacotherapy trials in Parkinson's disease (PD) using dopaminergic neuroimaging as outcome parameter failed to show significant relationships between imaging and clinical results. One possible explanation is that there is a non-linear relationship between striatal denervation and motor performance reflecting a statistical "floor" effect in the imaging data with advanced disease. Both the motor manifestations and the striatal dopamine denervation of idiopathic PD, however, are typically asymmetric and more meaningful associations may be found by comparing data from the least denervated striatum with motor performance in the corresponding body side. PD patients (n=28) underwent [11C]beta-CFT dopamine transporter (DAT) positron emission tomography (PET) and grooved pegboard testing. Voxel-based analysis of DAT PET and bimanual pegboard scores demonstrated significant correlation clusters within the bilateral striata (P<0.001). However, findings were most prominent in the least denervated striatum. There was a significant inverse correlation between pegboard scores of the least affected arm and DAT binding of the least denervated striatum (Rs=-0.69, P<0.0001) but no significant correlation between pegboard scores of the clinically most affected arm and DAT binding of the most denervated striatum (Rs=-0.15, ns). These data indicate that the robustness of the grooved pegboard test as a biomarker for nigrostriatal denervation in PD mainly reflects the relationship between test performance of the clinically least affected limb and the least denervated striatum. These findings indicate that there is both a statistical "floor" and "ceiling" effect for the most affected striatal and body sides that must be considered when employing imaging as an outcome measure in clinical trials in PD.