Nasim Vafai

Serotonin and dopamine transporter PET changes in the premotor phase of LRRK2 parkinsonism: cross-sectional studies

BACKGROUND People with Parkinsons disease can show premotor neurochemical changes in the dopaminergic and non-dopaminergic systems. Using PET, we assessed whether dopaminergic and serotonin transporter changes are similar in LRRK2 mutation carriers with Parkinsons disease and individuals with sporadic Parkinsons disease, and whether LRRK2 mutation carriers without motor symptoms show PET changes. METHODS We did two cross-sectional PET studies at the Pacific Parkinsons Research Centre in Vancouver, BC, Canada. We included LRRK2 mutation carriers with or without manifest Parkinsons disease, people with sporadic Parkinsons disease, and age-matched healthy controls, all aged 18 years or older. People with Parkinsons disease were diagnosed by a neurologist with movement disorder training, in accordance with the UK Parkinsons Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. In the first study, LRRK2 mutation carriers with or without manifest Parkinsons disease who were referred for investigation between July, 1999, and January, 2012, were scanned with PET tracers for the membrane dopamine transporter, and dopamine synthesis and storage (18F-6-fluoro-L-dopa; 18F-FDOPA). We compared findings with those in people with sporadic Parkinsons disease and age-matched healthy controls. In the second study, distinct groups of LRRK2 mutation carriers, individuals with sporadic Parkinsons disease, and age-matched healthy controls seen from November, 2012, to May, 2016, were studied with tracers for the serotonin transporter and vesicular monoamine transporter 2 (VMAT2). Striatal dopamine transporter binding, VMAT2 binding, 18F-FDOPA uptake, and serotonin transporter binding in multiple brain regions were compared by ANCOVA, adjusted for age. FINDINGS Between January, 1997, and January, 2012, we obtained data for our first study from 40 LRRK2 mutation carriers, 63 individuals with sporadic Parkinsons disease, and 35 healthy controls. We identified significant group differences in striatal dopamine transporter binding (all age ranges in caudate and putamen, p<0·0001) and 18F-FDOPA uptake (in caudate: age ≤50 years, p=0·0002; all other age ranges, p<0·0001; in putamen: all age ranges, p<0·0001). LRRK2 mutation carriers with manifest Parkinsons disease (n=15) had reduced striatal dopamine transporter binding and 18F-FDOPA uptake, comparable with amounts seen in individuals with sporadic Parkinsons disease of similar duration. LRRK2 mutation carriers without manifest Parkinsons disease (n=25) had greater 18F-FDOPA uptake and dopamine transporter binding than did individuals with sporadic Parkinsons disease, with 18F-FDOPA uptake comparable with controls and dopamine transporter binding lower than in controls. Between November, 2012, and May, 2016, we obtained data for our second study from 16 LRRK2 mutation carriers, 13 individuals with sporadic Parkinsons disease, and nine healthy controls. Nine LRRK2 mutation carriers without manifest Parkinsons disease had significantly elevated serotonin transporter binding in the hypothalamus (compared with controls, individuals with LRRK2 Parkinsons disease, and people with sporadic Parkinsons disease, p<0·0001), striatum (compared with people with sporadic Parkinsons disease, p=0·02), and brainstem (compared with LRRK2 mutation carriers with manifest Parkinsons disease, p=0·01), after adjustment for age. Serotonin transporter binding in the cortex did not differ significantly between groups after age adjustment. Striatal VMAT2 binding was reduced in all individuals with manifest Parkinsons disease and reduced asymmetrically in one LRRK2 mutation carrier without manifest disease. INTERPRETATION Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 mutation carriers with manifest Parkinsons disease and individuals with sporadic Parkinsons disease, but LRRK2 mutation carriers without manifest Parkinsons disease show increased serotonin transporter binding in the striatum, brainstem, and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of Parkinsons disease. Increased serotonergic innervation might contribute to clinical differences in LRRK2 Parkinsons disease, including the emergence of non-motor symptoms and, potentially, differences in the long-term response to levodopa. FUNDING Canada Research Chairs, Michael J Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinsons Research Institute, National Research Council of Canada.Summary Background Patients with Parkinson’s Disease (PD) may exhibit premotor neurochemical changes in dopaminergic (DA) and nondopaminergic systems. Using positron emission tomography (PET), we studied participants with leucine-rich repeat kinase 2 (LRRK2) mutations and with sporadic PD to assess whether DA and serotonin transporter (SERT) changes were similar in LRRK2 PD and sporadic PD, and whether asymptomatic LRRK2 mutation carriers exhibited PET changes in the absence of motor symptoms. Methods Between July 1999 and May 2016, we did two cross sectional PET studies at the Pacific Parkinson’s Research Centre (Vancouver, Canada) with LRRK2 mutation carriers with or without manifest PD, patients with sporadic PD, and age-matched healthy controls, all aged 18 years or older. Patients with PD were diagnosed by a neurologist with movement disorder training in accordance with the UK Parkinson’s Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bi-directional Sanger sequencing. First, affected and unaffected LRRK2 carriers seen from July 1999 to January 2012 were imaged with PET tracers for the membrane dopamine transporter (DAT) and dopamine synthesis and storage (18F-6-fluoro-L-dopa; FDOPA) and compared with sporadic PD and age-matched healthy controls. Second, distinct groups of LRRK2 mutation carriers, sporadic PD patients, and age-matched healthy controls seen from November 2012 to May 2016 were studied with tracers for the SERT and vesicular monoamine transporter 2 (VMAT2). Striatal DAT binding, DTBZ binding, FDOPA uptake and SERT binding in multiple brain regions were compared using analysis of covariance adjusted for age. Findings Using data from 40 LRRK2 mutation carriers, 63 patients with sporadic PD, and 35 controls, we identified significant group differences in striatal DAT binding (all age ranges p<0·0001 in caudate and putamen) and FDOPA uptake (age 50 or lower in caudate, p=0·0002; all other age ranges p<0·0001; in putamen, all age ranges p<0·0001). Affected LRRK2 mutation carriers (n=15) had reduced striatal DAT binding and FDOPA uptake, comparable to sporadic PD of similar duration. Unaffected carriers (n=25) had greater FDOPA uptake and DAT binding than sporadic PD (n=63), with FDOPA uptake comparable to and DAT binding lower than healthy controls. Unaffected LRRK2 carriers (n=9) had significantly elevated SERT binding in hypothalamus (greater than healthy controls, 7 LRRK2 PD and 13 sporadic PD subjects; p<0·0001), striatum (greater than sporadic PD; p=0·02) and brainstem (greater than affected LRRK2 carriers; p=0·01) after adjustment for age. SERT binding in cortex was not significantly different between groups after age adjustment. Striatal DTBZ binding was reduced in all affected patients and asymmetrically reduced in one unaffected carrier. Interpretation Dopaminergic and serotonergic changes progress in a similar fashion in LRRK2 PD and sporadic PD, but unaffected LRRK2 mutation carriers exhibit increased SERT binding in striatum, brainstem and hypothalamus, possibly reflecting compensatory changes in serotonergic innervation preceding the motor onset of PD. Funding Canada Research Chairs, Michael J. Fox Foundation, National Institutes of Health, Pacific Alzheimer Research Foundation, Pacific Parkinson’s Research Institute, National Research Council of Canada

PBB3 imaging in Parkinsonian disorders: Evidence for binding to tau and other proteins

Background and Objectives: To study selective regional binding for tau pathology in vivo, using PET with [11C]PBB3 in PSP patients, and other conditions not typically associated with tauopathy.

Positron Emission Tomography Study of the Effects of Tryptophan Depletion on Brain Serotonin2 Receptors in Subjects Recently Remitted From Major Depression

CONTEXT Decreased brain serotonin (5-hydroxytryptamine) levels are considered to mediate depressive relapse induced by the tryptophan depletion paradigm. However, in patients who recently achieved remission from a major depressive episode with antidepressant treatment, only about half become depressed following tryptophan depletion. We hypothesized that downregulation of brain serotonin(2) receptors might be a compensatory mechanism that prevents some patients from becoming depressed with tryptophan depletion. OBJECTIVE To assess, with use of positron emission tomography, whether brain serotonin(2) receptor downregulation occurs in patients with recently remitted depression who do not have depressive relapse, but not in those who become depressed, following tryptophan depletion. DESIGN Each patient underwent 2 fluorine 18-labeled- setoperone positron emission tomography scans, one following a tryptophan depletion session and another following a control session. The order of scanning was counterbalanced. SETTING Academic university hospital with imaging facilities. PARTICIPANTS Seventeen patients in recent remission from a DSM-IV major depressive episode following treatment with selective serotonin reuptake inhibitors. MAIN OUTCOME MEASURES Changes in brain serotonin(2) receptor binding. RESULTS Of the 17 patients, 8 (47%) became depressed during the tryptophan depletion session, and none developed depression during the control session. The depletion session was associated with a significant reduction in brain serotonin(2) receptor binding compared with the control session for all participants. A subgroup analysis revealed that the reduction in serotonin(2) receptor binding was significant only for the nondepressed group. CONCLUSION Reduction in brain serotonin(2) receptors might be a potential compensatory mechanism to prevent tryptophan depletion-induced depressive relapse.

Frame-to-frame image realignment assessment tool for dynamic brain positron emission tomography

PURPOSE Subject motion during positron emission tomography (PET) brain scans can reduce image quality and may lead to incorrect biological outcome measures, especially for data acquired with high resolution tomographs. A semiautomatic method for assessing the quality of frame-to-frame image realignments to compensate for subject motion in dynamic brain PET is proposed and evaluated. METHODS A test set of 256 11C-raclopride (a dopamine D2-type receptor antagonist) brain PET image frames was used to develop and evaluate the proposed method. The transformation matrix to be applied to each image to achieve a frame-to-frame realignment was calculated with two independent methods: Using motion data measured with the Polaris Vicra optical tracking device and using the image-based realignment algorithm AIR (automated image registration). The quality assessment method is based on the observation that there is a very low probability that two independent approaches to motion detection will produce equal, but incorrect results. Agreement between transformation matrices was taken to be a signature of an accurate motion determination and thus realignment. Each pair of realignment matrices was compared and used to calculate a metric describing the frame-to-frame image realignment accuracy. In order to determine the range of values of the metric that correspond to a successful realignment, a comparison was made to a detailed visual inspection of the frame-to-frame realigned images for each image in the test set. The threshold on the metric for realignment acceptance was then selected to optimize the numbers of true-positives (realignments accepted by both the protocol and the operator) and minimize the number of false-positives (accepted by the protocol but not the operator). RESULTS The proposed method categorized 53% of the image realignments in the test dataset as successful, of which 11% were incorrectly categorized (6% of the total dataset). Implementation of the proposed assessment tool resulted in a 45% time savings compared to the same visual inspection applied to all image realignments. CONCLUSIONS The frame-to-frame image realignment assessment tool presented here required less operator time to evaluate realignment success compared to a method requiring visual inspection of all realigned images, while maintaining the same level of accuracy in the realigned dataset. This practical method can be easily implemented at any center with motion monitoring capabilities or, for centers lacking this technology, methods of estimating image realignment parameters that use independent information. In addition, the procedure is flexible, allowing modifications to be made for different tracer types and/or downstream analysis goals.

A scan without evidence is not evidence of absence: Scans without evidence of dopaminergic deficit in a symptomatic leucine‐rich repeat kinase 2 mutation carrier

The basis for SWEDD is unclear, with most cases representing PD mimics but some later developing PD with a dopaminergic deficit.

Exploring the use of shape and texture descriptors of positron emission tomography tracer distribution in imaging studies of neurodegenerative disease

Positron emission tomography (PET) data related to neurodegeneration are most often quantified using methods based on tracer kinetic modeling. In contrast, here we investigate the ability of geometry and texture-based metrics that are independent of kinetic modeling to convey useful information on disease state. The study was performed using data from Parkinson’s disease subjects imaged with 11C-dihydrotetrabenazine and 11C-raclopride. The pattern of the radiotracer distribution in the striatum was quantified using image-based metrics evaluated over multiple regions of interest that were defined on co-registered PET and MRI images. Regression analysis showed a significant degree of correlation between several investigated metrics and clinical evaluations of the disease (p < 0.01). The best results were obtained with the first-order moment invariant of the radioactivity concentration values estimated over the full structural extent of the region as defined by MRI (R2 = 0.94). These results demonstrate that there is clinically relevant quantitative information in the tracer distribution pattern that can be captured using geometric and texture descriptors. Such metrics may provide an alternate and complementary data analysis approach to traditional kinetic modeling.

A positron emission tomography study of norepinephrine transporter occupancy and its correlation with symptom response in depressed patients treated with quetiapine XR

Abstract Background Quetiapine is effective in treating depressive symptoms in major depressive disorder and bipolar disorder, but the mechanisms underlying its antidepressants effects are unknown. Norquetiapine, a metabolite of quetiapine, has high affinity for norepinephrine transporter, which might account for its therapeutic efficacy. Methods In this study, we used positron emission tomography with (S,S)-[11C]O-methyl reboxetine to estimate norepinephrine transporter density and assess the relationship between norepinephrine transporter occupancy by quetiapine XR and improvement in depression in patients with major depressive disorder (n=5) and bipolar disorder (n=5). After the baseline positron emission tomography scan, patients were treated with quetiapine XR with a target dose of 150 mg in major depressive disorder and 300 mg in bipolar disorder. Patients had a second positron emission tomography scan at the end of week 2 and a final scan at week 7. Results Norepinephrine transporter density was significantly lower in locus ceruleus in patients compared with healthy subjects. Further, there was a significant positive correlation between quetiapine XR dose and norepinephrine transporter occupancy in locus ceruleus at week 2. The norepinephrine transporter occupancy at week 2 in hypothalamus but not in other regions predicted improvement in depression as reflected by reduction in MADRS scores from baseline to week 7. The estimated dose of quetiapine XR associated with 50% norepinephrine transporter occupancy in hypothalamus at week 2 was 256 mg and the estimated plasma levels of norquetiapine to achieve 50% norepinephrine transporter occupancy was 36.8 µg/L. Conclusion These data provide preliminary support for the hypothesis that norepinephrine transporter occupancy by norquetiapine may be a contributor to the antidepressant effects of quetiapine.

The effect of LRRK2 mutations on the cholinergic system in manifest and premanifest stages of Parkinson's disease: a cross-sectional PET study

BACKGROUND Markers of neuroinflammation are increased in some patients with LRRK2 Parkinsons disease compared with individuals with idiopathic Parkinsons disease, suggesting possible differences in disease pathogenesis. Previous PET studies have suggested amplified dopamine turnover and preserved serotonergic innervation in LRRK2 mutation carriers. We postulated that patients with LRRK2 mutations might show abnormalities of central cholinergic activity, even before the diagnosis of Parkinsons disease. METHODS Between June, 2009, and December, 2015, we recruited participants from four movement disorder clinics in Canada, Norway, and the USA. Patients with Parkinsons disease were diagnosed by movement disorder neurologists on the basis of the UK Parkinsons Disease Society Brain Bank criteria. LRRK2 carrier status was confirmed by bidirectional Sanger sequencing. We used the PET tracer N-11C-methyl-piperidin-4-yl propionate to scan for acetylcholinesterase activity. The primary outcome measure was rate of acetylcholinesterase hydrolysis, calculated using the striatal input method. We compared acetylcholinesterase hydrolysis rates between groups using ANCOVA, with adjustment for age based on the results of linear regression analysis. FINDINGS We recruited 14 patients with LRRK2 Parkinsons disease, 16 LRRK2 mutation carriers without Parkinsons disease, eight patients with idiopathic Parkinsons disease, and 11 healthy controls. We noted significant between-group differences in rates of acetylcholinesterase hydrolysis in cortical regions (average cortex p=0·009, default mode network-related regions p=0·006, limbic network-related regions p=0·020) and the thalamus (p=0·008). LRRK2 mutation carriers without Parkinsons disease had increased acetylcholinesterase hydrolysis rates compared with healthy controls in the cortex (average cortex, p=0·046). Patients with LRRK2 Parkinsons disease had significantly higher acetylcholinesterase activity in some cortical regions (average cortex p=0·043, default mode network-related regions p=0·021) and the thalamus (thalamus p=0·004) compared with individuals with idiopathic disease. Acetylcholinesterase hydrolysis rates in healthy controls were correlated inversely with age. INTERPRETATION LRRK2 mutations are associated with significantly increased cholinergic activity in the brain in mutation carriers without Parkinsons disease compared with healthy controls and in LRRK2 mutation carriers with Parkinsons disease compared with individuals with idiopathic disease. Changes in cholinergic activity might represent early and sustained attempts to compensate for LRRK2-related dysfunction, or alteration of acetylcholinesterase in non-neuronal cells. FUNDING Michael J Fox Foundation, National Institutes of Health, and Pacific Alzheimer Research Foundation.

Quality control protocol for frame-to-frame PET motion correction

Subject motion during Position Emission Tomography (PET) brain scans can reduce image quality, and may lead to incorrect biological outcome measures, especially during analysis of dynamic data sets. This is particularly relevant when imaging with state-of-the-art scanners such as the High Resolution Research Tomograph (HRRT, Siemens Medical Solutions). Motion correction via frame-to-frame image realignment is simpler to implement and requires fewer computing resources than methods that correct for motion during data reconstruction and has been shown to significantly improve the accuracy of dynamically-derived biological variables. However, an ongoing problem is a lack of objective criteria to validate the accuracy of frame-to-frame realignment. Visual inspection of realigned images is a common method of validation but requires a significant amount of operator time and results may vary from one operator to another. This work presents a quality control protocol that automatically flags inadequate realignments based on the comparison of motion transformation matrices obtained from two independent sources: the Polaris Vicra optical tracking device and the image based realignment algorithm AIR (Automated Image Registration). A metric was computed to determine the difference between the transformations from both methods. Realignments were accepted or flagged based on the value of the metric. Since the two methods rely on independent motion assessment tools, the chance of both algorithms giving consistently wrong estimates is low. Human test cases show that the quality control protocol is capable of correctly identifying both acceptable and incorrect realigned images, thus providing an objective quality control metric. Implementation of the protocol reduces the number of images requiring visual inspection by 72% and operator time required by 50%, decreasing both operator labour and operator-dependent biases.

Investigation of serotonergic Parkinson's disease-related covariance pattern using [11C]-DASB/PET

We used positron emission tomography imaging with [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)- benzonitrile (DASB) and principal component analysis to investigate whether a specific Parkinsons disease (PD)-related spatial covariance pattern could be identified for the serotonergic system. We also explored if non-manifesting leucine-rich repeat kinase 2 (LRRK2) mutation carriers, with normal striatal dopaminergic innervation as measured with [11C]-dihydrotetrabenazine (DTBZ), exhibit a distinct spatial covariance pattern compared to healthy controls and subjects with manifest PD. 15 subjects with sporadic PD, eight subjects with LRRK2 mutation-associated PD, nine LRRK2 non-manifesting mutation carriers, and nine healthy controls participated in the study. The analysis was applied to the DASB non-displaceable binding potential values evaluated in 42 pre-defined regions of interest. PD was found to be associated with a specific spatial covariance pattern, comprising relatively decreased DASB binding in the caudate, putamen and substantia nigra and relatively preserved binding in the hypothalamus and hippocampus; the expression of this pattern in PD subjects was significantly higher than in healthy controls (P < 0.001) and correlated significantly with disease duration (P < 0.01) and with DTBZ binding in the more affected putamen (P < 0.01). The LRRK2 non-manifesting mutation carriers expressed a different pattern, also significantly different from healthy controls (P < 0.001), comprising relatively decreased DASB binding in the pons, pedunculopontine nucleus, thalamus and rostral raphe nucleus, and with relatively preserved binding in the hypothalamus, amygdala, hippocampus and substantia nigra. This pattern was not present in either sporadic or LRRK2 mutation-associated PD subjects. These findings, although obtained with a relatively limited number of subjects, suggest that specific and overall distinct spatial serotonergic patterns may be associated with PD and LRRK2 mutations. Alterations in regions where relative upregulation is observed in both patterns may be indicative of compensatory mechanisms preceding or protecting from disease manifestation.