Research
Original Investigation
The Phosphodiesterase 10 Positron Emission Tomography Tracer, [18F]MNI-659, as a Novel Biomarker for Early Huntington Disease David S. Russell, MD, PhD; Olivier Barret, PhD; Danna L. Jennings, MD; Joseph H. Friedman, MD; Gilles D. Tamagnan, PhD; David Thomae, PhD; David Alagille, PhD; Thomas J. Morley, PhD; Caroline Papin, PhD; Spyridon Papapetropoulos, MD, PhD; Rikki N. Waterhouse, PhD; John P. Seibyl, MD; Kenneth L. Marek, MD
IMPORTANCE In Huntington disease (HD) striatal neuron loss precedes and predicts motor
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signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need. Intracellular proteins whose expression is altered by the mutant huntingtin protein may be superior markers for early HD stages. OBJECTIVE To evaluate whether [18F]MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-
methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a novel phosphodiesterase 10 positron emission tomography (PET) ligand, is a sensitive marker for striatal changes in early HD. DESIGN, SETTING, AND PARTICIPANTS A cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [18F]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging. MAIN OUTCOMES AND MEASURES Binding potentials (BPnds) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between participants with HD and the HVs and correlated with markers of HD severity and atrophy of basal ganglia nuclei. RESULTS Eleven participants with HD (8 mHD and 3 pre-HD) and 9 HVs participated. Ten of 11 HD participants had known huntingtin CAG repeat length, allowing determination of a burden of pathology (BOP) score. One individual with HD declined CAG determination. All participants with mHD had relatively early-stage disease (4 with stage 1 and 4 with stage 2) and a Unified Huntington’s Disease Rating Scale (UHDRS) total Motor subscale score of less than 50. The HD cohort had significantly lower striatal [18F]MNI-659 uptake than did the HV cohort (mean, −48.4%; P < .001). The HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of the level in the HVs (mean, −47.6%; P < .001). The 3 pre-HD participants had intermediate basal ganglia BPnds. Striatal [18F]MNI-659 uptake correlated strongly with the severity of disease measured by the clinical scale (UHDRS Motor subscale; R = 0.903; P < .001), the molecular marker (BOP; R = 0.908; P < .001), and regional atrophy (R = 0.667; P < .05). CONCLUSIONS AND RELEVANCE As a promising striatal imaging biomarker, [18F]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [18F]MNI-659 may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted.
JAMA Neurol. 2014;71(12):1520-1528. doi:10.1001/jamaneurol.2014.1954 Published online October 13, 2014. 1520
Author Affiliations: Institute for Neurodegenerative Disorders, New Haven, Connecticut (Russell, Barret, Jennings, Tamagnan, Thomae, Alagille, Morley, Papin, Seibyl, Marek); Molecular NeuroImaging, LLC, New Haven, Connecticut (Russell, Barret, Jennings, Tamagnan, Thomae, Alagille, Morley, Papin, Seibyl, Marek); Department of Neurology, Alpert Medical School of Brown, Providence, Rhode Island (Friedman); currently with Department of Pharmaceutical Sciences, University Hospital Antwerp, Antwerp, Belgium (Thomae); Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc, Cambridge, Massachusetts (Papapetropoulos, Waterhouse). Corresponding Author: David S. Russell, MD, PhD, Institute for Neurodegenerative Disorders and Molecular NeuroImaging, LLC, 60 Temple St, Ste 8B, New Haven, CT 06510 ([email protected]). jamaneurology.com
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[18F]MNI-659 as Biomarker for Huntington Disease
E
arly disease detection provides a window of opportunity to evaluate initial disease processes and potentially intervene before significant tissue destruction. However, for several degenerative brain conditions, including Huntington disease (HD), significant cell loss exists before the emergence of identifiable signs or symptoms.1 Nuclear imaging has been shown2,3 to have the potential to detect changes in brain biomarkers at an earlier stage in neurodegenerative diseases than can be detected by the clinician. For illnesses involving changes in the brain striatal nuclei, such as HD, several imaging biomarkers have been evaluated.4-6 Phosphodiesterase 10 (PDE10) is a particularly promising marker of early striatal neuron changes.7-9 We conducted a study in early HD using a novel positron emission tomography (PET) radiotracer, [18F]MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4isopropoxyisoindoline-1,3-dione). Alterations in striatal neurons underlie disease pathology in a wide range of brain disorders, from neurodegenerative conditions such as HD to mental illnesses such as addiction. Accurate clarification of the extent and timing of these changes would be beneficial in understanding and treating these diseases. Phosphodiesterase 10 is a promising candidate biomarker of striatal function. Cyclic nucleotide PDEs are ubiquitously expressed, but individual PDE genes display tissue specificity. Unlike most PDE gene families, the PDE10 family consists of only 1 gene and gene product with 2 coexpressed splice variants, present almost exclusively in the striatum.7,9-14 Within the striatum, PDE10 is expressed primarily in all medium spiny neurons (MSNs), where it is thought to play a role in integrating dopaminergic and glutaminergic signals.8,15,16 Phosphodiesterases function by degrading cyclic nucleotides, thus playing roles in many diverse cellular functions.11 Inhibitors of PDE10 are in development for several diseases including schizophrenia, cognitive dysfunction, and hyperkinetic movement disorders. 17-21 In HD mouse models,21 inhibition of PDE10 normalizes molecular abnormalities and, furthermore, slows loss of MSNs. Medium spiny neurons are among the earliest neurons lost in HD,22,23 and substantial loss occurs before the onset of motor abnormalities.24-27 As a marker of MSN loss, PDE10 is an excellent candidate for biomarker development owing to its high level of expression, striatal specificity, and expression within the cell body and throughout cellular compartments.8-10 Furthermore, in mouse models of HD,28-33 PDE10 is among the first proteins to be downregulated in MSNs, perhaps due to direct interference of PDE10 expression by the mutant huntingtin protein. A previous in vitro study34 identified [18F]MNI-659 as a potential PET radiotracer with high specificity for PDE10. This has been confirmed in vivo in nonhuman primates. Studies34 in healthy volunteers (HVs) have shown highly specific uptake in the striatum, good test-retest reliability, accurate estimation of striatal binding potentials by a noninvasive method, and acceptable whole-body radiation dosimetry with no identified safety concerns. In the studies presented here, we evaluated [18F]MNI-659 PET imaging as a biomarker of human striatal PDE10 expression in HD across early diseases stages.
Original Investigation Research
Methods Study Population The study procedures were approved by the New England Institutional Review Board. Written informed consent was obtained from all research participants, and they received a stipend. Individuals were recruited for this study through local neurologists and the Institute for Neurodegenerative Disorders’ clinical database. Twenty individuals were enrolled, including 9 HVs and 11 participants with HD: 3 with premanifest HD (pre-HD) and 8 with manifest HD (mHD). Participants were considered as pre-HD if they had genetic confirmation of an expanded trinucleotide repeat (>39 CAG repeats on chromosome 4p16.3) in the range expected for HD and no apparent motor manifestations specific for HD (ie, a Unified Huntington’s Disease Rating Scale [UHDRS] Motor subscale [UHDRS-M] score of 0 ascertained by a movement disorders specialist).35 Individuals with mHD met International Statistical Classification of Diseases, 10th Revision, diagnostic criteria for symptomatic HD. Two of the 8 patients with mHD exhibited psychiatric manifestations and subtle motor changes without chorea. Participants were aged 18 years or older and were considered medically stable by the clinical investigators. The HV participants had no history of neurologic disease and no current neurologic symptoms. All participants underwent a complete physical and neurologic examination before the study including medical history, electrocardiogram, blood hematology and chemistry testing, and urinalysis. Caffeine ingestion was restricted for 24 hours before imaging and the HVs had no nicotine exposure for 6 months before imaging. Although neither caffeine nor nicotine is known to interfere with PDE10 measurements, these pharmacologic agents were restricted in this early study because they could theoretically affect PDE10 measurements. Brain magnetic resonance imaging (MRI) was obtained on all participants. Individuals with HD were evaluated using the UHDRS-M, the Total Functional Capacity (TFC) scale, and a UHDRS diagnostic confidence level. All clinical assessments were performed by the investigator.35-37 The HD stage was assigned according to the TFC scale (stage 0, pre-HD; stage 1, TFC score 11-13; stage 2, TFC score 7-10; stage 3, TFC score 3-6, and stage 4, TFC score 1-2). The diagnostic confidence levels include 0 (normal), 1 (50% annual risk of conversion) was 5 to 10 years for participant HD-10, 10 to 15 years for patients HD-06 and HD-07, and 15 to 20 years for patients HD-08 and HD-09.
MRI Analysis Total volumes for the caudate, putamen, globus pallidus, striatum, and basal ganglia were measured (eTable in the Supplement). As expected, based on previous studies5,25,42-44 of nuclear volumes in early HD, the caudate nucleus showed the greatest mean reduction in volume. In addition, as expected in a cohort of individuals with early HD, the mean reductions in volumes were modest (≤11% mean reduction in the mHD cohort). The volumes of the nuclei in the HV cohort were comparable to the volumes reported in HV cohorts in other published studies.5,25 The mean volume losses in the nuclei were less pronounced than volumes reported in other studies5,25,42-44 of patients with mHD and more closely resembled late pre-HD cohorts, even though most participants in this cohort had mHD. However, mHD in the present study was more clinically mild than in most comparative mHD groups. This finding supports the assertion that the mHD cohort in the present study represented patients spanning the early stages of HD.
PDE10 PET Imaging All participants underwent 90 minutes of PET imaging following injection of [18F]MNI-659. The mean radioactivity injected was 4.79 mCi (range, 4.42-5.05 mCi) and the mean mass dose was 0.22 μg (range, 0.080-0.390 μg). There was rapid [18F]MNI-659 distribution and high retention throughout the basal ganglia. No technical failures occurred in the present study and all participants who received the injection completed the study. Imaging using [18F]MNI-659 PET was generally well tolerated by the HV and HD participants. Three adverse events were possibly related to the radiopharmaceutical injection pro-
A
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Mean [18F]MNI-659 PET images for the first 90 minutes of acquisition presented in the axial (A), sagittal (B), and coronal (C) planes demonstrated good brain penetrance and high uptake in the basal ganglia, a region rich with phosphodiesterase 10. The color scale represents the standardized uptake value (SUV) from 0.0 to 2.2 in this individual. The bright bilateral structures in red through green are the basal ganglia. The signal was particularly intense in the putamen and globus pallidus. Little uptake was seen in other, nonbasal ganglia brain regions.
cedures or scanning procedures: headache (n = 2) and nausea (n = 1); all were rated as mild and resolved spontaneously. The uptake of [18F]MNI-659 was high in all basal ganglia nuclei (globus palladus ≈ putamen > caudate). Figure 1 shows a typical pattern of uptake in 3 planes in an HV participant, with intense uptake specifically in these nuclei and very low signals in other brain regions. The progression of loss of signal within the basal ganglia can be seen clearly in the 4 images presented in Figure 2. The pre-HD participant in Figure 2 had a reduced signal compared with the HV; the 2 individuals with mHD had a further reduced signal, especially HD-11, who had the highest BOP and UHDRS-M scores and lowest TFC score among the participants. The large reduction in the mean (SD) basal ganglia BPnd between the HV and HD groups was statistically significant (HV, 2.88 [0.50] and HD, 1.51 [0.83]; P < .001 by a 2-tailed t test), as well as selectively within the mean striatum (HV, 2.79 [0.52] and HD, 1.44 [0.81]; P < .001 by a 2-tailed t test). Figure 3 demonstrates that this difference existed to a similar extent and was significant in each of the 3 basal ganglia subnuclei, with the 3 pre-HD individuals clustering among those in the HD cohort with the least signal loss. Despite the small number of participants, the mean reduction in striatal BPnd in the mHD compared with
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Research Original Investigation
Figure 2. Loss of [18F]MNI-659 (2-(2-(3-(4-(2-[18F]Fluoroethoxy)Phenyl)-7-Methyl-4-Oxo-3,4Dihydroquinazolin-2-Yl)Ethyl)-4-Isopropoxyisoindoline-1,3-Dione) Uptake From the Striatum Through the Course of Huntington Disease (HD) A
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the pre-HD participants was statistically significant (mHD, 1.15 [0.68]; pre-HD, 2.21 [0.67]; P < .05). The 2 mHD individuals with diagnostic certainty scores of 2 or less also had less signal loss compared with the other mHD participants, all of whom had diagnostic certainty scores of 4. All of the mHD participants had basal ganglia uptake lower than the lowest of the HVs. Loss of specific striatal biomarkers assessed by PET imaging should correlate with loss of striatal volume determined by MRI. Published pathologic and imaging studies5,25,42-44 show that the loss of caudate volume is the most sensitive marker of early regional atrophy in HD. Loss of [18F]MNI-659 uptake in the caudate correlates with reduction in MRI volume (eFigure in the Supplement). In the present cohort, reduction in [18F]MNI-659 uptake was more pronounced than caudate volume loss. Nine of the 11 participants with HD had [18F]MNI659 loss greater than 1 SD below the mean of our HV cohort, including all of those with mHD. In contrast, only 5 of the 11 HD participants had a caudate volume that was greater than 1 SD below the HV mean. The mean caudate volume loss of the HD cohort relative to the HV cohort was −14.3% (21.6%) compared with a caudate loss of [18F]MNI-659 uptake of −49.2% (30.8%). For the striatum as a whole, the mean volume loss in the HD cohort was −11.4% (19.5%) compared with a loss of −48.4% (30.4%; P < .001) of [ 18 F]MNI-659 uptake. As ex1524
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Brain images are shown for 4 participants ranging from a representative healthy volunteer (HV) to the most affected individuals with HD in the study. A, HV-03. B, Participant HD-10, who had premanifest HD (pre-HD) with a burden of pathology (BOP) of 364. C, Participant HD-02, who had HD stage 1 with a BOP of 410. D, Participant HD-11, who had HD stage 2 with a BOP of 646. The top row shows transaxial T1 magnetic resonance images at the level of the caudate nucleus. The middle row is the corresponding [18F]MNI-659 positron emission tomography (PET) images. The bottom row is the merged image to demonstrate the striatal localization of the PET signal. The PET images are the mean images for the acquisition period from 60 to 90 minutes after injection. Note the progressive loss of striatal [18F]MNI-659 uptake across the clinical stages of HD. The color scale represents the standardized uptake value. The bright bilateral structures in red through green are the striata. The striata are essentially undetectable in participant HD-11. Little uptake was seen in other brain regions for any participant.
pected, the loss of striatal volume correlated with the loss of [18F]MNI-659 uptake (R = 0.667; P < .05). We considered the possibility that the changes in signal observed between these groups derived from the expected differences in nuclei volume owing to HD-associated atrophy. This effect would be most pronounced in smaller or narrower structures, such as the putamen tail, and less in larger, more spherically shaped regions. We estimated the atrophy-related signal loss differences in the putamen in 4 participants spanning the range of disease severity. The signal loss differences never exceeded more than 3% between 3 individuals (HV-03, HD02, and HD-10). For HD-11, clearly the most affected individual in our cohort, there was a signal loss difference ranging from approximately 7% in the globus pallidus to approximately 19% in the caudate compared with the HV. Although this is notable in the patient with more extreme volume loss, it cannot account for the degree of reduction in [18F]MNI-659 uptake observed in the present study. Within the HD cohort as a whole (mHD and pre-HD), the decrease in [18F]MNI-659 PET binding demonstrated a strong inverse correlation with cellular pathology as estimated by BOP (Figure 4A) (R = 0.908; P < .001). Furthermore, the PDE10 loss also strongly correlated with the clinical measure of severity, the UHDRS-M score (Figure 4B) (R = 0.903; P < .001). Among the
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[18F]MNI-659 as Biomarker for Huntington Disease
HVs, there may have been a weak inverse correlation of the striatal signal with age (approximately −0.7%/y; R = 0.659; P = 0.54), but this does not account for the correlations seen with BOP (which corrects for age) or the UHDRS-M scores. With the development of a larger HV database, BPnd in each group could be age adjusted to further refine the observed correlations.
Original Investigation Research
Figure 3. The [18F]MNI-659 (2-(2-(3-(4-(2-[18F]Fluoroethoxy)Phenyl)-7Methyl-4-Oxo-3,4-Dihydroquinazolin-2-Yl)Ethyl)-4Isopropoxyisoindoline-1,3-Dione) Binding Potential (BPnd) Using the Simplified Reference Tissue Method in Select Basal Ganglia Brain Regions in Healthy Volunteer (HV) and Huntington Disease (HD) Cohorts
Discussion Identification of sensitive and reliable biomarkers of disease progression and severity remains an unmet need for several neurodegenerative diseases, including HD, to facilitate basic research and hasten drug development.45 Standard MRI assessments, such as volumetrics, have revealed regional volume loss in early pre-HD.5,25-27,42,46 However, while the average regional volume loss can be relatively large in pre-HD, the measure is variable and has significant overlap with healthy controls even through stage 2 HD. Other MRI methods such as diffusion tensor imaging and MR spectroscopy, may be more useful as early HD biomarkers,4,47 but are still in the early stages of evaluation. Changes in striatal markers revealed by nuclear imaging (PET and single-photon emission computed tomography) have been reported6,48-52 for the dopamine D2 receptor, glucose metabolism, and the γ-aminobutyric acid-a receptor, as well as more complex patterns of change in regional glucose metabolism ratios.53 Of these, D2 receptor binding was found to correlate well with the product of age and CAG repeat length,43 but was not a good predictor of conversion to mHD.52 The current biomarkers are inadequate for the reliable early detection and prediction of conversion to mHD, which is a necessity for the development of diseasemodifying drugs in pre-HD cohorts.54 As a promising biomarker to detect early HD, PDE10 PET imaging with [18F]MNI-659 correlated strongly with markers of disease severity in this small sample. Several possible reasons exist for this potential superiority over prior imaging agents. First, preclinical studies 29-33,55-60 indicated that PDE10 loss is not just linear to neuron loss in the striatum, but also that the mutant huntingtin protein may directly interfere with PDE10 expression, perhaps on levels of both transcription and protein expression. Second, unlike receptors, PDE10 is expressed throughout the perikarya and the processes.8-10 Third, previous studies34 have revealed that [18F]MNI-659 possesses excellent brain penetration, signal to background, and test-retest reliability. The loss of basal ganglia [18F]MNI-659 binding in HD demonstrated in the present study further supports the specificity of the ligand for PDE10. Although the HD population in the present study represents mild disease from stage 0 through stage 2, the findings show that [18F]MNI-659 and PET imaging can clearly detect loss of striatal PDE10, a biomarker of the MSN pathology expected among individuals with HD. The majority of the observed signal must derive from striatal MSNs; however, an additional contribution from other, smaller populations of cells within these regions, such as interneurons, cannot be excluded. The degree of loss seen in this relatively early HD group, to a mean
[18F]MNI-659 Striatal BPnd
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The BPnd within the 3 basal ganglia brain regions of interest is represented. The mean for both groups for each brain region is indicated with a horizontal black bar. The reduction was similar (approximately 50%) and significant (P < .001 in all 3 groups by 2-tailed t test) in all 3 nuclei. mHD indicates manifest HD; pre-HD, premanifest HD.
of approximately 50% of the loss in the control group, is striking when viewed relative to other published imaging biomarkers.4-6,25-27,42,43,45-53 Although with larger sample sizes we might expect some overlap between mild mHD and HV groups, the full separation between these 9 HV participants and 8 mHD individuals in the present study is notable. The correlation with both BOP and the burden of motor symptoms suggests that [18F]MNI-659 PET has the potential to be a useful progression biomarker for early HD and may be superior to other imaging approaches reported.4-6,25-27,42,43,45-53 A different, distinct PDE10 PET tracer ([18F]-JNJ42259152) was recently reported61 to reveal a large reduction in striatal signal in HD. In contrast to our study, the study by Ahmad and colleagues61 did not find any correlations between observed PDE10A tracer binding and clinical disease severity measures. Although this finding supports our conclusion that PDE10 is a robust and sensitive marker of striatal abnormalities in HD, the primary strength of the present study is that [18F]MNI-659 PET correlates strongly with clinical and molecular markers of HD disease severity. Several possibilities exist for this discrepancy, including use of a different tracer, the smaller HD cohort in the Ahmad et al61 study, or a more clinically advanced cohort in the Ahmad et al study that did not include individuals with pre-HD. Such a finding might be predicted if PDE10 loss reaches a very low level by clinically moderate disease (ie, a “floor effect”). Although the number of participants with pre-HD in the present study was too small to make definitive conclusions, it is interesting to speculate on these individuals relative to each other and the other 2 groups (ie, HV and mHD). Given that the 3 pre-HD participants were approximately the same age, the participant with the greater CAG repeat length would be predicted to be the first to convert to mHD, consistent with the
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[18F]MNI-659 as Biomarker for Huntington Disease
Research Original Investigation
Figure 4. Correlation of [18F]MNI-659 (2-(2-(3-(4-(2-[18F]Fluoroethoxy)Phenyl)-7-Methyl-4-Oxo-3,4Dihydroquinazolin-2-Yl)Ethyl)-4-Isopropoxyisoindoline-1,3-Dione) Striatal Binding With Molecular and Clinical Markers of Huntington Disease (HD) Progression B
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lower striatal BPnd. It may be that [18F]MNI-659 uptake is lower in individuals with pre-HD in general than in age-matched HVs, but drops into the mHD range near conversion to mHD. The small cohort sizes and lack of prospective imaging data are limitations of the present study. A larger number of participants and prospective observation will be required to test these hypotheses. Further studies will also be required to correlate findings obtained with the use of [18F]MNI-659 PET with specific clinical features or with other imaging biomarkers and to develop methods to reliably identify a population of individuals near the time of conversion for inclusion in clinical trials.
ARTICLE INFORMATION Accepted for Publication: June 4, 2014. Published Online: October 13, 2014. doi:10.1001/jamaneurol.2014.1954. Author Contributions: Dr Russell had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Russell, Barret, Jennings, Tamagnan, Thomae, Alagille, Morley, Papin, Papapetropoulos, Waterhouse, Seibyl, Marek. Acquisition, analysis, or interpretation of data: Russell, Barret, Jennings, Friedman, Tamagnan, Thomae, Alagille, Morley, Papin, Seibyl, Marek. Drafting of the manuscript: Russell, Marek. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Russell. Obtained funding: Marek. Administrative, technical, or material support: Barret, Jennings, Friedman, Thomae, Morley, Waterhouse, Seibyl. Study supervision: Jennings, Tamagnan, Seibyl, Marek. Conflict of Interest Disclosures: Dr Russell is an employee of Molecular NeuroImaging, LLC, and has served as a consultant for GE Healthcare and Teva Neuroscience. Dr Friedman lectures for GE Healthcare, Teva Neuroscience, and UCB; consults for Addex, Auspex, Lundbeck, Pfizer Inc, Roche, Teva Neuroscience, and UCB; has received funding for research from Avid, EMD Serono, the National Institutes of Health, Schering-Plough, and Teva
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A, Burden of pathology, an estimate of the extent of cellular or molecular disease, for all of the HD participants except the one who declined genetic testing vs the [18F]MNI-659 striatal binding potential (BPnd) for each one (Pearson correlation coefficient, R = 0.908). B, The Unified Huntington’s Disease Rating Scale–Motor subscale score, a marker of clinical severity, against the BPnd for each participant (Pearson correlation coefficient, R = 0.903). Note the strong inverse correlation of each HD marker of disease severity with phosphodiesterase 10 signal across the clinical stages from premanifest (pre-HD) to stage 2 HD. The lines indicate the linear trend lines. The mean striatal BPnd for the HV cohort was not included in the regression analysis.
Conclusions The sensitivity and reliability of [18F]MNI-659 PET for basal ganglia PDE10 in the HV and HD cohorts in this preliminary study demonstrate that this is a promising biomarker for longitudinal studies in pre-HD and mHD, as well as for rapid evaluation of potential HD therapeutics. Furthermore, since many neurologic and psychiatric diseases involve dysfunction within the striatal nuclei, this PET imaging biomarker may have value for studies across a range of brain diseases.
Neuroscience; and receives royalties from Demos Press. Drs Barret, Jennings, Tamagnan, Alagille, Morley, and Papin are employees of Molecular NeuroImaging, LLC. Drs Papapetropoulos and Waterhouse are employees of Pfizer, Inc. Dr Seibyl has an equity interest in Molecular NeuroImaging, LLC, and serves as a consultant to GE Healthcare, Navidea, and Piramal. Dr Marek has ownership in Molecular NeuroImaging, LLC, and has served as a consultant for Bristol-Myers Squibb, Eli Lilly, GE Healthcare, Merck, NeuroPhage Pharmaceuticals, nLife Therapeutics, Pfizer, Piramal, Prothena, and Roche.
disease: from early detection of the at-risk patient to improving pharmacotherapy of later-stage disease. Semin Nucl Med. 2012;42(6):406-414.
Funding/Support: Pfizer, Inc, provided partial funding for the study.
5. Tabrizi SJ, Langbehn DR, Leavitt BR, et al; TRACK-HD investigators. Biological and clinical manifestations of Huntington’s disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol. 2009;8(9): 791-801.
Role of the Funder/Sponsor: Pfizer, Inc, had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. Pfizer, Inc, reviewed the manuscript for proprietary information prior to the decision to submit the manuscript for publication. No changes in the manuscript resulted from this review. Additional Contributions: Pfizer, Inc, provided scientific assistance. REFERENCES 1. Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011;10(1):83-98. 2. Seibyl J, Russell D, Jennings D, Marek K. Neuroimaging over the course of Parkinson’s
3. Jack CR Jr, Knopman DS, Jagust WJ, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 2013; 12(2):207-216. 4. van den Bogaard S, Dumas E, van der Grond J, van Buchem M, Roos R. MRI biomarkers in Huntington’s disease. Front Biosci (Elite Ed). 2012;4: 1910-1925.
6. Paulsen JS. Functional imaging in Huntington’s disease. Exp Neurol. 2009;216(2):272-277. 7. Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology. 2010;59(6):367-374. 8. Xie Z, Adamowicz WO, Eldred WD, et al. Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase. Neuroscience. 2006;139(2):597-607. 9. Seeger TF, Bartlett B, Coskran TM, et al. Immunohistochemical localization of PDE10A in the rat brain. Brain Res. 2003;985(2):113-126.
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[18F]MNI-659 as Biomarker for Huntington Disease
10. Coskran TM, Morton D, Menniti FS, et al. Immunohistochemical localization of phosphodiesterase 10A in multiple mammalian species. J Histochem Cytochem. 2006;54(11): 1205-1213. 11. Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev. 2011;91(2):651-690. 12. Kleppisch T. Phosphodiesterases in the central nervous system. In: Schmidt HHHW, Hofmann F, Stasch J-P, eds. cGMP: Generators, Effectors and Therapeutic Implications. Berlin, Germany: Springer; 2009:71-92. 13. Surapisitchat J, Beavo JA, Ralph AB, Edward AD. Phosphodiesterase Families: Handbook of Cell Signaling. 2nd ed. San Diego, CA: Academic Press; 2010:1409-1414. 14. Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem. 2007;76(1):481-511. 15. Nishi A, Kuroiwa M, Miller DB, et al. Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J Neurosci. 2008;28(42):10460-10471. 16. Nishi A, Kuroiwa M, Shuto T. Mechanisms for the modulation of dopamine D1 receptor signaling in striatal neurons. Front Neuroanat. 2011;5:43. doi: 10.3389/fnana.2011.00043. 17. Wallace TL, Ballard TM, Pouzet B, Riedel WJ, Wettstein JG. Drug targets for cognitive enhancement in neuropsychiatric disorders. Pharmacol Biochem Behav. 2011;99(2):130-145. 18. Kleiman RJ, Kimmel LH, Bove SE, et al. Chronic suppression of phosphodiesterase 10A alters striatal expression of genes responsible for neurotransmitter synthesis, neurotransmission, and signaling pathways implicated in Huntington’s disease. J Pharmacol Exp Ther. 2011;336(1):64-76.
Original Investigation Research
25. Aylward EH, Sparks BF, Field KM, et al. Onset and rate of striatal atrophy in preclinical Huntington disease. Neurology. 2004;63(1):66-72. 26. van den Bogaard SJ, Dumas EM, Acharya TP, et al; TRACK-HD Investigator Group. Early atrophy of pallidum and accumbens nucleus in Huntington’s disease. J Neurol. 2011;258(3):412-420. 27. Henley SMD, Wild EJ, Hobbs NZ, et al. Relationship between CAG repeat length and brain volume in premanifest and early Huntington’s disease. J Neurol. 2009;256(2):203-212.
29. Menalled LB, Kudwa AE, Miller S, et al. Comprehensive behavioral and molecular characterization of a new knock-in mouse model of Huntington’s disease: zQ175. PLoS One. 2012;7(12): e49838. doi:10.1371/journal.pone.0049838.
44. Georgiou-Karistianis N, Scahill R, Tabrizi SJ, Squitieri F, Aylward E. Structural MRI in Huntington’s disease and recommendations for its potential use in clinical trials. Neurosci Biobehav Rev. 2013;37(3):480-490.
30. Hebb ALO, Robertson HA, Denovan-Wright EM. Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington’s disease transgenic mice prior to the onset of motor symptoms. Neuroscience. 2004;123(4):967-981.
45. Weir DW, Sturrock A, Leavitt BR. Development of biomarkers for Huntington’s disease. Lancet Neurol. 2011;10(6):573-590.
31. Hu H, McCaw EA, Hebb ALO, Gomez GT, Denovan-Wright EM. Mutant huntingtin affects the rate of transcription of striatum-specific isoforms of phosphodiesterase 10A. Eur J Neurosci. 2004;20 (12):3351-3363. 32. Rising AC, Xu J, Carlson A, Napoli VV, Denovan-Wright EM, Mandel RJ. Longitudinal behavioral, cross-sectional transcriptional and histopathological characterization of a knock-in mouse model of Huntington’s disease with 140 CAG repeats. Exp Neurol. 2011;228(2):173-182. 33. Desplats PA, Kass KE, Gilmartin T, et al. Selective deficits in the expression of striatal-enriched mRNAs in Huntington’s disease. J Neurochem. 2006;96(3):743-757.
20. Chappie TA, Helal CJ, Hou X. Current landscape of phosphodiesterase 10A (PDE10A) inhibition. J Med Chem. 2012;55(17):7299-7331.
35. Huntington Study Group. Unified Huntington's Disease Rating Scale: reliability and consistency. Mov Disord. 1996;11(2):136-142.
21. Giampà C, Laurenti D, Anzilotti S, Bernardi G, Menniti FS, Fusco FR. Inhibition of the striatal specific phosphodiesterase PDE10A ameliorates striatal and cortical pathology in R6/2 mouse model of Huntington’s disease. PLoS One. 2010;5(10): e13417. doi:10.1371/journal.pone.0013417.
36. Shoulson I, Fahn S. Huntington disease: clinical care and evaluation. Neurology. 1979;29(1):1-3.
24. Aylward EH, Codori AM, Rosenblatt A, et al. Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington’s disease. Mov Disord. 2000;15(3):552-560.
42. Hobbs NZ, Barnes J, Frost C, et al. Onset and progression of pathologic atrophy in Huntington disease: a longitudinal MR imaging study. AJNR Am J Neuroradiol. 2010;31(6):1036-1041. 43. van Oostrom JC, Maguire RP, Verschuuren-Bemelmans CC, et al. Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease. Neurology. 2005; 65(6):941-943.
34. Barret O, Thomae D, Tavares A, et al. Dosimetry and in vivo assessment of two novel PDE10A positron emission tomography radiotracers in human [18F]MNI-659 and [18F]MNI-654. J Nucl Med. 2014;55(8):1297-1304.
23. Albin RL, Reiner A, Anderson KD, et al. Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease. Ann Neurol. 1992;31(4): 425-430.
41. Celen S, Koole M, De Angelis M, et al. Preclinical evaluation of 18F-JNJ41510417 as a radioligand for PET imaging of phosphodiesterase-10A in the brain. J Nucl Med. 2010;51(10):1584-1591.
28. Menalled L, Zanjani H, MacKenzie L, et al. Decrease in striatal enkephalin mRNA in mouse models of Huntington’s disease. Exp Neurol. 2000; 162(2):328-342.
19. Grauer SM, Pulito VL, Navarra RL, et al. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther. 2009;331(2):574-590.
22. Reiner A, Albin RL, Anderson KD, D’Amato CJ, Penney JB, Young AB. Differential loss of striatal projection neurons in Huntington disease. Proc Natl Acad Sci U S A. 1988;85(15):5733-5737.
the development rate of pathology in Huntington’s disease. Ann Neurol. 1997;41(5):689-692.
37. Marder K, Zhao H, Myers RH, et al; Huntington Study Group. Rate of functional decline in Huntington’s disease. Neurology. 2000;54(2): 452-458. 38. Tabrizi SJ, Scahill RI, Owen G, et al; TRACK-HD Investigators. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington’s disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol. 2013;12(7):637-649. 39. Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR; International Huntington’s Disease Collaborative Group. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet. 2004;65 (4):267-277. 40. Penney JB Jr, Vonsattel J-P, MacDonald ME, Gusella JF, Myers RH. CAG repeat number governs
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46. Kipps CM, Duggins AJ, Mahant N, Gomes L, Ashburner J, McCusker EA. Progression of structural neuropathology in preclinical Huntington’s disease: a tensor based morphometry study. J Neurol Neurosurg Psychiatry. 2005;76(5): 650-655. 47. Versluis MJ, van der Grond J, van Buchem MA, van Zijl P, Webb AG. High-field imaging of neurodegenerative diseases. Neuroimaging Clin N Am. 2012;22(2):159-171. 48. Antonini A, Leenders KL, Eidelberg D. [11C]Raclopride-PET studies of the Huntington’s disease rate of progression: relevance of the trinucleotide repeat length. Ann Neurol. 1998;43 (2):253-255. 49. Weeks RA, Piccini P, Harding AE, Brooks DJ. Striatal D1 and D2 dopamine receptor loss in asymptomatic mutation carriers of Huntington’s disease. Ann Neurol. 1996;40(1):49-54. 50. Ciarmiello A, Cannella M, Lastoria S, et al. Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. J Nucl Med. 2006;47(2): 215-222. 51. Pinborg LH, Videbaek C, Hasselbalch SG, et al. Benzodiazepine receptor quantification in Huntington’s disease with [123I]omazenil and SPECT. J Neurol Neurosurg Psychiatry. 2001;70(5): 657-661. 52. van Oostrom JCH, Dekker M, Willemsen ATM, de Jong BM, Roos RAC, Leenders KL. Changes in striatal dopamine D2 receptor binding in pre-clinical Huntington’s disease. Eur J Neurol. 2009;16(2): 226-231. 53. Feigin A, Tang C, Ma Y, et al. Thalamic metabolism and symptom onset in preclinical Huntington’s disease. Brain. 2007;130(Pt 11):28582867. 54. Kieburtz K, Venuto C. TRACK-HD: both promise and disappointment. Lancet Neurol. 2012;11(1): 24-25. 55. Cha J-HJ. Transcriptional signatures in Huntington’s disease. Prog Neurobiol. 2007;83(4): 228-248.
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56. Seredenina T, Luthi-Carter R. What have we learned from gene expression profiles in Huntington’s disease? Neurobiol Dis. 2012;45(1): 83-98.
element-mediated transcription: an early event in exon 1 and full-length cell models of Huntington’s disease that contributes to polyglutamine pathogenesis. J Biol Chem. 2004;279(6):4988-4999.
60. Nucifora FC Jr, Sasaki M, Peters MF, et al. Interference by huntingtin and atrophin-1 with cbp-mediated transcription leading to cellular toxicity. Science. 2001;291(5512):2423-2428.
57. Savas JN, Ma B, Deinhardt K, et al. A role for Huntington disease protein in dendritic RNA granules. J Biol Chem. 2010;285(17):13142-13153.
59. Shimohata T, Nakajima T, Yamada M, et al. Expanded polyglutamine stretches interact with TAFII130, interfering with CREB-dependent transcription. Nat Genet. 2000;26(1):29-36.
61. Ahmad R, Bourgeois S, Postnov A, et al. PET imaging shows loss of striatal PDE10A in patients with Huntington disease. Neurology. 2014;82(3): 279-281.
58. Sugars KL, Brown R, Cook LJ, Swartz J, Rubinsztein DC. Decreased cAMP response
Call for Papers JAMA Neurology is announcing a new journal feature, Clinical Challenge, which will be published quarterly, under the section editorship of Lawrence S. Honig, MD, PhD. The goal of this feature is to present short clinical problems to challenge readers to arrive at the correct diagnosis from a small data set, including images. Readers will see a short clinical synopsis and relevant images or laboratory information allowing them to exercise their diagnostic skills. Actual correct diagnosis and a brief discussion will be available on the following page of the journal or on the Discussion tab online. The overall format of this feature will be like that of the current highly successful feature What is Your Diagnosis?, which has been running since January 2011, available on the web quarterly, only online. Clinical Challenge will be the successor to this feature but will be an integral journal section, viewable interactively online and in the print version of the journal, and indexed like other articles. JAMA Neurology welcomes submissions to this feature, for which any submission should include a maximum of up to 3 authors. The format must include (1) a paragraph introducing and describing the clinical case (no more than 250 words); (2) 1 to 3 figures including imaging, electrophysiological, and/or other laboratory data; (3) 4 multiple-choice potential answers for diagnosis; and (4) a paragraph of discussion (no more than 600 words) disclosing the actual diagnosis (confirmed by conclusive tissue pathology, genetic, or other test), and including up to 10 references. We invite submissions through the standard JAMA Neurology submissions process.
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Original Investigation
The Phosphodiesterase 10 Positron Emission Tomography Tracer, [18F]MNI-659, as a Novel Biomarker for Early Huntington Disease David S. Russell, MD, PhD; Olivier Barret, PhD; Danna L. Jennings, MD; Joseph H. Friedman, MD; Gilles D. Tamagnan, PhD; David Thomae, PhD; David Alagille, PhD; Thomas J. Morley, PhD; Caroline Papin, PhD; Spyridon Papapetropoulos, MD, PhD; Rikki N. Waterhouse, PhD; John P. Seibyl, MD; Kenneth L. Marek, MD
IMPORTANCE In Huntington disease (HD) striatal neuron loss precedes and predicts motor
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signs or symptoms. Current imaging biomarkers lack adequate sensitivity for assessing the early stages of HD. Developing an imaging biomarker for HD spanning the time of onset of motor signs remains a major unmet research need. Intracellular proteins whose expression is altered by the mutant huntingtin protein may be superior markers for early HD stages. OBJECTIVE To evaluate whether [18F]MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)-7-
methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione), a novel phosphodiesterase 10 positron emission tomography (PET) ligand, is a sensitive marker for striatal changes in early HD. DESIGN, SETTING, AND PARTICIPANTS A cohort of individuals with HD, including premanifest (pre-HD) or manifest with motor signs (mHD), underwent clinical assessments, genetic determination, [18F]MNI-659 PET imaging, and brain magnetic resonance imaging. Age-matched healthy volunteers (HVs) also received clinical assessments and PET and magnetic resonance imaging. MAIN OUTCOMES AND MEASURES Binding potentials (BPnds) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between participants with HD and the HVs and correlated with markers of HD severity and atrophy of basal ganglia nuclei. RESULTS Eleven participants with HD (8 mHD and 3 pre-HD) and 9 HVs participated. Ten of 11 HD participants had known huntingtin CAG repeat length, allowing determination of a burden of pathology (BOP) score. One individual with HD declined CAG determination. All participants with mHD had relatively early-stage disease (4 with stage 1 and 4 with stage 2) and a Unified Huntington’s Disease Rating Scale (UHDRS) total Motor subscale score of less than 50. The HD cohort had significantly lower striatal [18F]MNI-659 uptake than did the HV cohort (mean, −48.4%; P < .001). The HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of the level in the HVs (mean, −47.6%; P < .001). The 3 pre-HD participants had intermediate basal ganglia BPnds. Striatal [18F]MNI-659 uptake correlated strongly with the severity of disease measured by the clinical scale (UHDRS Motor subscale; R = 0.903; P < .001), the molecular marker (BOP; R = 0.908; P < .001), and regional atrophy (R = 0.667; P < .05). CONCLUSIONS AND RELEVANCE As a promising striatal imaging biomarker, [18F]MNI-659 is potentially capable of assessing the extent of disease in early mHD. Furthermore, [18F]MNI-659 may identify early changes in medium spiny neurons and serve as a marker to predict conversion to mHD. Additional studies with larger, stratified cohorts of patients with HD and prospective studies of individuals with pre-HD are warranted.
JAMA Neurol. 2014;71(12):1520-1528. doi:10.1001/jamaneurol.2014.1954 Published online October 13, 2014. 1520
Author Affiliations: Institute for Neurodegenerative Disorders, New Haven, Connecticut (Russell, Barret, Jennings, Tamagnan, Thomae, Alagille, Morley, Papin, Seibyl, Marek); Molecular NeuroImaging, LLC, New Haven, Connecticut (Russell, Barret, Jennings, Tamagnan, Thomae, Alagille, Morley, Papin, Seibyl, Marek); Department of Neurology, Alpert Medical School of Brown, Providence, Rhode Island (Friedman); currently with Department of Pharmaceutical Sciences, University Hospital Antwerp, Antwerp, Belgium (Thomae); Neuroscience Research Unit, Worldwide Research and Development, Pfizer, Inc, Cambridge, Massachusetts (Papapetropoulos, Waterhouse). Corresponding Author: David S. Russell, MD, PhD, Institute for Neurodegenerative Disorders and Molecular NeuroImaging, LLC, 60 Temple St, Ste 8B, New Haven, CT 06510 ([email protected]). jamaneurology.com
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[18F]MNI-659 as Biomarker for Huntington Disease
E
arly disease detection provides a window of opportunity to evaluate initial disease processes and potentially intervene before significant tissue destruction. However, for several degenerative brain conditions, including Huntington disease (HD), significant cell loss exists before the emergence of identifiable signs or symptoms.1 Nuclear imaging has been shown2,3 to have the potential to detect changes in brain biomarkers at an earlier stage in neurodegenerative diseases than can be detected by the clinician. For illnesses involving changes in the brain striatal nuclei, such as HD, several imaging biomarkers have been evaluated.4-6 Phosphodiesterase 10 (PDE10) is a particularly promising marker of early striatal neuron changes.7-9 We conducted a study in early HD using a novel positron emission tomography (PET) radiotracer, [18F]MNI-659 (2-(2-(3-(4-(2-[18F]fluoroethoxy)phenyl)7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4isopropoxyisoindoline-1,3-dione). Alterations in striatal neurons underlie disease pathology in a wide range of brain disorders, from neurodegenerative conditions such as HD to mental illnesses such as addiction. Accurate clarification of the extent and timing of these changes would be beneficial in understanding and treating these diseases. Phosphodiesterase 10 is a promising candidate biomarker of striatal function. Cyclic nucleotide PDEs are ubiquitously expressed, but individual PDE genes display tissue specificity. Unlike most PDE gene families, the PDE10 family consists of only 1 gene and gene product with 2 coexpressed splice variants, present almost exclusively in the striatum.7,9-14 Within the striatum, PDE10 is expressed primarily in all medium spiny neurons (MSNs), where it is thought to play a role in integrating dopaminergic and glutaminergic signals.8,15,16 Phosphodiesterases function by degrading cyclic nucleotides, thus playing roles in many diverse cellular functions.11 Inhibitors of PDE10 are in development for several diseases including schizophrenia, cognitive dysfunction, and hyperkinetic movement disorders. 17-21 In HD mouse models,21 inhibition of PDE10 normalizes molecular abnormalities and, furthermore, slows loss of MSNs. Medium spiny neurons are among the earliest neurons lost in HD,22,23 and substantial loss occurs before the onset of motor abnormalities.24-27 As a marker of MSN loss, PDE10 is an excellent candidate for biomarker development owing to its high level of expression, striatal specificity, and expression within the cell body and throughout cellular compartments.8-10 Furthermore, in mouse models of HD,28-33 PDE10 is among the first proteins to be downregulated in MSNs, perhaps due to direct interference of PDE10 expression by the mutant huntingtin protein. A previous in vitro study34 identified [18F]MNI-659 as a potential PET radiotracer with high specificity for PDE10. This has been confirmed in vivo in nonhuman primates. Studies34 in healthy volunteers (HVs) have shown highly specific uptake in the striatum, good test-retest reliability, accurate estimation of striatal binding potentials by a noninvasive method, and acceptable whole-body radiation dosimetry with no identified safety concerns. In the studies presented here, we evaluated [18F]MNI-659 PET imaging as a biomarker of human striatal PDE10 expression in HD across early diseases stages.
Original Investigation Research
Methods Study Population The study procedures were approved by the New England Institutional Review Board. Written informed consent was obtained from all research participants, and they received a stipend. Individuals were recruited for this study through local neurologists and the Institute for Neurodegenerative Disorders’ clinical database. Twenty individuals were enrolled, including 9 HVs and 11 participants with HD: 3 with premanifest HD (pre-HD) and 8 with manifest HD (mHD). Participants were considered as pre-HD if they had genetic confirmation of an expanded trinucleotide repeat (>39 CAG repeats on chromosome 4p16.3) in the range expected for HD and no apparent motor manifestations specific for HD (ie, a Unified Huntington’s Disease Rating Scale [UHDRS] Motor subscale [UHDRS-M] score of 0 ascertained by a movement disorders specialist).35 Individuals with mHD met International Statistical Classification of Diseases, 10th Revision, diagnostic criteria for symptomatic HD. Two of the 8 patients with mHD exhibited psychiatric manifestations and subtle motor changes without chorea. Participants were aged 18 years or older and were considered medically stable by the clinical investigators. The HV participants had no history of neurologic disease and no current neurologic symptoms. All participants underwent a complete physical and neurologic examination before the study including medical history, electrocardiogram, blood hematology and chemistry testing, and urinalysis. Caffeine ingestion was restricted for 24 hours before imaging and the HVs had no nicotine exposure for 6 months before imaging. Although neither caffeine nor nicotine is known to interfere with PDE10 measurements, these pharmacologic agents were restricted in this early study because they could theoretically affect PDE10 measurements. Brain magnetic resonance imaging (MRI) was obtained on all participants. Individuals with HD were evaluated using the UHDRS-M, the Total Functional Capacity (TFC) scale, and a UHDRS diagnostic confidence level. All clinical assessments were performed by the investigator.35-37 The HD stage was assigned according to the TFC scale (stage 0, pre-HD; stage 1, TFC score 11-13; stage 2, TFC score 7-10; stage 3, TFC score 3-6, and stage 4, TFC score 1-2). The diagnostic confidence levels include 0 (normal), 1 (50% annual risk of conversion) was 5 to 10 years for participant HD-10, 10 to 15 years for patients HD-06 and HD-07, and 15 to 20 years for patients HD-08 and HD-09.
MRI Analysis Total volumes for the caudate, putamen, globus pallidus, striatum, and basal ganglia were measured (eTable in the Supplement). As expected, based on previous studies5,25,42-44 of nuclear volumes in early HD, the caudate nucleus showed the greatest mean reduction in volume. In addition, as expected in a cohort of individuals with early HD, the mean reductions in volumes were modest (≤11% mean reduction in the mHD cohort). The volumes of the nuclei in the HV cohort were comparable to the volumes reported in HV cohorts in other published studies.5,25 The mean volume losses in the nuclei were less pronounced than volumes reported in other studies5,25,42-44 of patients with mHD and more closely resembled late pre-HD cohorts, even though most participants in this cohort had mHD. However, mHD in the present study was more clinically mild than in most comparative mHD groups. This finding supports the assertion that the mHD cohort in the present study represented patients spanning the early stages of HD.
PDE10 PET Imaging All participants underwent 90 minutes of PET imaging following injection of [18F]MNI-659. The mean radioactivity injected was 4.79 mCi (range, 4.42-5.05 mCi) and the mean mass dose was 0.22 μg (range, 0.080-0.390 μg). There was rapid [18F]MNI-659 distribution and high retention throughout the basal ganglia. No technical failures occurred in the present study and all participants who received the injection completed the study. Imaging using [18F]MNI-659 PET was generally well tolerated by the HV and HD participants. Three adverse events were possibly related to the radiopharmaceutical injection pro-
A
B
C
0.0
SUV
2.2
Mean [18F]MNI-659 PET images for the first 90 minutes of acquisition presented in the axial (A), sagittal (B), and coronal (C) planes demonstrated good brain penetrance and high uptake in the basal ganglia, a region rich with phosphodiesterase 10. The color scale represents the standardized uptake value (SUV) from 0.0 to 2.2 in this individual. The bright bilateral structures in red through green are the basal ganglia. The signal was particularly intense in the putamen and globus pallidus. Little uptake was seen in other, nonbasal ganglia brain regions.
cedures or scanning procedures: headache (n = 2) and nausea (n = 1); all were rated as mild and resolved spontaneously. The uptake of [18F]MNI-659 was high in all basal ganglia nuclei (globus palladus ≈ putamen > caudate). Figure 1 shows a typical pattern of uptake in 3 planes in an HV participant, with intense uptake specifically in these nuclei and very low signals in other brain regions. The progression of loss of signal within the basal ganglia can be seen clearly in the 4 images presented in Figure 2. The pre-HD participant in Figure 2 had a reduced signal compared with the HV; the 2 individuals with mHD had a further reduced signal, especially HD-11, who had the highest BOP and UHDRS-M scores and lowest TFC score among the participants. The large reduction in the mean (SD) basal ganglia BPnd between the HV and HD groups was statistically significant (HV, 2.88 [0.50] and HD, 1.51 [0.83]; P < .001 by a 2-tailed t test), as well as selectively within the mean striatum (HV, 2.79 [0.52] and HD, 1.44 [0.81]; P < .001 by a 2-tailed t test). Figure 3 demonstrates that this difference existed to a similar extent and was significant in each of the 3 basal ganglia subnuclei, with the 3 pre-HD individuals clustering among those in the HD cohort with the least signal loss. Despite the small number of participants, the mean reduction in striatal BPnd in the mHD compared with
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Research Original Investigation
Figure 2. Loss of [18F]MNI-659 (2-(2-(3-(4-(2-[18F]Fluoroethoxy)Phenyl)-7-Methyl-4-Oxo-3,4Dihydroquinazolin-2-Yl)Ethyl)-4-Isopropoxyisoindoline-1,3-Dione) Uptake From the Striatum Through the Course of Huntington Disease (HD) A
HV
B
Pre-HD
C
HD-1
the pre-HD participants was statistically significant (mHD, 1.15 [0.68]; pre-HD, 2.21 [0.67]; P < .05). The 2 mHD individuals with diagnostic certainty scores of 2 or less also had less signal loss compared with the other mHD participants, all of whom had diagnostic certainty scores of 4. All of the mHD participants had basal ganglia uptake lower than the lowest of the HVs. Loss of specific striatal biomarkers assessed by PET imaging should correlate with loss of striatal volume determined by MRI. Published pathologic and imaging studies5,25,42-44 show that the loss of caudate volume is the most sensitive marker of early regional atrophy in HD. Loss of [18F]MNI-659 uptake in the caudate correlates with reduction in MRI volume (eFigure in the Supplement). In the present cohort, reduction in [18F]MNI-659 uptake was more pronounced than caudate volume loss. Nine of the 11 participants with HD had [18F]MNI659 loss greater than 1 SD below the mean of our HV cohort, including all of those with mHD. In contrast, only 5 of the 11 HD participants had a caudate volume that was greater than 1 SD below the HV mean. The mean caudate volume loss of the HD cohort relative to the HV cohort was −14.3% (21.6%) compared with a caudate loss of [18F]MNI-659 uptake of −49.2% (30.8%). For the striatum as a whole, the mean volume loss in the HD cohort was −11.4% (19.5%) compared with a loss of −48.4% (30.4%; P < .001) of [ 18 F]MNI-659 uptake. As ex1524
D
HD-2
Brain images are shown for 4 participants ranging from a representative healthy volunteer (HV) to the most affected individuals with HD in the study. A, HV-03. B, Participant HD-10, who had premanifest HD (pre-HD) with a burden of pathology (BOP) of 364. C, Participant HD-02, who had HD stage 1 with a BOP of 410. D, Participant HD-11, who had HD stage 2 with a BOP of 646. The top row shows transaxial T1 magnetic resonance images at the level of the caudate nucleus. The middle row is the corresponding [18F]MNI-659 positron emission tomography (PET) images. The bottom row is the merged image to demonstrate the striatal localization of the PET signal. The PET images are the mean images for the acquisition period from 60 to 90 minutes after injection. Note the progressive loss of striatal [18F]MNI-659 uptake across the clinical stages of HD. The color scale represents the standardized uptake value. The bright bilateral structures in red through green are the striata. The striata are essentially undetectable in participant HD-11. Little uptake was seen in other brain regions for any participant.
pected, the loss of striatal volume correlated with the loss of [18F]MNI-659 uptake (R = 0.667; P < .05). We considered the possibility that the changes in signal observed between these groups derived from the expected differences in nuclei volume owing to HD-associated atrophy. This effect would be most pronounced in smaller or narrower structures, such as the putamen tail, and less in larger, more spherically shaped regions. We estimated the atrophy-related signal loss differences in the putamen in 4 participants spanning the range of disease severity. The signal loss differences never exceeded more than 3% between 3 individuals (HV-03, HD02, and HD-10). For HD-11, clearly the most affected individual in our cohort, there was a signal loss difference ranging from approximately 7% in the globus pallidus to approximately 19% in the caudate compared with the HV. Although this is notable in the patient with more extreme volume loss, it cannot account for the degree of reduction in [18F]MNI-659 uptake observed in the present study. Within the HD cohort as a whole (mHD and pre-HD), the decrease in [18F]MNI-659 PET binding demonstrated a strong inverse correlation with cellular pathology as estimated by BOP (Figure 4A) (R = 0.908; P < .001). Furthermore, the PDE10 loss also strongly correlated with the clinical measure of severity, the UHDRS-M score (Figure 4B) (R = 0.903; P < .001). Among the
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[18F]MNI-659 as Biomarker for Huntington Disease
HVs, there may have been a weak inverse correlation of the striatal signal with age (approximately −0.7%/y; R = 0.659; P = 0.54), but this does not account for the correlations seen with BOP (which corrects for age) or the UHDRS-M scores. With the development of a larger HV database, BPnd in each group could be age adjusted to further refine the observed correlations.
Original Investigation Research
Figure 3. The [18F]MNI-659 (2-(2-(3-(4-(2-[18F]Fluoroethoxy)Phenyl)-7Methyl-4-Oxo-3,4-Dihydroquinazolin-2-Yl)Ethyl)-4Isopropoxyisoindoline-1,3-Dione) Binding Potential (BPnd) Using the Simplified Reference Tissue Method in Select Basal Ganglia Brain Regions in Healthy Volunteer (HV) and Huntington Disease (HD) Cohorts
Discussion Identification of sensitive and reliable biomarkers of disease progression and severity remains an unmet need for several neurodegenerative diseases, including HD, to facilitate basic research and hasten drug development.45 Standard MRI assessments, such as volumetrics, have revealed regional volume loss in early pre-HD.5,25-27,42,46 However, while the average regional volume loss can be relatively large in pre-HD, the measure is variable and has significant overlap with healthy controls even through stage 2 HD. Other MRI methods such as diffusion tensor imaging and MR spectroscopy, may be more useful as early HD biomarkers,4,47 but are still in the early stages of evaluation. Changes in striatal markers revealed by nuclear imaging (PET and single-photon emission computed tomography) have been reported6,48-52 for the dopamine D2 receptor, glucose metabolism, and the γ-aminobutyric acid-a receptor, as well as more complex patterns of change in regional glucose metabolism ratios.53 Of these, D2 receptor binding was found to correlate well with the product of age and CAG repeat length,43 but was not a good predictor of conversion to mHD.52 The current biomarkers are inadequate for the reliable early detection and prediction of conversion to mHD, which is a necessity for the development of diseasemodifying drugs in pre-HD cohorts.54 As a promising biomarker to detect early HD, PDE10 PET imaging with [18F]MNI-659 correlated strongly with markers of disease severity in this small sample. Several possible reasons exist for this potential superiority over prior imaging agents. First, preclinical studies 29-33,55-60 indicated that PDE10 loss is not just linear to neuron loss in the striatum, but also that the mutant huntingtin protein may directly interfere with PDE10 expression, perhaps on levels of both transcription and protein expression. Second, unlike receptors, PDE10 is expressed throughout the perikarya and the processes.8-10 Third, previous studies34 have revealed that [18F]MNI-659 possesses excellent brain penetration, signal to background, and test-retest reliability. The loss of basal ganglia [18F]MNI-659 binding in HD demonstrated in the present study further supports the specificity of the ligand for PDE10. Although the HD population in the present study represents mild disease from stage 0 through stage 2, the findings show that [18F]MNI-659 and PET imaging can clearly detect loss of striatal PDE10, a biomarker of the MSN pathology expected among individuals with HD. The majority of the observed signal must derive from striatal MSNs; however, an additional contribution from other, smaller populations of cells within these regions, such as interneurons, cannot be excluded. The degree of loss seen in this relatively early HD group, to a mean
[18F]MNI-659 Striatal BPnd
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The BPnd within the 3 basal ganglia brain regions of interest is represented. The mean for both groups for each brain region is indicated with a horizontal black bar. The reduction was similar (approximately 50%) and significant (P < .001 in all 3 groups by 2-tailed t test) in all 3 nuclei. mHD indicates manifest HD; pre-HD, premanifest HD.
of approximately 50% of the loss in the control group, is striking when viewed relative to other published imaging biomarkers.4-6,25-27,42,43,45-53 Although with larger sample sizes we might expect some overlap between mild mHD and HV groups, the full separation between these 9 HV participants and 8 mHD individuals in the present study is notable. The correlation with both BOP and the burden of motor symptoms suggests that [18F]MNI-659 PET has the potential to be a useful progression biomarker for early HD and may be superior to other imaging approaches reported.4-6,25-27,42,43,45-53 A different, distinct PDE10 PET tracer ([18F]-JNJ42259152) was recently reported61 to reveal a large reduction in striatal signal in HD. In contrast to our study, the study by Ahmad and colleagues61 did not find any correlations between observed PDE10A tracer binding and clinical disease severity measures. Although this finding supports our conclusion that PDE10 is a robust and sensitive marker of striatal abnormalities in HD, the primary strength of the present study is that [18F]MNI-659 PET correlates strongly with clinical and molecular markers of HD disease severity. Several possibilities exist for this discrepancy, including use of a different tracer, the smaller HD cohort in the Ahmad et al61 study, or a more clinically advanced cohort in the Ahmad et al study that did not include individuals with pre-HD. Such a finding might be predicted if PDE10 loss reaches a very low level by clinically moderate disease (ie, a “floor effect”). Although the number of participants with pre-HD in the present study was too small to make definitive conclusions, it is interesting to speculate on these individuals relative to each other and the other 2 groups (ie, HV and mHD). Given that the 3 pre-HD participants were approximately the same age, the participant with the greater CAG repeat length would be predicted to be the first to convert to mHD, consistent with the
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Research Original Investigation
Figure 4. Correlation of [18F]MNI-659 (2-(2-(3-(4-(2-[18F]Fluoroethoxy)Phenyl)-7-Methyl-4-Oxo-3,4Dihydroquinazolin-2-Yl)Ethyl)-4-Isopropoxyisoindoline-1,3-Dione) Striatal Binding With Molecular and Clinical Markers of Huntington Disease (HD) Progression B
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lower striatal BPnd. It may be that [18F]MNI-659 uptake is lower in individuals with pre-HD in general than in age-matched HVs, but drops into the mHD range near conversion to mHD. The small cohort sizes and lack of prospective imaging data are limitations of the present study. A larger number of participants and prospective observation will be required to test these hypotheses. Further studies will also be required to correlate findings obtained with the use of [18F]MNI-659 PET with specific clinical features or with other imaging biomarkers and to develop methods to reliably identify a population of individuals near the time of conversion for inclusion in clinical trials.
ARTICLE INFORMATION Accepted for Publication: June 4, 2014. Published Online: October 13, 2014. doi:10.1001/jamaneurol.2014.1954. Author Contributions: Dr Russell had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Russell, Barret, Jennings, Tamagnan, Thomae, Alagille, Morley, Papin, Papapetropoulos, Waterhouse, Seibyl, Marek. Acquisition, analysis, or interpretation of data: Russell, Barret, Jennings, Friedman, Tamagnan, Thomae, Alagille, Morley, Papin, Seibyl, Marek. Drafting of the manuscript: Russell, Marek. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Russell. Obtained funding: Marek. Administrative, technical, or material support: Barret, Jennings, Friedman, Thomae, Morley, Waterhouse, Seibyl. Study supervision: Jennings, Tamagnan, Seibyl, Marek. Conflict of Interest Disclosures: Dr Russell is an employee of Molecular NeuroImaging, LLC, and has served as a consultant for GE Healthcare and Teva Neuroscience. Dr Friedman lectures for GE Healthcare, Teva Neuroscience, and UCB; consults for Addex, Auspex, Lundbeck, Pfizer Inc, Roche, Teva Neuroscience, and UCB; has received funding for research from Avid, EMD Serono, the National Institutes of Health, Schering-Plough, and Teva
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10
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30
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50
Unified Huntington’s Disease Rating Scale–Motor Subscale Score
Burden of Pathology
A, Burden of pathology, an estimate of the extent of cellular or molecular disease, for all of the HD participants except the one who declined genetic testing vs the [18F]MNI-659 striatal binding potential (BPnd) for each one (Pearson correlation coefficient, R = 0.908). B, The Unified Huntington’s Disease Rating Scale–Motor subscale score, a marker of clinical severity, against the BPnd for each participant (Pearson correlation coefficient, R = 0.903). Note the strong inverse correlation of each HD marker of disease severity with phosphodiesterase 10 signal across the clinical stages from premanifest (pre-HD) to stage 2 HD. The lines indicate the linear trend lines. The mean striatal BPnd for the HV cohort was not included in the regression analysis.
Conclusions The sensitivity and reliability of [18F]MNI-659 PET for basal ganglia PDE10 in the HV and HD cohorts in this preliminary study demonstrate that this is a promising biomarker for longitudinal studies in pre-HD and mHD, as well as for rapid evaluation of potential HD therapeutics. Furthermore, since many neurologic and psychiatric diseases involve dysfunction within the striatal nuclei, this PET imaging biomarker may have value for studies across a range of brain diseases.
Neuroscience; and receives royalties from Demos Press. Drs Barret, Jennings, Tamagnan, Alagille, Morley, and Papin are employees of Molecular NeuroImaging, LLC. Drs Papapetropoulos and Waterhouse are employees of Pfizer, Inc. Dr Seibyl has an equity interest in Molecular NeuroImaging, LLC, and serves as a consultant to GE Healthcare, Navidea, and Piramal. Dr Marek has ownership in Molecular NeuroImaging, LLC, and has served as a consultant for Bristol-Myers Squibb, Eli Lilly, GE Healthcare, Merck, NeuroPhage Pharmaceuticals, nLife Therapeutics, Pfizer, Piramal, Prothena, and Roche.
disease: from early detection of the at-risk patient to improving pharmacotherapy of later-stage disease. Semin Nucl Med. 2012;42(6):406-414.
Funding/Support: Pfizer, Inc, provided partial funding for the study.
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Role of the Funder/Sponsor: Pfizer, Inc, had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. Pfizer, Inc, reviewed the manuscript for proprietary information prior to the decision to submit the manuscript for publication. No changes in the manuscript resulted from this review. Additional Contributions: Pfizer, Inc, provided scientific assistance. REFERENCES 1. Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011;10(1):83-98. 2. Seibyl J, Russell D, Jennings D, Marek K. Neuroimaging over the course of Parkinson’s
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[18F]MNI-659 as Biomarker for Huntington Disease
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Call for Papers JAMA Neurology is announcing a new journal feature, Clinical Challenge, which will be published quarterly, under the section editorship of Lawrence S. Honig, MD, PhD. The goal of this feature is to present short clinical problems to challenge readers to arrive at the correct diagnosis from a small data set, including images. Readers will see a short clinical synopsis and relevant images or laboratory information allowing them to exercise their diagnostic skills. Actual correct diagnosis and a brief discussion will be available on the following page of the journal or on the Discussion tab online. The overall format of this feature will be like that of the current highly successful feature What is Your Diagnosis?, which has been running since January 2011, available on the web quarterly, only online. Clinical Challenge will be the successor to this feature but will be an integral journal section, viewable interactively online and in the print version of the journal, and indexed like other articles. JAMA Neurology welcomes submissions to this feature, for which any submission should include a maximum of up to 3 authors. The format must include (1) a paragraph introducing and describing the clinical case (no more than 250 words); (2) 1 to 3 figures including imaging, electrophysiological, and/or other laboratory data; (3) 4 multiple-choice potential answers for diagnosis; and (4) a paragraph of discussion (no more than 600 words) disclosing the actual diagnosis (confirmed by conclusive tissue pathology, genetic, or other test), and including up to 10 references. We invite submissions through the standard JAMA Neurology submissions process.
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