HD Insights of the Year
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HD Insights recognized three papers from 2016 with awards. Flavia Niccolini of King's College London won for "Altered PDE10A Expression Detectable Early Before Symptomatic Onset in Huntington's Disease." Jong-Min Lee of the GeM-HD Consortium, won for "Genetic Modifiers of HD"
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HD Insights of the Year
- 1. HD Insights Insights of the Year Michael Geschwind, MD, PhD UCSF Memory and Aging Center
- 2. Most Influential Insights HSG 2016: DISCOVERING OUR FUTURE In imaging and biomarkers… Altered PDE10A expression detectable early before symptomatic onset in HD Presented by: Flavia Niccolini, PhD In the clinic… Identification of genetic factors that modify clinical onset of Huntington’s disease Presented by: Jong-Min Lee, PhD
- 3. Institute of Psychiatry, Psychology and Neuroscience (IoPPN) Department of Basic and Clinical Neuroscience ALTERED PDE10A EXPRESSION DETECTABLE EARLY BEFORE SYMPTOMATIC ONSET IN HUNTINGTON’S DISEASE Niccolini F, Haider S, Reis Marques T, Muhlert N, Tziortzi AC, Searle GE, Natesan S, Piccini P, Kapur S, Rabiner EA, Gunn RN, Tabrizi SJ and Politis M Neurodegeneration Imaging Group www.nig-politis.com
- 4. PDE10Awww.nig-politis.com extracellular intracellular DA DA STRIATUM AC D1R D2R β γ PKA ATP cAMP DA DA CA DA DA DA DADA PDE10A DARP32-CREB Gsα DA DA CA DA DA DA DA DA DA DA DA DA DA
- 5. PDE10A & HDwww.nig-politis.com o Preclinical research in transgenic HD animal models suggests a direct effect of mutant huntingtin on PDE-10A expression via the alteration of transcription, synthesis and trafficking Hu et al., 2004; Leuti et al., 2013 Leuti et al., 2013 Hebb et al., 2004
- 6. PDE10A inhibition & HDwww.nig-politis.com Giampà et al., 2009, 2010
- 7. AIMwww.nig-politis.com To study a unique cohort of Early Premanifest HD gene expansion carriers (HDGECs) and investigate the expression of PDE10A enzyme using [11C]IMA107 PET molecular imaging Participants o 12 early premanifest HDGECs who were the furthest from the predicted disease onset o 12 aged and sex-matched healthy controls
- 8. Study procedures - 1 Motor: UHDRS TMS Cognitive: CANTAB® : o Psychomotor speed: RTI o Episodic memory: PAL & PRM o Working memory & executive function: OTS o Language processing: GNT Neuropsychiatric : • PBA-S • BDI-II • HDRS Clinical assessments: Functional capacity: • UHDRS-TFC • UHDRS-IS • UHDRS-FAS • SF-36 www.nig-politis.com
- 9. Study procedures - 2 Imaging assessments: • One [11C]IMA107 PET scan (no arterial metabolites, 90 min) • One 3-T MRI scan (T1-weighted; FGATIR; FLAWS; DTI 32 Dir BLIPUP & BLIPDOWN) PET analysis • Frame-by-frame realignment for movement correction • SRTM – cerebellum reference, coreg, BPND MRI analysis • FreeSurfer’s image analysis suite (version 5.3.0 ) • VBM morphometry SPM8 software package www.nig-politis.com Mansur et al., 2016
- 10. www.nig-politis.com Clinical characteristics Healthy controls Premanifest HDGECs No (Sex) 12 (8M/4F) 12 (7M/5F) Age (years ± SD) 40.0 (±6.2) 41.1 (±7.5) CAGr (± SD) [range] - 41.8 (±1.3) [40-44] DBS1 (± SD) [range] - 254.4 (± 46.8) [153-323] 90% p to onset2 (years ±SD) [range] - 25 (±6.9) [17-43] UHDRS TMS (±SD) 0 (±0) 0 (±0) UHDRS DCL (±SD) - 0 (±0) 1Disease burden score: age x (CAG length–35.5); 290% p to onset: Paulsen et al., 2008
- 11. Clinical assessmentswww.nig-politis.com Healthy controls Premanifest HDGECs P values UHDRS-TMS (±SD) 0 (±0) 0 (±0) - UHDRS-TFC (±SD) 13 (±0) 13 (±0) - UHDRS-IS (±SD) 100 (±0) 100 (±0) - UHDRS-FAS (±SD) 25 (±0) 25 (±0) - SF-36 (±SD) 94.71 (±2.2) 92.28 (±4.4) 0.12 Motor and functional measures
- 12. Clinical assessmentswww.nig-politis.com Healthy controls Premanifest HDGECs P values Episodic Memory PAL Memory score (±SD) 21.00 (±2.5) 20.08 (±2.9) 0.97 PAL Stages completed on 1st trial (±SD) 6.00 (±0) 6.08 (±0.7) 0.79 PRM No correct (±SD) 21.40 (±2.2) 21.67 (±2.3) 0.99 PRM Mean latency to correct (±SD) [msec] 1686.92 (±533.9) 2159.50 (±610.1) 0.10 Working memory & Executive Functions OTS Mean latency to correct (±SD) 13668.93 (±9688) 13176.69 (±8334) 0.75 OTS Problems solved on 1st choice (±SD) 15.60 (±2.7) 17.10 (±2.5) 0.29 Cognitive measures - 1
- 13. Clinical assessmentswww.nig-politis.com Healthy controls Premanifest HDGECs P values Psychomotor Speed Simple movement time (±SD) [msec] 431. 24 (±99.5) 371.41 (±90.4) 0.32 Simple reaction time (±SD) [msec] 299.80 (±60.5) 319.34 (±44.5) 0.43 5-choice movement time (±SD) [msec] 408.78 (±82.7) 368.10 (±71.8) 0.25 5 choice reaction time (±SD) [msec] 331.00 (±61.8) 324.78 (±111.1) 0.47 Language processing GNT Total errors (±SD) 8.00 (±6.8) 5.67 (±2.3) 0.29 Cognitive measures - 2
- 14. Clinical assessmentswww.nig-politis.com Healthy controls Premanifest HDGECs P values PBA apathy (±SD) 0 (±0) 0.08 (±0.3) 0.54 PBA affect (±SD) 0 (±0) 1 (±1.8) 0.20 PBA irritability (±SD) 0 (±0) 1.6 (±2.2) 0.13 BDI-II (±SD) 2.4 (±2.9) 4.7 (±5.3) 0.40 HDRS (±SD) 1.4 (±2.1) 4.2 (±5.5) 0.30 Neuropsychiatric measures
- 15. Freesurfer MRI volumetric analysis www.nig-politis.com Healthy controls Premanifest HDGECs P values Caudate (±SD) [mm3] 3803.08 (±428.9) 3538.58 (±571.9) >1.0 Putamen (±SD) [mm3] 5587.29 (±529.5) 4996.00 (±771.0) 0.31 Pallidum (±SD) [mm3] 1454.29 (±147.2) 1287.50 (±135.06) 0.07 Thalamus (±SD) [mm3] 8085.13 (±540.3) 7336.29 (±948.03) 0.22 Hippocampus (±SD) [mm3] 4284.38 (±324.35) 4124.38 (±441.5) >1.0 Amygdala (±SD) [mm3] 1670.08 (±130.4) 1664.92 (±226.7) >1.0 Accumbens (±SD) [mm3] 583.25 (±122.34) 488.92 (±111.47) 0.43 Ventricle (±SD) [mm3] 7774.25 (±2621.1) 10199.83 (±2898.0) 0.34 All means are corrected for total intracranial volume
- 16. PDE10A PET analysiswww.nig-politis.com LAYER 1: [11C]IMA-107 BPND based on anatomically defined ROIs LAYER 2: [11C]IMA-107 BPND based on connectivity-based parcellations of ROIs (limbic, cognitive and sensorimotor striatum) according to cortical-striatal connectivity profiles LAYER 3: [11C]IMA-107 BPND based on connectivity-based parcellations of ROIs (striatonigral/striatopallidal internal and striatopallidal external projecting segments of striatum) based on striatal connections with GPe and SN/GPi
- 17. [11C]IMA107 BPND based on anatomy www.nig-politis.com % changes Caudate −33.0% Putamen −30.5% Ventral striatum −16.9% Pallidum −25.6% Motor Thal Nuclei +34.5% Sub Nigra +9.0%
- 18. www.nig-politis.com [11C]IMA107 BPND based on anatomy `
- 19. www.nig-politis.com [11C]IMA107 BPND based on cortical connectivity HCs pHDGECs P values % change Limbic (mean±SD) 0.83 (±0.3) 0.65 (±0.2) >0.10 -11.3% Cognitive (mean±SD) 1.30 (±0.3) 1.06 (±0.3) >0.10 -18.5% Sensorimotor (mean±SD) 1.95 (±0.3) 1.29 (±0.4) <0.001 -34.0%
- 20. www.nig-politis.com [11C]IMA107 BPND based on D1 and D2 pathways HCs pHDGECs P values % change D1 direct pathway (mean±SD) 1.61 (±0.3) 1.09 (±0.3) 0.008 -32.6% D2 indirect pathway (mean±SD) 1.73 (±0.4) 1.15 (±0.3) <0.001 -33.9%
- 21. Correlations between PDE10A and clinical characteristicswww.nig-politis.com
- 22. Probability of symptomatic conversionwww.nig-politis.com Microglia Politis et al., 2011 r=0.809 P=0.022 D2 receptor van Oostrom et al., 2009 r=0.25 P=0.034 PDE10A r=0.82 P=0.001
- 23. PDE10A in manifest HDGECswww.nig-politis.com 5 Manifest HDGECs (HD1-4) UHDRS-TMS = 37 DBS = 426 [18F]JNJ42259152 Ahmad et al., 2014 -63% -71%
- 24. PDE10A in HDGECs www.nig-politis.com 8 Early Manifest HDGECs (HD1-2) 3 Premanifest HDGECs (mean of 12 years from predicted onset) [18F]MNI-659 Russell et al., 2014
- 25. PDE10A changes in HDGECs www.nig-politis.com Russell et al., 2016 6 manifest and 2 premanifest HDGECs [18F]MNI-659 PDE10A mean annualized rates of decline −5.8% −6.9% −16.6
- 26. Conclusions o Bidirectional changes in PDE10A expression in premanifest HDGECs, which are associated with the risk of symptomatic conversion, and are detectable up to a mean of 25 years before the predicted onset of clinical symptoms o PDE-10A expression could be a biomarker of striatal MSNs integrity and [11C]IMA107 PET may be a useful tool for future trials of disease-modifying therapeutics aiming to delay the onset and slow the progression of HD www.nig-politis.com
- 27. Neurodegeneration Imaging Group Marios Politis Heather Wilson Tayyabah Yousaf Gennaro Pagano George Dervenoulas Konstantinos Diamantopoulos Sotirios Polychronis Juan Bonfante www.nig-politis.com KCL NIHR BRC
- 28. Inclusion/Exclusion Criteriawww.nig-politis.com Inclusion: 12 Early Premanifest HDGECs: • Age 21–75 years • Capable of giving informed consent • HD gene carriers with ≥ 40 CAG repeats • UHDRS TMS of 0 indicating lack of motor signs with UHDRS DCL = 0 12 Healthy Controls: • Ability to give informed consent • No history of any psychiatric or neurological diseases Exclusion: • No medications with known action on PDE10A • Presence of psychiatric and/or other neurological disorders • Standard for PET and MRI scanning (e.g. pregnancy, cancer, etc) • Standard for the ligand (e.g. coffee, tea, papaverine etc) The Huntington Study Group, 1996
- 29. CANTAB tests Psychomotor Speed RTI – simple & 5-choice Language Processing GNT Working memory & Executive Function OTS www.nig-politis.com Episodic Memory PAL PRM
- 30. PDE10A in HDGECswww.nig-politis.com 33-34% PDE-10A signal loss in D1 and D2 projecting striatal segments 35% increases of PDE-10A signal in the motor thalamic nuclei
- 31. Genetic modifiers of HD Jong-Min Lee, Ph.D. Assistant Professor on behalf of the GeM-HD Consortium Center for Human Genetic Research, Massachusetts General Hospital Department of Neurology, Harvard Medical School
- 32. Genetically supported targets can double the success rates of clinical trials Nature Genetics, 2015, 47, 856 Cell, 1993, 72, 971 Cell, 2015, 162, 516
- 33. Cell, 1993, 72, 971 Discovery of the cause of HD Autosomal dominant HD Normal
- 34. The cause of HD was described in 1993 paper Duff beer is HTT CAG expansion mutation Beer belly caused by drinking beer is HD
- 35. Partial list Outcomes of 1993 cloning paper: Therapeutic developments
- 36. CRISPR strategy for perfect allele specificity PAM-altering SNPs PromotorNCG NGT gRNA 1 gRNA 2 Normal chromosome Normal CAG Transcription start Promotor NGGNGG gRNA 1 gRNA 2 Expanded CAG Mutant chromosome PAM-altering SNP PAM-altering SNP Large deletion
- 37. Permanent inactivation of mutant allele by CRISPR B. CAG region in DNA Mutant Normal GM01169 TSCC 1 Normal Mutant GM01169 TSCC 1 C. CAG region in RNA D. Total HTT protein Mutant GM01169 TSCC 1 Total GM01169 TSCC 1 E. Mutant HTT protein A. Targeted DNA ~700 bp GM01169 TSCC 1 F. ACTB protein GM01169 TSCC 1 ~44kb deletion Normal Mutant Normal HTT RNA Mutant HTT RNAx
- 38. Nature Reviews Genetics Nature Reviews Neurology Human Molecular Genetics Outcomes of 1993 cloning paper: CRISPR treatment strategy
- 39. 2015 HD genetic modifier paper
- 40. Genetic modifiers of HD Comparing two groups of beer lovers Duff beer is HTT CAG expansion mutation Beer belly caused by drinking beer is HD TV time is a genetic modifier
- 41. Age at onset is determined by HTT CAG repeat length and modifiers
- 42. 40 45 50 55 20 40 60 80 CAG Ageatonset 28years 10 CAGs ~30years Therapeutic potential of modifiers
- 43. Steps to identify HD genetic modifiers by GWA 2.Genotyping3.Associationanalysis (examples) Genome-wide SNP genotyping and genotype imputation CAG Ageatonset(AO) DistancetoexpectedAO (Residual) 1.Phenotyping CAG DistancetoexpectedAO (residual) ExpectedAO Residual 0 1 2 SNP minor allele count Continuous analysis Genotype A Genotype C Phenotype: Early 200 80 Phenotype: Late 200 120 Dichotomous analysis
- 44. Significance Identification of genetic modifiers of HD through GWA: CAG 40-55 Suggestive significance (p-value < 0.00001) 3 genome-wide significant signals and numerous suggestive loci Genome-wide significance (p-value < 0.00000005)
- 45. 2 independent genome-wide significant modifier signals at Chr15ConditionalanalysisSingleSNPanalysis Effect of green SNP was removed Effect of red SNP was removed
- 46. Genome-wide significant modifier signals at Chr8ConditionalanalysisSingleSNPanalysis Effect of red SNP was removed Effect of red SNP was removed
- 47. 0 2 4 6 8 R-squared (%) 0 0.1 0.2 0.3 Frequency of significance (density) FrequencyofR-squared (density) Significance(-log10(p-value)) Grey, top SNP Orange, SNPs p < 0.00001 Blue, SNPs p < 0.0001 Green, SNPs p < 0.001 Red, SNPs p < 0.01 Purple, SNPs p < 0.05 010203040506000.511.52 0 2 4 6 8 More to find in the genome
- 48. HD modifier GWA results (GeM MOA) are available at HDinHD.org Journal of Huntington’s Disease
- 49. Identified mother nature’s experiments that resulted in modification of age at onset Genome-wide significant loci: chromosome 15 and 8 Numerous suggestive loci were also discovered The causal modifier variation / gene is not yet unequivocally known Pathway analysis implicated DNA maintenance and mitochondria-related pathways Follow-up genetic analysis and molecular experiments are on going Genetics increases success rate of clinical trials Identification of the cause of HD made gene targeting approaches possible Discovery of genetic modifiers may contribute to the development of disease-delaying treatments Summary
- 50. Michael Chao Kawther Abu Elneel Tammy Gillis Diane Lucente Jayalakshmi Mysore Marisa Ramos Denise Harold, Cardiff Peter Holmans, Cardiff Lesley Jones, Cardiff Seung Kwak, CHDI Richard Myers, BU Michael Orth, Ulm Vanessa Wheeler, CHGR, MGH Marcy MacDonald, CHGR, MGH James Gusella, CHGR, MGH Samples and data Huntington Study Group HD-MAPS Collaboration PREDICT-HD Study of the HSG REGISTRY Study of the EHDN MIGEN Consortium for control data Acknowledgements Funding GeM-HD Consortium
- 51. Authors from HSG HSG’s contribution to genetic study will lead to: more samples, more phenotypes more discoveries being more successful in HD clinical trials
Notes de l'éditeur
- PDE10A is a dual substrate enzyme highly expressed in the striatal medium spiny neurons PDE-10A regulates cAMP and cGMP downstream signaling cascades (e.g. cAMP/PKA/DARPP-32) that control the phosphorylation state and activity of several physiological effectors including gene transcription factors such as CREB, and various neurotransmitter receptors and voltage-gated ion channels
- Previous work explored PDE-10A expression in transgenic Huntington’s disease mice, showing decreased PDE-10A protein and mRNA levels in the striatum In humans, decreased PDE-10A levels were found in post-mortem striatal tissue
- Moreover, PDE-10A inhibition with TP-10 was able to reduce the loss of striatal and cortical neurons, to increase striatal and cortical CREB phosphorylation, and to delay the development of neurological deficits in HD animal models
- Motor function was assessed with the UHDRS TMS. Functional capacity was assessed with clinician-based [Total Functional Capacity Scale (TFC), Independence Scale (IS), UHDRS functional assessment] and participant self-reported [36-Item Short Form Health Survey (SF-36) functional and quality-of-life measures and assessments. Neuropsychiatric symptoms were assessed with the shortened form of the problem behavior assessment (PBA, the Beck Depression Inventory-II (BDI-II), and the Hamilton Depression Rating Scale (HDRS). Cognitive assessments were carried out using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and included assessments related to psychomotor speed (Reaction Time) episodic memory (Paired Associate Learning & Pattern Recognition Memory), executive function (One Touch Stockings of Cambridge) and language processing (Graded Naming Test).
- MRI included a T1-weighted for co-registration with the PET images and for morphometric analysis; fast grey matter (GM) T1 inversion recovery (FGATIR ) and fluid and white matter (WM) suppression (FLAWS ) for improving delineation of subcortical brain regions Diffusion-weighted data were acquired for performing a two-layered probabilistic tractography and connectivity-based functional parcellation of the striatum We tested correction for movement using a frame-by-frame realignment procedure Parametric images of 11C-IMA107 non-displaceable binding potential (BPND) were generated from the dynamic 11CIMA107 scans using a basis function implementation of the simplified reference tissue model, with the cerebellum as the reference tissue for non-specific binding using an in-house software (c-wave) implemented in Matlab 8.2 As grey and white matter volumetric brain changes have been reported as one of the earliest changes in the course of HD, we wanted to explore whether this was also true for the earlier cohort of premanifest HDGECS studied here. We applied both voxel-based morphometry and volumetric analysis with Freesurfer.
- predicted years to HD symptoms onset (90% probability) calculated on the basis of the variant of the survival analysis formula described by Langbehn (Paulsen et al., 2008)
- All subjects underwent a battery of clinical assessments, which showed no deficits in motor and functional (P>0.10), neuropsychiatric (P>0.10), and cognitive (P>0.10) performance in early premanifest Huntington’s disease gene carriers compared to healthy controls
- Neuropsychiatric assessments showed small non-significant differences between healthy controls and premanifest HDGECs, however the neuropsychiatric burden in our cohort of early premanifest HDGECs was minimal.
- We found no volume changes at a voxel level in any brain regions, and Freesurfer subcortical and ventricle volumetric measures did not show significant differences between healthy controls and early premanifest HDGECs
- we assessed the expression of PDE-10A enzyme in vivo with [11C]IMA107 PET, which is a specific and highly potent PDE-10A selective PET radioligand for human use. We performed a three-layered analysis of the [11C]IMA107 PET BPND in: (a) MR-based anatomically defined ROIs (caudate, putamen, ventral striatum, globus pallidus, substantia nigra and motor thalamic nuclei); (b) connectivity-based parcellations of ROIs (limbic, cognitive and sensorimotor striatum) according to cortical-striatal connectivity profiles; (c) connectivity-based parcellations of ROIs (striatonigral/striatopallidal internal and striatopallidal external projecting segments of striatum) based on striatal connections with globus pallidus externus and substantia nigra/globus pallidus internus, and so reflect the major parts of the indirect and direct pathways, respectively.
- We found that [11C]IMA107 BPND was decreased in caudate (-33%), putamen (-30.5%) and globus pallidus (-25.6%), and increased in motor thalamic nuclei (+34.5%), with no significant changes observed in substantia nigra (+9%) and ventral striatum (-16.9%) in early premanifest HDGECs compared to healthy controls Mean [11C]IMA107 BPND parametric images derived from 12 healthy controls (top) and 12 early premanifest HD gene carriers (bottom) in stereotaxic space overlaid onto the T1 weighted MNI template showing significant loss of striatal PDE-10A signal in the early premanifest HD gene carriers. Color bar reflects range of [11C]IMA107 BPND intensity
- Individual [11C]IMA107 BPND analysis showed that 10 out of 12 early premanifest HDGECs (83.3%) had abnormally reduced striatal and abnormally increased motor thalamic nuclei [11C]IMA107 BPND values Coronal summed [11C]IMA107 PET images co-registered and fused with 3-T MRI images for the thalamus of a 33-year-old healthy male showing normal thalamus [11C]IMA107 binding (BPND = 0.43) (left); a 38-year-old male premanifest Huntington’s disease gene carrier (CAGr: 44; DBS: 323; 17 years from predicted onset) showing high increases in thalamic [11C]IMA107 binding (BPND = 0.93) (middle-left); a 35-year-old male premanifest Huntington’s disease gene carrier (CAGr: 40; DBS: 153; 43 years from predicted onset) showing moderate increases in thalamic [11C]IMA107 binding (BPND = 0.64) (middle-right); and a 37-year-old male premanifest Huntington’s disease gene carrier (CAGr: 43; DBS: 277.5; 22 years from predicted onset) showing mild to moderate increases in thalamic [11C]IMA107 binding (BPND = 0.58) (right). Color bar reflects range of [11C]IMA107 BPND intensity.
- We calculated [11C]IMA107 BPND in functional striatal subdivisions following probabilistic tractography and connectivity-based functional striatal parcellation Cortico-striatal connectivity-based functional analysis 34% decreases in sensorimotor striatum but not limbic or cognitive in early premanifest HDGECs compared to healthy controls
- Hence, we used the sensorimotor striatum as a seed mask since it was the only subdivision with significant PDE-10A decreases, to perform striatonigral and striatopallidal connectivity-based functional analysis We found 33-34% [11C]IMA107 BPND decreases in striatonigral/striatopallidal internal and striatopallidal external projecting sensorimotor striatal segments
- We found correlations between: (a) higher motor-thalamic-nuclei/striatal [11C]IMA107 BPND ratio and higher two (r=0.59; P=0.044) and five (r=0.59; P=0.043) year probability for symptomatic conversion; (b) higher motor-thalamic-nuclei/sensorimotor [11C]IMA107 BPND ratio and higher two (r=0.66; P=0.020), five (r=0.66; P=0.019) and 10 (r=0.63; P=0.027) year probability for symptomatic conversion and; (c) higher motor-thalamic-nuclei/striatopallidal [11C]IMA107 BPND ratio and higher two (r=0.85; P=0.001), five (r=0.82; P=0.001), 10 (r=0.76; P=0.004) and 15 (r=0.65; P=0.023) year probability for symptomatic conversion
- Previous studies using similar samples have reported correlations at a 0.05 α level between decreased D2-receptors (van Oostrom et al., 2009) and increased activated microglia (Politis et al., 2011) in the striatum, and predicted 5-year probability of Huntington’s HD between decreased PDE-10A in striatopallidal projections and increased PDE-10A in motor thalamic nuclei correlated with the risk for symptomatic conversion up to a 0.001 α level with power to associate with predicted onset up to 15 years. To our knowledge, this is the strongest reported correlation with the risk of symptomatic HD conversion
- A pilot PDE-10A PET study reported 60-70% decreases in striatal PDE-10A expression of five manifest Huntington’s disease patients with significant striatal atrophy
- Using PET with [18F]MNI-659, Russell and colleagues (2014) have found 47.6% decreases in striatal and pallidal PDE-10A expression in eight early manifest Huntington’s disease patients and lower striatal [18F]MNI-659 binding was associated with disease severity and disease burden of pathology. Three premanifest Huntington’s disease gene carriers, who were a mean of 12 years from predicted onset, displayed decreases in striatal PDE-10A expression with a lesser degree compared to the group of manifest Huntington’s disease patients
- The mean annualized rates of decline in signal in the caudate, putamen, and globus pallidus and the putamen were 16.6%, 6.9%, and 5.8%, respectively. In HC, the annualized reduction in signal in striatal regions was less than 1%. Longitudinal data in this small cohort of participants with early HD support [18F]MNI-659 PET imaging of PDE10 as a useful biomarker to track HD disease progression
- All early premanifest HDGECs were asymptomatic based on the standardized total motor score (TMS) subscale (TMS = 0) of the Unified Huntington Disease Rating Scale (UHDRS) with a diagnostic confidence level of 0 (The Huntington Study Group, 1996). We recruited 12 healthy individuals, matched for age and gender All participants screened successfully to undertake PET and MRI scanning under standard criteria, had no history of other neurological or psychiatric disorders, and were not under treatment with substances with known actions in PDEs (e.g. apremilast, cilomilast, luteolin, piclamilast, roflumilast and ibudilast).
- RTI=it provides measure of motor and mental response speeds, as well as measures of movement time and reaction time. The task is divided into five stages and the participant must react as soon as a yellow dot appears. PAL= Boxes are displayed on the screen and are opened in a randomized order. One or more of them will contain a pattern. The patterns are then displayed in the middle of the screen, and the participant must touch the box where the pattern was originally located. PRM is a test of visual pattern recognition memory in a 2-choice forced discrimination paradigm. Subject is presented with series visual patterns, one at a time, in the center of the screen. OTS assesses executive function, spatial planning and working memory and is based on the Tower of Hanoi test. OTS is a variant of the Stockings of Cambridge test and places greater demands on working memory as the subject has to visualize the solution. GNT assesses object-naming ability, but is in addition graded in difficulty to allow for individual differences.
- In early premanifest Huntington’s disease gene carriers PDE-10A levels are decreased in the striatonigral (direct) and striatopallidal (indirect) neurons potentiating dopamine D1 and D2 receptors signaling and leading to disinhibition of motor thalamic nuclei. Increased PDE-10A levels in the motor thalamic nuclei may counterbalance the decreased inhibitory signals incoming from globus pallidus and substantia nigra and consequently, physiologically stimulate the cortex. In manifest Huntington’s disease, ongoing and significant degeneration of striatopallidal projecting neurons and further PDE-10A decreases would lead to an even more unbalanced striatonigral/striatopallidal signaling. Motor-thalamic-nuclei compensatory mechanisms could gradually fail leading to an overflow of glutamate activity to the cortex, which will result in expression of Huntington’s disease symptoms.