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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. 1. HD Insights Insights of the Year Michael Geschwind, MD, PhD UCSF Memory and Aging Center
  2. 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. 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. 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. 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. 6. PDE10A inhibition & HDwww.nig-politis.com Giampà et al., 2009, 2010
  7. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 18. www.nig-politis.com [11C]IMA107 BPND based on anatomy `
  19. 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. 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. 21. Correlations between PDE10A and clinical characteristicswww.nig-politis.com
  22. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 33. Cell, 1993, 72, 971 Discovery of the cause of HD Autosomal dominant HD Normal
  34. 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. 35. Partial list Outcomes of 1993 cloning paper: Therapeutic developments
  36. 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. 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. 38. Nature Reviews Genetics Nature Reviews Neurology Human Molecular Genetics Outcomes of 1993 cloning paper: CRISPR treatment strategy
  39. 39. 2015 HD genetic modifier paper
  40. 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. 41. Age at onset is determined by HTT CAG repeat length and modifiers
  42. 42. 40 45 50 55 20 40 60 80 CAG Ageatonset 28years 10 CAGs ~30years Therapeutic potential of modifiers
  43. 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. 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. 45. 2 independent genome-wide significant modifier signals at Chr15ConditionalanalysisSingleSNPanalysis Effect of green SNP was removed Effect of red SNP was removed
  46. 46. Genome-wide significant modifier signals at Chr8ConditionalanalysisSingleSNPanalysis Effect of red SNP was removed Effect of red SNP was removed
  47. 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. 48. HD modifier GWA results (GeM MOA) are available at HDinHD.org Journal of Huntington’s Disease
  49. 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. 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. 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

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