EC Neurology

PET studies of Huntington’s Disease (HD) have been used to monitor receptor binding and transport, oxygen utilization, and cell signaling related to synaptic loss and cell death. This focus has left earlier molecular events that precipitate neuronal cell loss poorly identified. Given the monogenetic origin of HD, however, there is increasing recognition that therapeutic intervention will need to be based on a knowledge of these early events, particularly that of the mutant huntingtin protein (mHTT). Studies of the normal variant (HTT) are providing insight into the protein’s structure, genetic expression, various cellular processes such as transport and autophagy, and interactions between huntingtin and its protein partners, illuminating the potential early role of mHTT in HD dysfunction.

Advances in PET instrumentation and radioligand procedures are helping to bridge this molecular scale domain with the macroscale domain of brain communication. Driving these advances is the search for multi-information data sources that can be precisely targeted, which has yielded multimodal sensing technology and precision guided probes like reporter proteins and immunoconjugates. This chapter reviews current developments in nuclear medicine that seek to address early-stage HD dysfunction.

 Keywords: Huntington’s Disease; Positron Emission Tomography; PET/MRI; Huntingtin; Radiogenomics; Intrabodies; Reporter Genes; Anti-Sense Oligonucleotides; fMRI; PET/MRS

1. Tang C and Feigin A. “Monitoring Huntington's disease progression through preclinical and early stages”. Neurodegenerative Disease Management 4 (2012): 421-435.
2. Aylward EH., et al. “Longitudinal change in regional brain volumes in prodromal Huntington disease”. Journal of Neurology, Neurosurgery, and Psychiatry4 (2011): 405-410.
3. Reiner A., et al. “Genetics and neuropathology of Huntington's disease”. International Review of Neurobiology 98 (2011): 325-372.
4. Saudou F and Humbert S. “The biology of huntingtin”. Neuron5 (2016): 910-926.
5. Herrmann F., et al. “Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates”. Scientific Reports1 (2021): 17977.
6. Vaz SC., et al. “Nuclear medicine and molecular imaging advances in the 21^st century”. British Journal of Radiology1110 (2020): 20200095.
7. Cybulska K., et al. “Huntington’s disease: a review of the known PET imaging biomarkers and targeting radiotracers”. Molecules3 (2020): 482.
8. Roussakis AA and Piccini P. “PET Imaging in Huntington's disease”. Journal of Huntington’s Disease4 (2015): 287-296.
9. Denis HL., et al. “Antibody-based therapies for Huntington's disease: current status and future directions”. Neurobiology Disease 132 (2019): 104569.
10. Gao T., et al. “Reporter genes for brain imaging using MRI, SPECT and PET”. International Journal of Molecular Sciences15 (2022): 8443.
11. Catana C. “Principles of simultaneous PET/MR imaging”. Magnetic Resonance Imaging Clinics of North America 2 (2017): 231-243.
12. Lois C., et al. “Neuroinflammation in Huntington’s Disease: new insights with 11C‐PBR28 PET/MRI”. ACS Chemistry Neuroscience11 (2018): 2563-2571.
13. Chiang GC., et al. “Magnetic resonance spectroscopy, positron emission tomography and radiogenomics-relevance to glioma”. Frontiers in Neurology 9 (2018): 33.
14. Ramanathan S., et al. “Theranostic applications of nanoparticles in neurodegenerative disorders”. International Journal of Nanomedicine 13 (2018): 5561-5576.
15. Evers MM., et al. “AAV5-miHTT. Gene therapy demonstrates broad distribution and strong human mutant huntingtin lowering in a Huntington’s disease minipig model”. Molecular Therapy9 (2018): 2163-2177.
16. Gawne PJ., et al. “Direct cell radiolabeling for in vivo cell tracking with PET and SPECT imaging”. Chemistry Reviews11 (2022): 10266-10318.
17. Steffan JS., et al. “SUMO modification of Huntingtin and Huntington’s disease pathology”. Science5667 (2004): 100-104.
18. Bae BI., et al. “p53 mediates cellular dysfunction and behavioral abnormalities in Huntington’s disease”. Neuron 1 (2005): 29-41.
19. Igarashi S., et al. “Inducible PC12 cell model of Huntington's disease shows toxicity and decreased histone acetylation”. Neuroreport4 (2003): 565-568.
20. Warby SC., et al. “Activated caspase-6 and caspase-6-cleaved fragments of huntingtin specifically colocalize in the nucleus”. Human Molecular Genetics15 (2008): 2390-2404.
21. Ravikumar B., et al. “Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease”. Nature Genetics6 (2004): 585-595.
22. Ross CA and Tabrizi SJ. “Huntington’s disease: from molecular pathogenesis to clinical treatment”. Lancet Neurology1 (2011): 83-98.
23. Drouet V., et al. “Allele-specific silencing of mutant huntingtin in rodent brain and human stem cells”. PLoS ONE6 (2014): e99341.
24. Indersmitten T., et al. “Altered excitatory and inhibitory inputs to striatal medium- sized spiny neurons and cortical pyramidal neurons in the Q175 mouse model of Huntington's disease”. Journal of Neurophysiology 7 (2015): 2953-2966..
25. Victor MB., et al. “Striatal neurons directly converted from Huntington's disease patient fibroblasts recapitulate age-associated disease phenotypes”. Nature Neuroscience 3 (2018): 341-352.
26. Shirasaki DI., et al. “Network organization of the huntingtin proteomic interactome in mammalian brain”. Neuron1 (2012): 41-57.
27. Zimbelman JL., et al. “fMRI detection of early neural dysfunction in preclinical Huntington’s disease”. Journal of the International Neuropsychological Society 5 (2007): 758-769.
28. Gunn RN., et al. “Quantitative imaging of protein targets in the human brain with PET”. Physics in Medicine and Biology22 (2015): R363-R411.
29. van Oostrom JC., et al. “Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease”. Neurology6 (2005): 941-943.
30. Oliveira MC and Correia JD. “Biomedical applications of radioiodinated peptides”. European Journal of Medicinal Chemistry 179 (2019): 56-77.
31. Garret M., et al. “Alteration of GABAergic neurotransmission in Huntington’s disease”. CNS Neuroscience and Therapeutics 4 (2018): 292-300.
32. Blum D., et al. “The role of adenosine tone and adenosine receptors in Huntington’s Disease”. Journal of Caffeine and Adenosine Research 2 (2018): 43-58.
33. Kendall DA and Yudowski GA. “Cannabinoid receptors in the central nervous system: their signaling and roles in disease”. Frontiers in Cellular Neuroscience 10 (2017): 294.
34. Niccolini F., et al. “Altered PDE10A expression detectable early before symptomatic onset in Huntington’s Disease”. Brain10 (2015): 3016-3029.
35. Guillemin GJ and Brew BJ. “Microglia, macrophages, perivascular macrophages, and pericytes: A review of function and identification”. Journal of Leukocyte Biology 3 (2004): 388-397.
36. Schlemmer H-PW., et al. “Simultaneous MRI/PET imaging of the human brain: feasibility study”. Radiology3 (2008): 1028-1035.
37. Dixon WT. “Simple proton spectroscopic imaging”. Radiology1 (1984): 189-194.
38. Robson MD., et al. “Magnetic resonance: an introduction to ultrashort TE (UTE) imaging”. Journal of Computer Assisted Tomography 6 (2003): 825-846.
39. Zuendorf G., et al. “Efficient principal component analysis for multivariate 3D voxel-based mapping of brain functional imaging data sets as applied to FDG-PET and normal aging”. Human Brain Mapping1 (2002): 13-21.
40. Catana C., et al. “PET/MRI for neurologic applications”. Journal of Nuclear Medicine 12 (2012): 1916-1925.
41. Lawn T., et al. “From neurotransmitters to networks: Transcending organisational hierarchies with molecular-informed functional imaging”. Neuroscience and Biobehavioral Review 150 (2023): 105193.
42. Biswal B., et al. “Functional connectivity in the motor cortex of resting human brain using echo-planar MRI”. Magnetic Resonance in Medicine4 (1995): 537-541.
43. Larrivee D. “Resting-State fMRI Advances for functional brain dynamics”. In Larrivee D, editor. New Advances in Magnetic Resonance Imaging. London: Intech Open (2024).
44. Harrington DL., et al. “Network topology and functional connectivity disturbances precede the onset of Huntington’s disease”. Brain 8 (2015): 2332-2346.
45. Kuo MD and Jamshidi M. “Behind the numbers: decoding molecular phenotypes with radiogenomics”. Radiology 2 (2014): 320-325.
46. Tognarelli JM., et al. “Magnetic resonance spectroscopy: principles and techniques: lessons for clinicians”. Journal of Clinical and Experimental Hepatology 4 (2015): 320-328.
47. Kurhanewicz J., et al. “Hyperpolarized 13C MRI: path to clinical translation in oncology”. Neoplasia1 (2019): 1-16.
48. Stewart NJ and Matsumoto S. “Biomedical applications of the dynamic nuclear polarization and parahydrogen induced polarization techniques for hyperpolarized 13C MR imaging”. Magnetic Resonance in Medicine Science1 (2021): 1-17.
49. Tabrizi SJ., et al. “Potential disease-modifying therapies for Huntington's disease: lessons learned and future opportunities”. Lancet Neurology7 (2022): 645-658.
50. Enlow E and Abbaszadeh S. “State-of-the-art challenges and emerging technologies in radiation detection for nuclear medicine imaging: A review”. Frontiers in Physiology 11 (2023): 1106546.
51. Hutton BF., et al. “Advances in clinical molecular imaging instrumentation”. Clinical and Translational Imaging 6 (2018): 31-45.
52. Schramm G. “Reconstruction-free positron emission imaging: Fact or fiction?” Frontiers in Nuclear Medicine 2 (2022): 936091.
53. Gonzalez-Cartera D., et al. “Targeting nanoparticles to the brain by exploiting the blood- brain barrier impermeability to selectively label the brain endothelium”. Proceedings of the National Academy of Sciences 32 (2020): 19141-19150.
54. Choudhurya SR., et al. “Viral vectors for therapy of neurologic diseases”. Neuropharmacology 120 (2017): 63-80.
55. Edelmann MR. “Radiolabelling small and biomolecules for tracking and monitoring”. Royal Society of Chemistry Advances50 (2022): 32383-32400.
56. Cardinale A and Biocca S. “The potential of intracellular antibodies for therapeutic targeting of protein-misfolding diseases”. Trends in Molecular Medicine 9 (2008): 373-380.
57. Rui YN., et al. “Huntingtin functions as a scaffold for selective macroautophagy”. Nature Cell Biology 17 (2015): 262-275.
58. Li H., et al. “64Cu-Labeled ubiquitin for PET imaging of CXCR4 expression in mouse breast tumor”. ACS Omega 4,7 (2019): 12432-12437.
59. Allen S., et al. “mRNA nuclear clustering leads to a difference in mutant huntingtin mRNA and protein silencing by siRNAs in vivo”. bioRxiv preprint (2024).
60. Culver BP., et al. “Proteomic analysis of wild-type and mutant huntingtin-associated proteins in mouse brains identifies unique interactions and involvement in protein synthesis”. Journal of Biological Chemistry 26 (2012): 21599-21614.
61. Gawne P., et al. “Direct cell radiolabeling for in vivo cell tracking with PET and SPECT imaging”. Chemical Reviews11 (2022): 10266-10318.
62. Marks JD., et al. “By-passing immunization human antibodies from V-gene libraries displayed on phage”. Journal of Molecular Biology 3 (1991): 581-597.