scholarly journals Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington’s disease

2021 ◽  
Author(s):  
Daniele Bertoglio ◽  
Jeroen Verhaeghe ◽  
Alan Miranda ◽  
Leonie Wyffels ◽  
Sigrid Stroobants ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pet Imaging ◽  
Genotypic Differences ◽  
The Novel ◽  
Mutant Huntingtin ◽  
Post Mortem ◽  
Cross Sectional ◽  
Longitudinal Dynamic ◽  
Positron Emission

Abstract Purpose As several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington’s disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression. Here we characterized and longitudinally assessed the novel radioligand [11C]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD. Methods After evaluating radiometabolites and radioligand kinetics, we conducted longitudinal dynamic PET imaging at 3, 6, 9, and 13 months of age (M) in wild-type (WT, n = 17) and heterozygous (HET, n = 23) zQ175DN mice. Statistical analysis was performed to evaluate temporal and genotypic differences. Cross-sectional cohorts at each longitudinal time point were included for post-mortem [3H]CHDI-626 autoradiography. Results Despite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. Longitudinal quantification could discriminate between genotypes already at premanifest stage (3 M), showing an age-associated increase in signal in HET mice in parallel with mHTT aggregate load progression, as supported by the post-mortem [3H]CHDI-626 autoradiography. Conclusion With clinical evaluation underway, [11C]CHDI-626 PET imaging appears to be a suitable preclinical candidate marker to monitor natural HD progression and for the evaluation of mHTT-lowering therapies.

scholarly journals Longitudinal Preclinical Evaluation of the Novel Radioligand [11C]CHDI-626 for PET Imaging of Mutant Huntingtin Aggregates in Huntington’s Disease

2021 ◽  
Author(s):  
Daniele Bertoglio ◽  
Jeroen Verhaeghe ◽  
Alan Miranda ◽  
Leonie Wyffels ◽  
Sigrid Stroobants ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pet Imaging ◽  
Genotypic Differences ◽  
The Novel ◽  
Mutant Huntingtin ◽  
Post Mortem ◽  
Cross Sectional ◽  
Longitudinal Dynamic ◽  
Positron Emission

Abstract PurposeAs several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington’s disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression. Here we characterized and longitudinally assessed the novel radioligand [11C]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD.MethodsAfter evaluating radiometabolites and radioligand kinetics, we conducted longitudinal dynamic PET imaging at 3, 6, 9, and 13 months of age (M) in wild-type (WT, n = 17) and heterozygous (HET, n = 23) zQ175DN mice. Statistical analysis was performed to evaluate temporal and genotypic differences. Cross-sectional cohorts at each longitudinal time point were included for post-mortem [3H]CHDI-626 autoradiography.ResultsDespite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. Longitudinal quantification could discriminate between genotypes already at premanifest stage (3M), showing an age-associated increase in signal in HET mice in parallel with mHTT aggregate load progression, as supported by the post-mortem [3H]CHDI-626 autoradiography.ConclusionWith clinical evaluation underway, [11C]CHDI-626 PET imaging appears to be a suitable preclinical candidate marker to monitor natural HD progression and for the evaluation of mHTT-lowering therapies.

scholarly journals Elevated Type 1 Metabotropic Glutamate Receptor Availability in a Mouse Model of Huntington’s Disease: a Longitudinal PET Study

2020 ◽  
Vol 57 (4) ◽  
pp. 2038-2047 ◽  
Author(s):  
Daniele Bertoglio ◽  
Jeroen Verhaeghe ◽  
Špela Korat ◽  
Alan Miranda ◽  
Klaudia Cybulska ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pet Imaging ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Post Mortem ◽  
Metabotropic Glutamate ◽  
Group I

AbstractImpairment of group I metabotropic glutamate receptors (mGluRs) results in altered glutamate signalling, which is associated with several neurological disorders including Huntington’s Disease (HD), an autosomal neurodegenerative disease. In this study, we assessed in vivo pathological changes in mGluR1 availability in the Q175DN mouse model of HD using longitudinal positron emission tomography (PET) imaging with the radioligand [11C]ITDM. Ninety-minute dynamic PET imaging scans were performed in 22 heterozygous (HET) Q175DN mice and 22 wild-type (WT) littermates longitudinally at 6, 12, and 16 months of age. Analyses of regional volume of distribution with an image-derived input function (VT (IDIF)) and voxel-wise parametric VT (IDIF) maps were performed to assess differences between genotypes. Post-mortem evaluation at 16 months was done to support in vivo findings. [11C]ITDM VT (IDIF) quantification revealed higher mGluR1 availability in the brain of HET mice compared to WT littermates (e.g. cerebellum: + 15.0%, + 17.9%, and + 17.6% at 6, 12, and 16 months, respectively; p < 0.001). In addition, an age-related decline in [11C]ITDM binding independent of genotype was observed between 6 and 12 months. Voxel-wise analysis of parametric maps and post-mortem quantifications confirmed the elevated mGluR1 availability in HET mice compared to WT littermates. In conclusion, in vivo measurement of mGluR1 availability using longitudinal [11C]ITDM PET imaging demonstrated higher [11C]ITDM binding in extra-striatal brain regions during the course of disease in the Q175DN mouse model.

scholarly journals Synthesis and Evaluation of a Fluorine-18 Radioligand for Imaging Huntingtin Aggregates by Positron Emission Tomographic Imaging

2021 ◽  
Vol 15 ◽  
Author(s):  
Tanpreet Kaur ◽  
Allen F. Brooks ◽  
Alex Lapsys ◽  
Timothy J. Desmond ◽  
Jenelle Stauff ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Imaging Modality ◽  
Brain Slices ◽  
Post Mortem ◽  
Molar Activity ◽  
Positron Emission ◽  
Post Mortem Brain

Mutations in the huntingtin gene (HTT) triggers aggregation of huntingtin protein (mHTT), which is the hallmark pathology of neurodegenerative Huntington’s disease (HD). Development of a high affinity 18F radiotracer would enable the study of Huntington’s disease pathology using a non-invasive imaging modality, positron emission tomography (PET) imaging. Herein, we report the first synthesis of fluorine-18 imaging agent, 6-(5-((5-(2,2-difluoro-2-(fluoro-18F)ethoxy)pyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazin-3(2H)-one ([18F]1), a radioligand for HD and its preclinical evaluation in vitro (autoradiography of post-mortem HD brains) and in vivo (rodent and non-human primate brain PET). [18F]1 was synthesized in a 4.1% RCY (decay corrected) and in an average molar activity of 16.5 ± 12.5 GBq/μmol (445 ± 339 Ci/mmol). [18F]1 penetrated the blood-brain barrier of both rodents and primates, and specific saturable binding in post-mortem brain slices was observed that correlated to mHTT aggregates identified by immunohistochemistry.

scholarly journals Identification of Full-Length Wild-Type and Mutant Huntingtin Interacting Proteins by Crosslinking Immunoprecipitation in Mice Brain Cortex

2021 ◽  
pp. 1-13
Author(s):  
Karen A. Sap ◽  
Arzu Tugce Guler ◽  
Aleksandra Bury ◽  
Dick Dekkers ◽  
Jeroen A.A. Demmers ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Cortex ◽  
Full Length ◽  
Biological Processes ◽  
Interacting Proteins ◽  
Mutant Huntingtin ◽  
Wild Type ◽  
Mutant Huntingtin Protein ◽  
Mice Brain

Background: Huntington’s disease is a neurodegenerative disorder caused by a CAG expansion in the huntingtin gene, resulting in a polyglutamine expansion in the ubiquitously expressed mutant huntingtin protein. Objective: Here we set out to identify proteins interacting with the full-length wild-type and mutant huntingtin protein in the mice cortex brain region to understand affected biological processes in Huntington’s disease pathology. Methods: Full-length huntingtin with 20 and 140 polyQ repeats were formaldehyde-crosslinked and isolated via their N-terminal Flag-tag from 2-month-old mice brain cortex. Interacting proteins were identified and quantified by label-free liquid chromatography-mass spectrometry (LC-MS/MS). Results: We identified 30 interactors specific for wild-type huntingtin, 14 interactors specific for mutant huntingtin and 14 shared interactors that interacted with both wild-type and mutant huntingtin, including known interactors such as F8a1/Hap40. Syt1, Ykt6, and Snap47, involved in vesicle transport and exocytosis, were among the proteins that interacted specifically with wild-type huntingtin. Various other proteins involved in energy metabolism and mitochondria were also found to associate predominantly with wild-type huntingtin, whereas mutant huntingtin interacted with proteins involved in translation including Mapk3, Eif3h and Eef1a2. Conclusion: Here we identified both shared and specific interactors of wild-type and mutant huntingtin, which are involved in different biological processes including exocytosis, vesicle transport, translation and metabolism. These findings contribute to the understanding of the roles that wild-type and mutant huntingtin play in a variety of cellular processes both in healthy conditions and Huntington’s disease pathology.

scholarly journals Differential Diagnosis of Chorea—HIV Infection Delays Diagnosis of Huntington’s Disease by Years

2021 ◽  
Vol 11 (6) ◽  
pp. 710
Author(s):  
Jannis Achenbach ◽  
Simon Faissner ◽  
Carsten Saft
Keyword(s):  
Hiv Infection ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Onset ◽  
Diagnostic Delay ◽  
Depression Scale ◽  
Cag Repeat ◽  
Psychiatric Disease ◽  
Disease Manifestation ◽  
Cross Sectional

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

scholarly journals Embryonic Mutant Huntingtin Aggregate Formation in Mouse Models of Huntington’s Disease

2016 ◽  
Vol 5 (4) ◽  
pp. 343-346 ◽  
Author(s):  
Alexander P. Osmand ◽  
Terry Jo. Bichell ◽  
Aaron B. Bowman ◽  
Gillian P. Bates
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Mutant Huntingtin ◽  
Aggregate Formation

scholarly journals Msh2 Acts in Medium-Spiny Striatal Neurons as an Enhancer of CAG Instability and Mutant Huntingtin Phenotypes in Huntington’s Disease Knock-In Mice

PLoS ONE ◽  
2012 ◽  
Vol 7 (9) ◽  
pp. e44273 ◽  
Author(s):  
Marina Kovalenko ◽  
Ella Dragileva ◽  
Jason St. Claire ◽  
Tammy Gillis ◽  
Jolene R. Guide ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mutant Huntingtin ◽  
Striatal Neurons
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