Loss of extra-striatal phosphodiesterase 10A expression in early premanifest Huntington's disease gene carriers

Wilson, Heather; Niccolini, Flavia; Haider, Salman; Marques, Tiago Reis; Pagano, Gennaro; Coello, Christopher; Natesan, Sridhar; Kapur, Shitij; Rabiner, Eugenii A.; Gunn, Roger N.; Tabrizi, Sarah J.; Politis, Marios

doi:10.1016/j.jns.2016.07.033

Cited by 40 publications

(28 citation statements)

References 40 publications

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“…Recently, our group investigated PDE10A expression using PET with [ 11 C]IMA107 in 12 far-onset premanifest HDGECs who were on average 25 years from predicted symptomatic onset, clinically normal and had no volumetric brain changes as confirmed by MRI voxel-based morphometry and FreeSurfer volumetric analysis ( 83 , 84 ). Striatal and pallidal [ 11 C]IMA107 binding was reduced by 25–33%, and a 35% increase in binding was observed in the motor thalamic nuclei in premanifest HDGECs compared to HC ( 83 ).…”

Section: Resultsmentioning

confidence: 99%

Molecular Imaging Markers to Track Huntington’s Disease Pathology

et al. 2017

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Huntington’s disease (HD) is a progressive, monogenic dominant neurodegenerative disorder caused by repeat expansion mutation in the huntingtin gene. The accumulation of mutant huntingtin protein, forming intranuclear inclusions, subsequently leads to degeneration of medium spiny neurons in the striatum and cortical areas. Genetic testing can identify HD gene carriers before individuals develop overt cognitive, psychiatric, and chorea symptoms. Thus, HD gene carriers can be studied in premanifest stages to understand and track the evolution of HD pathology. While advances have been made, the precise pathophysiological mechanisms underlying HD are unclear. Magnetic resonance imaging (MRI) and positron emission tomography (PET) have been employed to understand HD pathology in presymptomatic and symptomatic disease stages. PET imaging uses radioactive tracers to detect specific changes, at a molecular level, which could be used as markers of HD progression and to monitor response to therapeutic treatments for HD gene expansion carriers (HDGECs). This review focuses on available PET techniques, employed in cross-sectional and longitudinal human studies, as biomarkers for HD, and highlights future potential PET targets. PET studies have assessed changes in postsynaptic dopaminergic receptors, brain metabolism, microglial activation, and recently phosphodiesterase 10A (PDE10A) as markers to track HD progression. Alterations in PDE10A expression are the earliest biochemical change identified in HD gene carriers up to 43 years before predicted symptomatic onset. Thus, PDE10A expression could be a promising marker to track HD progression from early premanifest disease stages. Other PET targets which have been less well investigated as biomarkers include cannabinoid, adenosine, and GABA receptors. Future longitudinal studies are required to fully validate these PET biomarkers for use to track disease progression from far-onset premanifest to manifest HD stages. PET imaging is a crucial neuroimaging tool, with the potential to detect early changes and validate sensitivity of biomarkers for tracking HD pathology. Moreover, continued development of novel PET tracers provides exciting opportunities to investigate new molecular targets, such as histamine and serotonin receptors, to further understand the mechanisms underlying HD pathology.

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Section: Resultsmentioning

confidence: 99%

Molecular Imaging Markers to Track Huntington’s Disease Pathology

et al. 2017

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“…Previous PET studies have shown that PDE10A expression decreased in the striatum and pallidum and increased in the motor thalamus of premanifest HD gene carriers compared to matched healthy controls [135]. PET imaging research using [ 11 C] IMA107 demonstrated a 25%–33% reduction in striatal PDE10A 25 years earlier than predicted symptomatic onset [135,136]. Decreased PDE10A expression was mostly restricted to the dorsal sensorimotor striatum [135], and lower striatal PDE10A expression was associated with disease burden and severity [137].…”

Section: Striatal Pathologymentioning

confidence: 99%

“…In a study of a transgenic rodent model of HD, preferential loss of striosomal neurons was reported [224]. Moreover, a PET study of early premanifest HD gene carriers revealed that extra-striatal PDE10A expression decreased by 25% and 50% in the insular cortex and occipital fusiform gyrus, respectively [136]. These cortical areas are associated with cognitive and limbic functions and are striosome-related areas [225].…”

Section: Striatal Pathologymentioning

confidence: 99%

Striatal Vulnerability in Huntington’s Disease: Neuroprotection Versus Neurotoxicity

Morigaki

Goto

2017

Brain Sciences

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Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of a CAG trinucleotide repeat encoding an abnormally long polyglutamine tract (PolyQ) in the huntingtin (Htt) protein. In HD, striking neuropathological changes occur in the striatum, including loss of medium spiny neurons and parvalbumin-expressing interneurons accompanied by neurodegeneration of the striosome and matrix compartments, leading to progressive impairment of reasoning, walking and speaking abilities. The precise cause of striatal pathology in HD is still unknown; however, accumulating clinical and experimental evidence suggests multiple plausible pathophysiological mechanisms underlying striatal neurodegeneration in HD. Here, we review and discuss the characteristic neurodegenerative patterns observed in the striatum of HD patients and consider the role of various huntingtin-related and striatum-enriched proteins in neurotoxicity and neuroprotection.

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“…Currently, PDE10 is considered a promising target for CNS diseases, especially schizophrenia and Huntington's disease (HD). Although numerous studies have reported that PDE10A expression in the striatum and different other brain regions of post-mortem HD patients [113][114][115] and HD animal models [113,116] is reduced, inhibition of PDE10A has shown rescue of behavioral, neurodegenerative, and electrophysiological deficits in HD animal models.…”

Section: Phosphodiesterase 10 Inhibitorsmentioning

confidence: 99%

Targeting the NO/cGMP/CREB Phosphorylation Signaling Pathway in Alzheimer’s Disease

Fiorito¹,

Deng²,

Landry³

et al. 2019

Neurochemical Basis of Brain Function and Dysfunction

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Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of senile dementia. Recently, scientists have put significant effort into exploring the molecular mechanisms involved in the pathological processes leading to the disease. A vast number of studies have focused on understanding the nitric oxide (NO) signaling pathway, which culminates with the phosphorylation of the transcription factor cAMP-responsive element-binding protein (CREB) through the increase of the second messenger cyclic guanosine monophosphate (cGMP) and activation of cGMP-dependent protein kinase. This book chapter provides an overview of the progress being made in modulating the hippocampal synaptic transmissions, which are critical for learning and memory, by targeting the different components of the NO/cGMP/CREB phosphorylation signaling pathway. Furthermore, a description of recent research on this pathway through the use of phosphodiesterase inhibitors is emphasized.

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Loss of extra-striatal phosphodiesterase 10A expression in early premanifest Huntington's disease gene carriers

Cited by 40 publications

References 40 publications

Molecular Imaging Markers to Track Huntington’s Disease Pathology

Molecular Imaging Markers to Track Huntington’s Disease Pathology

Striatal Vulnerability in Huntington’s Disease: Neuroprotection Versus Neurotoxicity

Targeting the NO/cGMP/CREB Phosphorylation Signaling Pathway in Alzheimer’s Disease

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