Synaptic Damage and Its Clinical Correlates in People With Early Huntington Disease

Delva, Aline; Michiels, Laura; Laere, Koen Van; Vandenberghe, Wim

doi:10.1212/wnl.0000000000012969

Cited by 39 publications

(61 citation statements)

References 49 publications

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“…A study of patients with premanifest and early Huntington’s disease revealed reduced [ 11 C]UCB-J binding in putamen, caudate, pallidum, cerebellum, and parietal, temporal, and frontal cortices of the patients. Comparative analyses with [ 18 F]-FDG revealed reduced metabolism only in putamen and caudate ( Delva et al, 2021 ).…”

Section: Synaptic Vesicle Glycoprotein 2a and Positron Emission Tomog...mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A: Features and Functions

et al. 2022

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In recent years, the field of neuroimaging dramatically moved forward by means of the expeditious development of specific radioligands of novel targets. Among these targets, the synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles, present in all synaptic terminals, irrespective of neurotransmitter content. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. The ubiquitous expression in gray matter regions of the brain is the basis of its candidacy as a marker of synaptic density. Following the development of molecules derived from the structure of the anti-epileptic drug levetiracetam, which selectively binds to SV2A, several radiolabeled markers have been synthetized to allow the study of SV2A distribution with positron emission tomography (PET). These radioligands permit the evaluation of in vivo changes of SV2A distribution held to be a potential measure of synaptic density in physiological and pathological conditions. The use of SV2A as a biomarker of synaptic density raises important questions. Despite numerous studies over the last decades, the biological function and the expressional properties of SV2A remain poorly understood. Some functions of SV2A were claimed, but have not been fully elucidated. While the expression of SV2A is ubiquitous, stronger associations between SV2A and Υ amino butyric acid (GABA)-ergic rather than glutamatergic synapses were observed in some brain structures. A further issue is the unclear interaction between SV2A and its tracers, which reflects a need to clarify what really is detected with neuroimaging tools. Here, we summarize the current knowledge of the SV2A protein and we discuss uncertain aspects of SV2A biology and physiology. As SV2A expression is ubiquitous, but likely more strongly related to a certain type of neurotransmission in particular circumstances, a more extensive knowledge of the protein would greatly facilitate the analysis and interpretation of neuroimaging results by allowing the evaluation not only of an increase or decrease of the protein level, but also of the type of neurotransmission involved.

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Section: Synaptic Vesicle Glycoprotein 2a and Positron Emission Tomog...mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A: Features and Functions

et al. 2022

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“…Loss of From Pathophysiology to Treatment of Huntington's Disease SV2A in the putamen correlated with the TMS. In premanifest HDEGC there was only significant decrease in SVA2 in the caudate and putamen [57].…”

Section: Pet-scanmentioning

confidence: 79%

“…One recent imaging study using both PET and MRI, found significant volume loss in caudate, putamen, and pallidum in premanifest HDEGC. In the early manifest HDEGC, they also found significant atrophy in the thalamus, occipital and frontal cortex, and whole gray matter [57].…”

Section: Volumetric Mrimentioning

confidence: 96%

Neuroimaging Biomarkers for Huntington’s Disease

Zande¹,

Ghariq²,

Bresser³

et al. 2022

From Pathophysiology to Treatment of Huntington's Disease

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Biomarkers are of great importance in the prediction of onset and follow-up of patients with Huntington’s disease (HD). Neuroimaging is a convenient biomarker, because of its non-invasive character. Since technology is continuously evolving, we are increasingly able to visualize detailed neural structures and functions. Furthermore, it could also identify new targets for therapeutic interventions. In this chapter, we review findings in neuroimaging research applied to HD. First, we will describe the neuroanatomical structures and cellular processes, which are important in the pathophysiology of HD and are therefore particularly interesting to focus on. We will then discuss the different imaging modalities; from structural to functional, from commonly used to novel imaging strategies. Striatal- and cortical-volume loss on conventional MRI and decrease in uptake of radiotracers on PET are currently the most robust markers of disease progression. The use of other MRI-metabolites, specific PET radioligands, DTI, and fMRI may have the potential to detect HD pathology earlier and more accurately but needs further investigation. These neuroimaging markers, possibly combined, can be useful clinical outcome measures in clinical trials and could improve the management and treatment of future patients.

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“…The progressive degeneration of cortico-striatal circuits and synaptic dysfunction and loss 7 , 8 in Huntington’s disease may induce changes to frequency-specific activities through several mechanisms. EEG activity may change as a direct consequence of the loss of contributing synapses and circuits.…”

Section: Discussionmentioning

confidence: 99%

“…Synaptic dysfunction and loss 7 , 8 and progressive neurodegeneration in Huntington’s disease may lead to changes in brain oscillatory activity as assessed with EEG. 9 In particular, a decrease in synchronized neuronal activity with specific spectral patterns such as reductions in power in the classical alpha (α) band and at the theta-alpha (θ/α) border (7–8 Hz) has been reported in premanifest and early-manifest Huntington’s disease.…”

Section: Introductionmentioning

confidence: 99%

Changes in brain activity with tominersen in early-manifest Huntington’s disease

Hawellek

Garcés

Meghdadi

et al. 2022

Brain Communications

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It is unknown whether alterations in EEG brain activity caused by Huntington’s disease may be responsive to huntingtin-lowering treatment. We analysed EEG recordings of 46 patients (mean age = 47.02 years; standard deviation = 10.19 years; 18 female) with early-manifest Stage 1 Huntington’s disease receiving the huntingtin-lowering antisense oligonucleotide tominersen for 4 months or receiving placebo as well as 39 healthy volunteers (mean age = 44.48 years; standard deviation = 12.94; 22 female) not receiving treatment. Patients on tominersen showed increased resting-state activity within a 4–8 Hz frequency range compared with patients receiving placebo (cluster-based permutation test, P < 0.05). The responsive frequency range overlapped with EEG activity that was strongly reduced in Huntington’s disease compared with healthy controls (cluster-based permutation test, P < 0.05). The underlying mechanisms of the observed treatment-related increase are unknown and may reflect neural plasticity as a consequence of the molecular pathways impacted by tominersen treatment. Hawellek et al. report that patients with Huntington’s disease treated with the huntingtin-lowering antisense oligonucleotide tominersen exhibited increased EEG power in the theta/alpha frequency range. The underlying mechanisms of the observed changes are unknown and may reflect neural plasticity as a consequence of the molecular pathways impacted by tominersen treatment.

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Synaptic Damage and Its Clinical Correlates in People With Early Huntington Disease

Cited by 39 publications

References 49 publications

Synaptic Vesicle Glycoprotein 2A: Features and Functions

Synaptic Vesicle Glycoprotein 2A: Features and Functions

Neuroimaging Biomarkers for Huntington’s Disease

Changes in brain activity with tominersen in early-manifest Huntington’s disease

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