Iron dysregulation in Huntington's disease

Müller, Michelle; Leavitt, Blair R.

doi:10.1111/jnc.12739

Cited by 101 publications

(65 citation statements)

References 279 publications

(281 reference statements)

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“…Findings suggesting increased neural iron in basal ganglia structures, including the caudate nucleus, mirror those found at lower field strengths and at postmortem 61. While using susceptibility effects as a proxy for iron burden corresponds well to prior postmortem findings, susceptibility effects in MRI may be caused by a number of different substrates, as previously described.…”

Section: Discussionsupporting

confidence: 74%

7T MRI for neurodegenerative dementias in vivo: a systematic review of the literature

McKiernan

O’Brien

2017

J Neurol Neurosurg Psychiatry

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The spatial resolution of 7T MRI approaches the scale of pathologies of interest in degenerative brain diseases, such as amyloid plaques and changes in cortical layers and subcortical nuclei. It may reveal new information about neurodegenerative dementias, although challenges may include increased artefact production and more adverse effects. We performed a systematic review of papers investigating Alzheimer's disease (AD), Lewy body dementia (LBD), frontotemporal dementia (FTD) and Huntington's disease (HD) in vivo using 7T MRI. Of 19 studies identified, 15 investigated AD (the majority of which examined hippocampal subfield changes), and 4 investigated HD. Ultrahigh resolution revealed changes not visible using lower field strengths, such as hippocampal subfield atrophy in mild cognitive impairment. Increased sensitivity to susceptibility-enhanced iron imaging, facilitating amyloid and microbleed examination; for example, higher microbleed prevalence was found in AD than previously recognised. Theoretical difficulties regarding image acquisition and scan tolerance were not reported as problematic. Study limitations included small subject groups, a lack of studies investigating LBD and FTD and an absence of longitudinal data. In vivo 7T MRI may illuminate disease processes and reveal new biomarkers and therapeutic targets. Evidence from AD and HD studies suggest that other neurodegenerative dementias would also benefit from imaging at ultrahigh resolution.

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Section: Discussionsupporting

confidence: 74%

7T MRI for neurodegenerative dementias in vivo: a systematic review of the literature

McKiernan

O’Brien

2017

J Neurol Neurosurg Psychiatry

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“…Striatal GABAergic medium spiny neurons (MSNs) are involved early in the pathophysiology of HD. MSNs, projecting to the Globus pallidus externus (indirect pathway), and predominantly causing chorea if damaged, are probably more susceptible to degeneration than those of the direct pathway (Muller and Leavitt 2014;Raymond et al 2011). Another hypothesis suggests that a time dependent, differential loss of the two populations of MSNs leads to disease progression in HD ).…”

Section: Discussionmentioning

confidence: 94%

“…Parkinson's disease (iron) or primary dystonia (copper) . A dysregulation of iron homeostasis in brain with changes in magnetic resonance imaging studies seems to be of particular relevance in the neurodegenerative process of HD (Muller and Leavitt 2014;van den Bogaard et al 2013). Striatal GABAergic medium spiny neurons (MSNs) are involved early in the pathophysiology of HD.…”

Section: Discussionmentioning

confidence: 96%

Echogenicity of basal ganglia structures in different Huntington’s disease phenotypes

et al. 2014

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In Huntington's disease (HD), a neurodegenerative-inherited disease, chorea as the typical kind of movement disorder is described. Beside chorea, however, all other kinds of movement disturbances, such as bradykinesia, dystonia, tremor or myoclonus can occur. Aim of the current study was to investigate alterations in the echogenicity of basal ganglia structures in different Huntington's disease phenotypes. 47 patients with manifest and genetically confirmed HD were recruited. All participants underwent a thorough neurological examination. According to a previously described method, classification into predominantly choreatic, mixed or bradykinetic-rigid motor phenotypes was performed depending on subscores of the Unified Huntington's Disease Rating Scale. In addition, findings in juvenile HD were compared to adult HD. Transcranial sonography was performed by investigators blinded to clinical classification. There were no significant differences in basal ganglia echogenicities between the three phenotypes. Size of echogenic area of substantia nigra (SN) correlated positively with CAG repeat and bradykinesia subscore, and negatively with age of onset and chorea subscore. Comparing juvenile and adult HD subtypes, SN hyperechogenicity was significantly more often detectable in the juvenile form (100 vs. 29.3 %, p = 0.002). Regarding echogenicity of caudate or lentiform nuclei, no significant differences were detected. HD patients with the juvenile variant exhibit marked hyperechogenicity of substantia nigra. No significant differences in basal ganglia echogenicities between predominantly choreatic, mixed or bradykinetic-rigid motor phenotypes were detected.

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“…While evidence for the involvement of metals in HD is limited, histological and MRI studies demonstrate elevated iron in the basal ganglia of HD patients (reviewed in [187]). Copper was also reported to be elevated in the basal ganglia of HD patients [188], although other studies report conflicting results, confirming elevated iron but not copper [189,190].…”

Section: Huntington's Diseasementioning

confidence: 98%

Targeting Mitochondrial Metal Dyshomeostasis for the Treatment of Neurodegeneration

Liddell

2015

Neurodegener. Dis. Manag.

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Mitochondrial impairment and metal dyshomeostasis are suggested to be associated with many neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Friedreich's ataxia. Treatments aimed at restoring metal homeostasis are highly effective in models of these diseases, and clinical trials hold promise. However, in general, the effect of these treatments on mitochondrial metal homeostasis is unclear, and the contribution of mitochondrial metal dyshomeostasis to disease pathogenesis requires further investigation. This review describes the role of metals in mitochondria in health, how mitochondrial metals are disrupted in neurodegenerative diseases, and potential therapeutics aimed at restoring mitochondrial metal homeostasis and function.

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Iron dysregulation in Huntington's disease

Cited by 101 publications

References 279 publications

7T MRI for neurodegenerative dementias in vivo: a systematic review of the literature

7T MRI for neurodegenerative dementias in vivo: a systematic review of the literature

Echogenicity of basal ganglia structures in different Huntington’s disease phenotypes

Targeting Mitochondrial Metal Dyshomeostasis for the Treatment of Neurodegeneration

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