Myelin Breakdown and Iron Changes in Huntington’s Disease: Pathogenesis and Treatment Implications

Bartzokis, George; Lu, Po H.; Tishler, Todd A.; Fong, Sophia M.; Oluwadara, Bolanle; Finn, Æ J. Paul; Huang, Danny; Bordelon, Yvette; Mintz, Jim; Perlman, Susan

doi:10.1007/s11064-007-9352-7

Cited by 210 publications

(306 citation statements)

References 89 publications

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“…Abnormalities in WM microstructure have been reported in postmortem studies of humans with HD (de la Monte et al 1988;Halliday et al 1998). This research was confirmed by in vivo studies with magnetic resonance imaging (MRI), which reported extensive WM volume loss (Aylward et al 1998, 2012Thieben et al 2002;Rosas et al 2003;Fennema-Notestine et al 2004;Beglinger et al 2005;Ciarmiello et al 2006;Paulsen et al 2006;Jech et al 2007;Squitieri et al 2009;Tabrizi et al 2009Tabrizi et al , 2011Tabrizi et al , 2012Tabrizi et al , 2013) and changes in WM microstructure (Mascalchi et al 2004;Reading et al 2005;Rosas et al 2006;Bartzokis et al 2007;Sritharan et al 2010;Stoffers et al 2010;Dumas et al 2012;Matsui et al 2014). Nevertheless, these previous macro-and microstructural studies focused on wholebrain WM or Region of Interest analyses.…”

Section: Introductionmentioning

confidence: 81%

The Corticospinal Tract in Huntington's Disease

Phillips¹,

Squitieri

Sánchez-Castañeda

et al. 2014

Cereb. Cortex

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Huntington's disease (HD) is characterized by progressive motor impairment. Therefore, the connectivity of the corticospinal tract (CST), which is the main white matter (WM) pathway that conducts motor impulses from the primary motor cortex to the spinal cord, merits particular attention. WM abnormalities have already been shown in presymptomatic (Pre-HD) and symptomatic HD subjects using magnetic resonance imaging (MRI). In the present study, we examined CST microstructure using diffusion tensor imaging (DTI)-based tractography in 30-direction DTI data collected from 100 subjects: Pre-HD subjects (n = 25), HD patients (n = 25) and control subjects (n = 50), and T 2 *-weighted (iron sensitive) imaging. Results show decreased fractional anisotropy (FA) and increased axial (AD), and radial diffusivity (RD) in the bilateral CST of HD patients. Pre-HD subjects had elevated iron in the left CST, regionally localized between the brainstem and thalamus. CAG repeat length in conjunction with age, as well as motor (UHDRS) assessment were correlated with CST FA, AD, and RD both in Pre-HD and HD. In the presymptomatic phase, increased iron in the inferior portion supports the "dying back" hypothesis that axonal damage advances in a retrograde fashion. Furthermore, early iron alteration may cause a high level of toxicity, which may contribute to further damage.

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Section: Introductionmentioning

confidence: 81%

The Corticospinal Tract in Huntington's Disease

Phillips¹,

Squitieri

Sánchez-Castañeda

et al. 2014

Cereb. Cortex

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“…Since the majority of brain cholesterol is synthesised during prenatal life [45], HD neurodegeneration may be seeded early, with individuals only becoming symptomatic later in life. A current hypothesis suggests that errors in myelination during development may be a factor in human HD, taking many years to manifest before onset due to compensatory mechanisms that function early but become overwhelmed in the aged brain [46]. Alternatively, early changes to cholesterol biosynthesis may be independent of the pathological processes in this HD model.…”

Section: Discussionmentioning

confidence: 98%

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

Kreilaus

Spiro

Hannan

et al. 2015

JHD

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. (2015). Brain cholesterol synthesis and metabolism is progressively disturbed in the R6/1 mouse model of Huntington's disease: a targeted GC-MS/MS sterol analysis. Journal of Huntington's Disease, 4 (4), 305-318.Brain cholesterol synthesis and metabolism is progressively disturbed in the R6/1 mouse model of Huntington' s disease: a targeted GC-MS/MS sterol analysis AbstractBackground:Cholesterol has essential functions in neurological processes that require tight regulation of synthesis and metabolism. Perturbed cholesterol homeostasis has been demonstrated in Huntington's disease, however the exact role of these changes in disease pathogenesis is not fully understood. Objective:This study aimed to comprehensively examine changes in cholesterol biosynthetic precursors, metabolites and oxidation products in the striatum and cortex of the R6/1 transgenic mouse model of Huntington's disease. We also aimed to characterise the progression of the physical phenotype in these mice. Methods:GC-MS/MS was used to quantify a broad range of sterols in the striatum and cortex of R6/1 and wild type mice at 6, 12, 20, 24 and 28 weeks of age. Motor dysfunction was assessed over 28 weeks using the RotaRod and the hind-paw clasping tests. Results:24(S)-Hydroxycholesterol and 27-hydroxycholesterol were the major cholesterol metabolites that significantly changed in R6/1 mice. These changes were specifically localised to the striatum and were detected at the end stages of the disease. Cholesterol synthetic precursors (lathosterol and lanosterol) were significantly reduced in the cortex and striatum by 6 weeks of age, prior to the onset of motor dysfunction, as well as the cognitive and affective abnormalities previously reported. Elevated levels of desmosterol, a substrate of delta(24)-sterol reductase (DHCR24), were also detected in R6/1 mice at the end time-point. Female R6/1 mice exhibited a milder weight loss and hind paw clasping phenotype compared to male R6/1 mice, however, no difference in the brain sterol profile was detected between sexes. Conclusion:Several steps in cholesterol biosynthetic and metabolic pathways are differentially altered in the R6/1 mouse brain as the disease progresses and this is most severe in the striatum. This provides further insights into early molecular mediators of HD onset and disease progression and identifies candidate molecular targets for novel therapeutic approaches.

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“…Differentiating oligodendrocytes have very high iron requirements and may have a critical role in brain iron uptake (reviewed in Bartzokis et al, 2007a;Bartzokis et al, 2007b). This may be especially important in the hippocampus where 50% of oligodendrocytes are juxtaposed directly on blood vessels and may thus be in a position to acquire iron directly from the vasculature (Vinet et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

Bartzokis

Tingus

et al. 2011

Neuropsychopharmacol

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Brain iron increases with age and is abnormally elevated early in the disease process in several neurodegenerative disorders that impact memory including Alzheimer's disease (AD). Higher brain iron levels are associated with male gender and presence of highly prevalent allelic variants in genes encoding for iron metabolism proteins (hemochromatosis H63D (HFE H63D) and transferrin C2 (TfC2)). In this study, we examined whether in healthy older individuals memory performance is associated with increased brain iron, and whether gender and gene variant carrier (IRON + ) vs noncarrier (IRONÀ) status (for HFE H63D/TfC2) modify the associations. Tissue iron deposited in ferritin molecules can be measured in vivo with magnetic resonance imaging utilizing the field-dependent relaxation rate increase (FDRI) method. FDRI was assessed in hippocampus, basal ganglia, and white matter, and IRON + vs IRONÀ status was determined in a cohort of 63 healthy older individuals. Three cognitive domains were assessed: verbal memory (delayed recall), working memory/attention, and processing speed. Independent of gene status, worse verbal-memory performance was associated with higher hippocampal iron in men (r ¼ À0.50, p ¼ 0.003) but not in women. Independent of gender, worse verbal working memory performance was associated with higher basal ganglia iron in IRONÀ group (r ¼ À0.49, p ¼ 0.005) but not in the IRON + group. Between-group interactions (p ¼ 0.006) were noted for both of these associations. No significant associations with white matter or processing speed were observed. The results suggest that in specific subgroups of healthy older individuals, higher accumulations of iron in vulnerable gray matter regions may adversely impact memory functions and could represent a risk factor for accelerated cognitive decline. Combining genetic and MRI biomarkers may provide opportunities to design primary prevention clinical trials that target high-risk groups.

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Myelin Breakdown and Iron Changes in Huntington’s Disease: Pathogenesis and Treatment Implications

Cited by 210 publications

References 89 publications

The Corticospinal Tract in Huntington's Disease

The Corticospinal Tract in Huntington's Disease

Brain Cholesterol Synthesis and Metabolism is Progressively Disturbed in the R6/1 Mouse Model of Huntington’s Disease: A Targeted GC-MS/MS Sterol Analysis

Gender and Iron Genes May Modify Associations Between Brain Iron and Memory in Healthy Aging

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