E05 Mutation-related apparent myelin, not axon density, drives white matter pathology in premanifest huntington’s disease: evidence from in vivo ultra-strong gradient MRI

2021 ◽  
Author(s):  
Chiara Casella ◽  
Maxime Chamberland ◽  
Pedro Luque Laguna ◽  
Greg D Parker ◽  
Anne Rosser ◽  
...  
Keyword(s):  
White Matter ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Axon Density ◽  
Strong Gradient ◽  
White Matter Pathology

scholarly journals Mutation-related apparent myelin, not axon density, drives white matter differences in premanifest Huntington's disease: Evidence from in vivo ultra-strong gradient MRI

2021 ◽  
Author(s):  
Chiara Casella ◽  
Maxime Chamberland ◽  
Pedro Luque-Laguna ◽  
Greg D Parker ◽  
Anne E Rosser ◽  
...  
Keyword(s):  
White Matter ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Volume Fraction ◽  
Diffusion Tensor ◽  
Direct Result ◽  
Magnetization Transfer Ratio ◽  
Axon Density ◽  
Strong Gradient

White matter (WM) alterations have been observed early in Huntington's disease (HD) progression but their role in the disease-pathophysiology remains unknown. We exploited ultra-strong-gradient MRI to tease apart contributions of myelin (with the magnetization transfer ratio), and axon density (with the restricted volume fraction from the Composite Hindered and Restricted Model of Diffusion) to WM differences between premanifest HD patients and age- and sex-matched controls. Diffusion tensor MRI (DT-MRI) measures were also assessed. We used tractometry to investigate region-specific changes across callosal segments with well-characterized early- and late-myelinating axonal populations, while brain-wise alterations were explored with tract-based cluster analysis (TBCA). Behavioural measures were included to explore disease-associated brain-function relationships. We detected lower myelin in the rostrum of patients (tractometry: p = 0.0343; TBCA: p = 0.030), but higher myelin in their splenium (p = 0.016). Importantly, patients' myelin and mutation size were positively associated (all p-values < 0.01), indicating that increased myelination might be a direct result of the mutation. Finally, myelin was higher than controls in younger patients but lower in older patients (p = 0.003), suggesting detrimental effects of increased myelination later in the course of the disease. Higher FR in patients' left cortico-spinal tract (CST) (p = 0.03) was detected, and was found to be positively associated with MTR in the posterior callosum (p = 0.033), possibly suggesting compensation to myelin alterations. This comprehensive, ultra-strong gradient MRI investigation provides novel evidence of CAG-driven myelin alterations in premanifest HD which may reflect neurodevelopmental, rather than neurodegenerative disease-associated changes.

scholarly journals In vivo characterization of white matter pathology in premanifest huntington's disease

2018 ◽  
Vol 84 (4) ◽  
pp. 497-504 ◽  
Author(s):  
Jiaying Zhang ◽  
Sarah Gregory ◽  
Rachael I. Scahill ◽  
Alexandra Durr ◽  
David L. Thomas ◽  
...  
Keyword(s):  
White Matter ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
White Matter Pathology ◽  
In Vivo Characterization

scholarly journals In Vivo Expression of Reprogramming Factor OCT4 Ameliorates Myelination Deficits and Induces Striatal Neuroprotection in Huntington’s Disease

2020 ◽  
Author(s):  
Ji Hea Yu ◽  
Bae-Geun Nam ◽  
MinGi Kim ◽  
Jung Hwa Seo ◽  
Sung-Rae Cho
Keyword(s):  
White Matter ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Grip Strength ◽  
Cell Fate ◽  
Gabaergic Neurons ◽  
Plastic State ◽  
Qrt Pcr ◽  
Virus Serotype

Abstract Background: White matter atrophy has been shown to precede the massive loss of striatal GABAergic neurons in Huntington’s disease (HD). The HD-induced white matter atrophy is associated with motor deficits. In vivo reprogramming toward a plastic state has emerged as a new approach for treating neurological diseases. Particularly, octamer-binding transcription factor 4 (OCT4) can induce myelin repair and functional recovery. This study investigated the effects of in situ expression of reprogramming factor OCT4 on behavioral performances, neural stem cell (NSC) niche activation in the subventricular zone (SVZ) and induction of cell fate specific to the changed microenvironment of HD. Methods: R6/2 mice, a transgenic mouse model of HD, randomly received adeno-associated virus serotype 9 (AAV9)-OCT4, AAV9-Null, or phosphate-buffered saline in both lateral ventricles at 4 weeks of age. To evaluate the behavioral improvement, rotarod test and grip strength test were performed at regular intervals. To investigate the expression of oligodendrocyte progenitor cell (OPC)-related genes, real-time quantitative reverse transcription PCR (qRT-PCR) and immunohistochemistry were performed. Next, we assessed the amelioration of myelination deficits via transmission electron microscope (TEM) and magnetic resonance imaging (MRI) at 13 weeks of age. Finally, we confimed striatal neuroprotecion by qRT-PCR and confocal microscopy.Results: The AAV9-OCT4 group displayed significantly improved rotarod performance and grip strength compared to the control groups. Following AAV9-OCT4 treatment, the number of newly generated NSCs and OPCs was significantly increased in the SVZ, and the expression of OPC-related genes such as NG2, Olig2, PDGFRα, Wnt3 and myelin regulatory factor (MYRF), and glial cell-derived neuroprotective factor (GDNF) was significantly increased. Further, the amelioration of myelination deficits in the corpus callosum was observed through TEM and MRI, and striatal DARPP32+ GABAergic neurons significantly increased in the AAV9-OCT4 group.

scholarly journals Longitudinal in vivo MRI in a Huntington’s disease mouse model: Global atrophy in the absence of white matter microstructural damage

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Jessica J. Steventon ◽  
Rebecca C. Trueman ◽  
Da Ma ◽  
Emma Yhnell ◽  
Zubeyde Bayram-Weston ◽  
...  
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Microstructural Damage

Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures

2006 ◽  
Vol 21 (9) ◽  
pp. 1317-1325 ◽  
Author(s):  
H. Diana Rosas ◽  
David S. Tuch ◽  
Nathanael D. Hevelone ◽  
Alexandra K. Zaleta ◽  
Mark Vangel ◽  
...  
Keyword(s):  
Diffusion Tensor Imaging ◽  
White Matter ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Diffusion Tensor ◽  
White Matter Pathology ◽  
Clinical Measures

scholarly journals In Vivo Expression of Reprogramming Factor OCT4 Ameliorates Myelination Deficits and Induces Striatal Neuroprotection in Huntington’s Disease

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 712
Author(s):  
Ji-Hea Yu ◽  
Bae-Geun Nam ◽  
Min-Gi Kim ◽  
Soonil Pyo ◽  
Jung-Hwa Seo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cell Fate ◽  
Gabaergic Neurons ◽  
Oligodendrocyte Progenitor Cells ◽  
Adeno Associated Virus ◽  
In Vivo Expression ◽  
Transcription Factor 4 ◽  
Phosphate Buffered Saline

White matter atrophy has been shown to precede the massive loss of striatal GABAergic neurons in Huntington’s disease (HD). This study investigated the effects of in vivo expression of reprogramming factor octamer-binding transcription factor 4 (OCT4) on neural stem cell (NSC) niche activation in the subventricular zone (SVZ) and induction of cell fate specific to the microenvironment of HD. R6/2 mice randomly received adeno-associated virus 9 (AAV9)-OCT4, AAV9-Null, or phosphate-buffered saline into both lateral ventricles at 4 weeks of age. The AAV9-OCT4 group displayed significantly improved behavioral performance compared to the control groups. Following AAV9-OCT4 treatment, the number of newly generated NSCs and oligodendrocyte progenitor cells (OPCs) significantly increased in the SVZ, and the expression of OPC-related genes and glial cell-derived neurotrophic factor (GDNF) significantly increased. Further, amelioration of myelination deficits in the corpus callosum was observed through electron microscopy and magnetic resonance imaging, and striatal DARPP32+ GABAergic neurons significantly increased in the AAV9-OCT4 group. These results suggest that in situ expression of the reprogramming factor OCT4 in the SVZ induces OPC proliferation, thereby attenuating myelination deficits. Particularly, GDNF released by OPCs seems to induce striatal neuroprotection in HD, which explains the behavioral improvement in R6/2 mice overexpressing OCT4.

In vivo examination of the Pre- and postsynaptic dopamine neurons in huntington's disease

1996 ◽  
Vol 6 ◽  
pp. 130
Author(s):  
N. Ginovart ◽  
A. Lundin ◽  
L. Farde ◽  
C. Halldin ◽  
C.G. Swahn ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Dopamine Neurons

scholarly journals Cortical circuit alterations precede disease onset in Huntington’s disease mice

2018 ◽  
Author(s):  
Johanna Neuner ◽  
Elena Katharina Schulz-Trieglaff ◽  
Sara Gutiérrez-Ángel ◽  
Fabian Hosp ◽  
Matthias Mann ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Primary Motor Cortex ◽  
Disease Onset ◽  
Single Neurons ◽  
Two Photon ◽  
Layer 2 ◽  
Cortical Circuit

AbstractHuntington’s disease (HD) is a devastating hereditary movement disorder, characterized by degeneration of neurons in the striatum and cortex. Studies in human patients and mouse HD models suggest that disturbances of neuronal function in the neocortex play an important role in the disease onset and progression. However, the precise nature and time course of cortical alterations in HD have remained elusive. Here, we use chronicin vivotwo-photon calcium imaging to monitor the activity of single neurons in layer 2/3 of the primary motor cortex in awake, behaving R6/2 transgenic HD mice and wildtype littermates. R6/2 mice show age-dependent changes in neuronal activity with a clear increase in activity at the age of 8.5 weeks, preceding the onset of motor and neurological symptoms. Furthermore, quantitative proteomics demonstrate a pronounced downregulation of synaptic proteins in the cortex, and histological analyses in R6/2 mice and HD patient samples reveal reduced inputs from parvalbumin-positive interneurons onto layer 2/3 pyramidal cells. Thus, our study provides a time-resolved description as well as mechanistic details of cortical circuit dysfunction in HD.Significance statementFuntional alterations in the cortex are believed to play an important role in the pathogenesis of Huntington’s disease (HD). However, studies monitoring cortical activity in HD modelsin vivoat a single-cell resultion are still lacking. We have used chronic two-photon imaging to investigate changes in the activity of single neurons in the primary motor cortex of awake presymptomatic HD mice. We show that neuronal activity increases before the mice develop disease symptoms. Our histological analyses in mice and in human HD autopsy cases furthermore demonstrate a loss inhibitory synaptic terminals from parvalbimun-positive interneurons, revealing a potential mechanism of cortical circuit impairment in HD.

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