Abstract
Background: Huntington’s disease (HD) is marked by a CAG-repeat expansion in the huntingtin gene that causes neuronal dysfunction and loss, affecting mainly the striatum and the cortex. Alterations in the neurovascular coupling system have been shown to lead to dysregulated energy supply to brain regions in several neurological diseases, including HD, which could potentially trigger the process of neurodegeneration. In particular, it has been observed in cross-sectional human HD studies that vascular alterations are associated to impaired cerebral blood flow (CBF). To assess whether whole-brain changes in CBF are present and follow a pattern of progression, we investigated both resting-state brain perfusion and vascular reactivity longitudinally in the zQ175DN mouse model of HD. Methods: Using pseudo-continuous arterial spin labelling (pCASL) MRI in the zQ175DN model of HD and age-matched wild-type (WT) mice, we assessed whole-brain, resting-state perfusion at 3, 6 and 9 and 13 months of age, and assessed hypercapnia-induced cerebrovascular reactivity (CVR), at 4.5, 6, 9 and 15 months of age. Results: We found increased perfusion in cortical regions of zQ175DN HET mice at 3 months of age, and a reduction of this anomaly at 6 and 9 months, ages at which behavioural deficits have been reported. On the other hand, under hypercapnia, CBF was reduced in zQ175DN HET mice as compared to the WT: for multiple brain regions at 6 months of age, for only somatosensory and retrosplenial cortices at 9 months of age, and brain-wide by 15 months. CVR impairments in cortical regions, the thalamus and globus pallidus were observed in zQ175DN HET mice at 9 months, with whole brain reactivity diminished at 15 months of age. Interestingly, blood vessel density was increased in the motor cortex at 3 months, while average vessel length was reduced in the lateral portion of the caudate putamen at 6 months of age. Conclusion: Our findings reveal early cortical resting-state hyperperfusion and impaired CVR at ages that present motor anomalies in this HD model, suggesting that further characterization of brain perfusion alterations in animal models is warranted as a potential therapeutic target in HD.
| Original language | English |
|---|---|
| Article number | 37 |
| Number of pages | 16 |
| Journal | Journal of Biomedical Science |
| Volume | 31 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2024 |
Funding
This work was funded by the CHDI Foundation, Inc., a non-profit biomedical research organization exclusively dedicated to collaboratively developing therapeutics that will substantially improve the lives of HD-affected individuals. The computational resources and services used in this work were provided by the HPC core facility CalcUA of the University of Antwerp, the VSC (Flemish Supercomputer Center), funded by the Hercules Foundation, and the Flemish Government department EWI. The Flemish Impulse funding for heavy scientific equipment under grant agreement number OZ3544 (granted to AVdL). MV, WDV, and IP are supported by the Research Foundation Flanders FWO (I000123N, I003420N).
| Funders | Funder number |
|---|---|
| University of Antwerp | |
| Flemish Government department EWI | OZ3544 |
| Fonds Wetenschappelijk Onderzoek | I003420N, I000123N |
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Molecular Biology
- Clinical Biochemistry
- Cell Biology
- Biochemistry, medical
- Pharmacology (medical)