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Impaired oxygen metabolism in the brain during visual stimulation in premanifest Huntington's Disease patients detected by 3D-TRIP MRI at 7T
Peter Klinkmueller1,2,3, Martin Kronenbuerger4,5, Xinyuan Miao2,3, Russell L. Margolis5, Peter C. M. van Zijl2,3, Christopher A. Ross4,5,6, and Jun Hua2,3

1Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD, United States, 2F.M. Kirby Research Center for Functional Brain Imaging, Kennedy Krieger Institute, Baltimore, MD, United States, 3Division of MRI Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 4Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 5Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States, 6Department of Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Synopsis

Huntington’s disease (HD) is a neurodegenerative disease caused by a single genetic mutation. Neurovascular abnormalities have been implicated in the pathophysiology of HD. Here, dynamic responses in BOLD, cerebral-blood-flow (CBF) and -volume (CBV) during visual stimulation were measured using 3D-TRiple-acquisition-after-Inversion-Preparation (3D-TRIP) MRI in premanifest HD patients and healthy controls, from which cerebral-metabolic-rate-of-oxygen (CMRO2) response was estimated. Decreased ΔCMRO2 and increased ΔCBV were observed in HD patients compared to controls, which correlated with genetic measures. The results suggested potential value of ΔCMRO2 as a biomarker for HD, and may shed light on the pathophysiology in HD in terms of mitochondrial deficiency.

Introduction

Huntington’s disease (HD) is a neurodegenerative disease caused by a CAG expansion in the Huntingtin gene1. The progression of HD can be separated into premanifest and manifest periods, where the approximate year-to-onset (YTO) of motor symptoms can be predicted from the length of CAG repeats2. Progressive atrophy of striatum is an imaging hallmark for HD3-7. However, ample evidence indicates existence of brain abnormalities in HD not reflected in brain structural changes (atrophy). Such abnormalities include perturbations in brain microvasculature8-15 and brain metabolic disturbances16-21. Previously, we have shown significantly altered baseline cerebral perfusion indicated by increased arteriolar-cerebral-blood-volume (CBVa) in the brain of prodromal HD patients22. Here, in addition to baseline microvascular changes, we examine potential abnormalities in dynamic responses in microvascular and metabolic parameters during functional stimulation in premanifest HD patients. The recently developed 3D-TRiple-acquisition-after-Inversion-Preparation (3D-TRIP) MRI allows the measurement of signal responses in BOLD, cerebral-blood-flow (CBF) and -volume (CBV) during functional stimulation in one single scan23, from which the cerebral-metabolic-rate-of-oxygen (CMRO2) response can be estimated24.

Methods

23 HD patients (15 premanifest, 8 early manifest), and 16 healthy controls matched in age and sex were studied. fMRI experiments were performed on a 7T Philips scanner using 3D-TRIP MRI (TR/TI1/TI2/TI3/FA=4.0s/0.6s/1.5s/2.4s/7º, voxel=3.5mm isotropic) during a flashing checker-board paradigm (4 blocks of alternating 20s flashing and 40s rest periods). Data analysis was performed using a pipeline implemented for 3D-TRIP MRI23. Only voxels that met activation detection criteria in all three modalities in the visual cortex were used to calculate signal changes in the analysis. The activation detection threshold was identical in all three modalities (adjusted P<0.05), and signal-to-noise ratio (SNR) thresholds established in previous studies were used to exclude voxels with low SNR23,25. Group comparisons were performed with two-tailed T-tests. Correlations between dynamic responses in BOLD, CBF, CBV, and CMRO2, and YTO were calculated using multiple regression. Age, sex, and brain atrophy were all accounted for as covariates. Multiple comparisons were corrected with the false-discovery rate (adjusted P<0.05).

Results

As shown in Fig. 1, trends (but not significant) of reduced responses in BOLD (ΔBOLD) and CBF (ΔCBF) during visual stimulation were observed in HD patients compared to controls, in congruence with some previous reports8-15. Meanwhile, CBV response (ΔCBV) significantly increased in HD patients, leading to the deduction of a significantly reduced CMRO2 response (ΔCMRO2) in HD patients. Note that all signal responses in the control group were in normal range23-25. Significant correlations (Fig. 2) were detected between YTO and ΔCBV (negative correlation) and ΔCMRO2 (positive correlation), but not between YTO and ΔBOLD and ΔCBF in HD patients. Note that all HD patients showed lower ΔCMRO2 than the average value from the control group, including the three patients with YTO>20yr (Fig. 2). Some of the patients showed completely abolished CMRO2 response during the visual stimulation (Fig. 2). To make sure that the subjects are awake during the flashing checker-board presentation, they were asked to press a button at the start and end of each flashing period.

Discussion and Conclusion

The impaired CMRO2 response during visual stimulation in HD patients can most likely be linked to the well-known mitochondrial deficiency in HD pathology16-21. It seems to be consistent with some prior literature. For instance, Mochel et al. showed unchanged Pi/PCr and Pi/ATP ratios during and after visual stimulation in early manifest HD patients using 31P MRS26. Our data also imply that metabolic deficits (ΔCMRO2) seem to occur earlier and present greater effect sizes than microvascular abnormalities (ΔCBV). Interestingly, ΔCBV increased here in HD patients, despite an elevated baseline CBVa shown previously22. This is somewhat surprising as a larger baseline value usually results in a smaller response during stimulation. One possible explanation is that the larger ΔCBV response may primarily originate from the venous vessels, whereas the baseline abnormality mainly occurs in the arteriolar compartment (CBVa). We chose to use visual stimulation here as a simple and robust paradigm to test our methodology. Nevertheless, the visual cortex is usually considered relatively spared in the early stages of HD. The fact that we can detect significant abnormality in the visual cortex in premanifest HD patients suggests that such effects may be more prominent in other brain regions more affected in HD. We believe that these preliminary results merit further investigation in a larger cohort and with a longitudinal design.

Acknowledgements

Funding through the Huntington’s Society of America (HDSA) and the Dana Foundation, NIBIB P41 EB015909.

References

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Figures

Figure 1: Responses in the BOLD, CBV, CBF, and CMRO2 signals in the visual cortex during visual stimulation in HD patients and controls. *P<0.05.

Figure 2: Correlation between responses in the BOLD, CBV, CBF, and CMRO2 signals in the visual cortex during visual stimulation and the estimate year-to-onset (YTO), which is derived from the extent of genetic mutation of the HD patients. The horizontal dotted line represents the mean value of the control group. The colored regions specify the stage of HD progression as measured by YTO (green: premanifest, >8yr., orange: premanifest, <8yr., and red: <0yr. or manifest HD). *P<0.05. R2: adjusted R2 from multiple regression.

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)
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