Seeking huntington disease biomarkers by multimodal, cross‐sectional basal ganglia imaging

Abstract

Neurodegeneration of the striatum in Huntington disease (HD) is characterized by loss of medium-spiny neurons, huntingtin nuclear inclusions, reactive gliosis, and iron accumulation. Neuroimaging allows in vivo detection of the macro- and micro-structural changes that occur from presymptomatic stages of the disease (preHD). The aim of our study was to evaluate the reliability of multimodal imaging as an in vivo biomarker of vulnerability and development of the disease and to characterize macro- and micro-structural changes in subcortical nuclei in HD. Macrostructure (T1-weighted images), microstructure (diffusion tensor imaging), and iron content (R 2* relaxometry) of subcortical nuclei and medial temporal lobe structures were evaluated by a 3 T scanner in 17 preHD carriers, 12 early-stage patients and 29 matched controls. We observed a volume reduction and microstructural changes in the basal ganglia (caudate, putamen, and globus pallidus) and iron accumulation in the globus pallidus in both preHD and symptomatic subjects; all these features were significantly more pronounced in patients, in whom degeneration extended to the other subcortical nuclei (i.e., thalamus and accumbens). Mean diffusivity (MD) was the most powerful predictor in models explaining more than 50% of the variability in HD development in the caudate, putamen, and thalamus. These findings suggest that the measurement of MD may further enhance the well-known predictive value of striatal volume to assess disease progression as it is highly sensitive to tissue microimpairment. Multimodal imaging may detect brain changes even in preHD stages.

Iron accumulation in the basal ganglia in Huntington's disease: cross-sectional data from the IMAGE-HD study

“…Evaluation of iron content in controls, as reflected in susceptibility values against reported iron content measured through biochemical techniques and QSM in previous studies,16 17 20 34 35 revealed excellent linear approximations: coefficient of determination (R 2 ) >0.90 (see online supplementary table S2 and supplementary figure S1A,B). Iron content in the HD groups, as previously estimated through relaxometry,7 MFC9 and FDRI,3 similarly exhibited good to excellent linear approximations with the iron content in the present study (pre-HD R 2 =0.77 and 0.80; symp-HD R 2 =0.80–0.97) (see online supplementary table S2 and supplementary figure S1C,D). We also found statistically significant positive correlations between susceptibility values and disease burden scores in all HD participants (pre-HD and symp-HD together) in the putamen (r=0.39, p<0.001) and caudate (r=0.32, p<0.01) (see figure 3).…”

“…However, the susceptibility values reported for controls were within the range of variation previously reported in other QSM studies,16 17 35 38 reflected the same rank ordering by brain structure (from highest to lowest: pallidum, putamen, caudate and thalamus) and obtained good to excellent linear approximation not only with measures from other QSM16 17 35 40 but also biochemical studies 20 34. This was also the case for pre-HD and symp-HD groups, with reference to iron content measured with MRI techniques other than QSM 3 7 9. Further studies that employ dual-echo acquisition of GRE data are, however, required to further validate the present findings.…”

Quantitative Susceptibility Mapping Suggests Altered Brain Iron in Premanifest Huntington Disease

“…Similar higher sensitivity of susceptibility compared to R2* has been observed previously in detecting tissue changes in multiple sclerosis, in which demyelination is a known disease hallmark 46 . In addition, some striatal demyelination and loss of tissue integrity in premanifest-HD might also partly explain the increased mean diffusivity observed in another study 19 . It is worth noticing that in most of the deep gray matter regions investigated in this study, myelin content is not expected to be very high, therefore iron change is still likely to be the dominant source of the observed susceptibility and R2* increases in premanifest-HD group.…”

“…These studies in advanced HD have sparked interest in investigating potentially abnormal iron accumulation during earlier stages of the disease. Several recent studies using R2* measurements 18, 19 or magnetic susceptibility-related measures, such as phase 20 , Magnetic Field Correlation 21 and field shift 17 , have indeed suggested that brain iron levels are increased in premanifest or early stage HD patients.…”

Basal Ganglia Volumes: MR-Derived Reference Ranges and Lateralization Indices for Children and Young Adults

“…Huntington disease (HD) 26 and dentatorubral-pallidoluysian atrophy (DRPLA) 27 are both late clinical onset, polyglutamine repeat disorders inherited in an autosomal dominant way and selectively causing atrophy of the CN in HD and the GP in DRPLA. In both disorders an anticipation phenomenon occurs meaning that the next generation of gene carriers will have a longer polyglutamine repeat region and will present clinical symptoms earlier in life.…”