Brain White-Matter Volume Loss and Glucose Hypometabolism Precede the Clinical Symptoms of Huntington's Disease

Brain White-Matter Volume Loss and Glucose Hypometabolism Precede the Clinical Symptoms of Huntington's Disease

Andrea Ciarmiello, MD¹, Milena Cannella, PhD², Secondo Lastoria, MD¹, Maria Simonelli, DPM², Luigi Frati, MD, PhD³^,4, David C. Rubinsztein, MB, PhD⁵ and Ferdinando Squitieri, MD, PhD²

¹ Nuclear Medicine Unit, IRCCS "G. Pascale," Naples, Italy; ² Neurogenetics Unit, IRCCS Neuromed, Pozzilli, Isernia, Italy; ³ Department of Experimental Medicine and Pathology, University "La Sapienza" of Rome, Rome, Italy; ⁴ IRCCS Neuromed, Pozzilli, Isernia, Italy; and ⁵ Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, England

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FIGURE 1. Graph of asymptomatic mutation carriers and estimated number of years until manifestation of HD symptoms. Age at onset was predicted by considering each subject's age and expected years until onset (y-axis) for a given CAG repeat expansion number (x-axis), according to published models (20,22,24–26). All subjects had an MMSE cognitive score—age and scholar corrected—within the reference range (18) and had minimal changes in UHDRS cognitive and MMSE scores after 2 y.

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FIGURE 2. Axial MR images from healthy subject (top row) and patient with symptomatic HD (bottom row). Note smaller fGM and fWM volumes in patient with HD than in healthy subject. Slices represent R1 and R2 relaxation rates and corresponding segmented images. Segmented images are coded gray for GM, white for WM, blue for CSF, green for putamen, and bright red for globus pallidus.

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FIGURE 3. Scatter plot of fGM ( ${square}$ ), fWM ( ${circ}$ ), and fCSF ( ${triangleup}$ ) volumes vs. age in healthy subjects (red shapes), affected subjects (white shapes), and presymptomatic population (blue shapes). Affected subjects (n = 47) have significantly smaller fGM and fWM volumes than do healthy subjects (46.7 ± 4.0 mL vs. 52.4 ± 2.1 mL, P < 0.0001, and 30.0 ± 3.5 mL vs. 37.7 ± 2.2 mL, P < 0.0001, respectively), with corresponding increase in fCSF (23.1 ± 5.1 mL vs. 10.0 ± 2.4 mL, P < 0.0001). Presymptomatic subjects (n = 24) have significantly smaller fGM and fWM volumes than do healthy subjects (n = 54) (51.2 ± 2.2 mL vs. 52.4 ± 2.1 mL, P = 0.0506, and 35.3 ± 2.5 mL vs. 37.7 ± 2.2 mL, P < 0.0001, respectively), with corresponding increase in fCSF volume (13.5 ± 3.5 mL vs. 10.0 ± 2.4 mL, P < 0.0001).

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FIGURE 4. Scatter plot of fractional WM volume vs. time to onset in asymptomatic HD mutation carriers. Positive linear correlation was found between WM volume loss and expected number of years until onset (r² = 0.39; P = 0.0011).

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FIGURE 5. Graph showing positive linear correlation between decline in ¹⁸F-FDG uptake in caudate (A; r² = 0.34, P = 0.003) or putamen (B; r² = 0.44, P = 0.0001) and estimated number of years until HD onset in presymptomatic gene-positive subjects. Positive linear correlation was found between decreased striatal ¹⁸F-FDG uptake and expected years until onset.

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FIGURE 6. Graph showing longitudinal changes in mean ¹⁸F-FDG uptake on follow-up of symptomatic (A; n = 21) and preclinical (B; n = 10) HD populations. X-axes show baseline and follow-up evaluation times, and y-axes show mean percentage of ¹⁸F-FDG uptake in each brain region. SEs range from 0.96% to 2.65%. Symptomatic population shows longitudinal change from baseline scan in frontal (–8.3%, P = 0.003), parietal (–8.4%, P = 0.003), and temporal (–4.6%, P = 0.017) cortices and in caudate (–6.9%, P = 0.036) and putamen (–12.4%, P = 0.027). Asymptomatic mutation carriers show longitudinal change from baseline scan in frontal (–5.4%, P = 0.031) and parietal (–5.5%, P = 0.027) cortices and in caudate (–7.2%, P = 0.037) and putamen (–11.5%, P = 0.022).