Abstract
The objective of this study was to investigate lobule-specific cerebellar structural alterations relevant to clinical behavioral characteristics of Prader-Willi syndrome (PWS). We performed a case-control study of 21 Japanese individuals with PWS (age; median 21.0, range 13–50 years, 14 males, 7 females) and 40 age- and sex-matched healthy controls with typical development. Participants underwent 3-Tesla magnetic resonance imaging. Three-dimensional T1-weighted images were assessed for cerebellar lobular volume and adjusted for total intracerebellar volume (TIV) using a spatially unbiased atlas template to give a relative volume ratio. A region of interest analysis included the deep cerebellar nuclei. A correlation analysis was performed between the volumetric data and the clinical behavioral scores derived from the standard questionnaires (hyperphagia, autism, obsession, and maladaptive index) for global intelligence assessment in paired subgroups. In individuals with PWS, TIV was significantly reduced compared with that of controls (p < 0.05, family-wise error corrected; mean [standard deviation], 1014.1 [93.0] mm3). Decreased relative lobular volume ratios were observed in posterior inferior lobules with age, sex, and TIV as covariates (Crus I, Crus II, lobules VIIb, VIIIa, VIIIb, and IX). However, increased ratios were found in the dentate nuclei bilaterally in individuals with PWS (p < 0.01); the mean (standard deviation) × 10−3 was as follows: left, 1.58 (0.26); right, 1.67 (0.30). The altered lobular volume ratios showed negative correlations with hyperphagic and autistic characteristics and positive correlations with obsessive and intellectual characteristics. This study provides the first objective evidence of topographic patterns of volume differences in cerebellar structures consistent with clinical behavioral characteristics in individuals with PWS and strongly suggests a cerebellar contribution to altered functional brain connectivity in PWS.
Highlights
Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder that is characterized by a specific developmental trajectory, which includes hypotonia, developmental delay, hyperphagia typically causing obesity, and a higher vulnerability to maladaptive behavior [1,2,3,4]
While significant relative volume reductions were observed in the posterior inferior lobules, as well as in total intracerebellar volume, increased volume ratios were detected in the cerebellar dentate nuclei (cDN)
Given the functional correlation that has been clinically observed, such as the cDN and cognitive function in patients with involvement of cDN [44], our current findings strongly suggest that the deep cerebellar nuclei including the cDN contribute to the developmental behavioral characteristics in PWS
Summary
Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder that is characterized by a specific developmental trajectory, which includes hypotonia, developmental delay, hyperphagia typically causing obesity, and a higher vulnerability to maladaptive behavior [1,2,3,4]. These symptoms typically develop in early life in a phase-dependent manner and frequently overlap. Previous magnetic resonance imaging (MRI) studies have noninvasively detected in vivo structural brain alterations in individuals with PWS.
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