BackgroundNeuronal intranuclear inclusion disease (NIID) is a heterogenous neurodegenerative disorder named after its pathological features. It has long been considered a disease of genetic origin. Recently, the GGC repeated expansion in the 5′-untranslated region (5′UTR) of the NOTCH2NLC gene has been found in adult-onset NIID in Japanese individuals. This study was aimed to investigate the causative mutations of NIID in Chinese patients.MethodsFifteen patients with NIID were identified from five academic neurological centres. Biopsied skin samples were analysed by histological staining, immunostaining and electron microscopic observation. Whole-genome sequencing (WGS) and long-read sequencing (LRS) were initially performed in three patients with NIID. Repeat-primed PCR was conducted to confirm the genetic variations in the three patients and the other 12 cases.ResultsOur patients included 14 adult-onset patients and 1 juvenile-onset patient characterised by degeneration of multiple nervous systems. All patients were identified with intranuclear inclusions in the nuclei of fibroblasts, fat cells and ductal epithelial cells of sweat glands. The WGS failed to find any likely pathogenic variations for NIID. The LRS successfully identified that three patients with adult-onset NIID showed abnormalities of GGC expansion in 5′UTR of the NOTCH2NLC gene. The GGC repeated expansion was further confirmed by repeat-primed PCR in seven familial cases and eight sporadic cases.ConclusionOur findings provided evidence that confirmed the GGC repeated expansion in the 5′UTR of the NOTCH2NLC gene is associated with the pathogenesis of NIID. Additionally, the GGC expansion was not only responsible for adult-onset patients, but also responsible for juvenile-onset patients.

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Purpose To quantify bulk bone water to test the hypothesis that bone water concentration (BWC) is negatively correlated with bone mineral density (BMD) and is positively correlated with age, and to propose the suppression ratio (SR) (the ratio of signal amplitude without to that with long-T2 suppression) as a potentially stronger surrogate measure of porosity, which is evaluated ex vivo and in vivo. Materials and Methods Human subject studies were conducted in compliance with institutional review board and HIPAA regulations. Healthy men and women (n = 72; age range, 20–80 years) were examined with a hybrid radial ultrashort echo time magnetic resonance (MR) imaging sequence at 3.0 T, and BWC was determined in the tibial midshaft. In a subset of 40 female subjects, the SR was measured with a similar sequence. Cortical volumetric BMD (vBMD) was measured by means of peripheral quantitative computed tomography (CT). The method was validated against mi-cro-CT–derived porosity in 13 donor human cortical bone specimens. Associations among parameters were evaluated by using standard statistical tools. Results BWC was positively correlated with age (r = 0.52; 95% confidence interval [CI]: 0.22, 0.73; P = .002) and negatively correlated with vBMD at the same location (r = −0.57; 95% CI: −0.76, −0.29; P < .001). Data were suggestive of stronger associations with SR (r = 0.64, 95% CI: 0.39, 0.81, P < .001 for age; r = −0.67, 95% CI: −0.82, −0.43, P < .001 for vBMD; P < .001 for both), indicating that SR may be a more direct measure of porosity. This interpretation was supported by ex vivo measurements showing SR to be strongly positively correlated with micro-CT porosity (r = 0.88; 95% CI: 0.64, 0.96; P < .001) and with age (r = 0.87; 95% CI: 0.62, 0.96; P < .001). Conclusion The MR imaging–derived SR may serve as a biomarker for cortical bone porosity that is potentially superior to BWC, but corroboration in larger cohorts is indicated.

Allogeneic hematopoietic stem-cell transplantation (alloHSCT) survivors treated with total body irradiation (TBI) exhibit bone deficits and excess adiposity, potentially related to altered mesenchymal stem cell differentiation into osteoblasts or adipocytes. We examined associations among fat distribution, bone microarchitecture, and insulin resistance in alloHSCT survivors after TBI. This was a cross-sectional observational study of 25 alloHSCT survivors (aged 12–25 years) a median of 9.7 (4.3–19.3) years after alloHSCT compared to 25 age-, race-, and sex-matched healthy controls. Vertebral MR spectroscopic imaging and tibia micro-MRI were used to quantify marrow adipose tissue (MAT) and trabecular microarchitecture. Additional measures included DXA whole-body fat mass (WB-FM), leg lean mass (Leg-LM), trunk visceral adipose tissue (VAT), and CT calf muscle density. Insulin resistance in alloHSCT survivors was estimated by HOMA-IR. AlloHSCT survivors had lower Leg-LM (p<0.001), and greater VAT (p<0.01), MAT (p<0.001) and fat infiltration of muscle (p=0.04) independent of WB-FM, vs. matched-controls; BMI did not differ. Survivors had lower bone volume fraction and abnormal microarchitecture including greater erosion and more rod-like structure vs. controls (all p=0.04); 14 had vertebral deformities and two had compression fractures. Greater WB-FM, VAT, MAT and muscle fat infiltration were associated with abnormal trabecular microarchitecture (p<0.04 for all). AlloHSCT HOMA-IR was elevated, associated with younger age at transplantation (p<0.01), and positively correlated with WB-FM and VAT (both p<0.01). In conclusion, the markedly increased marrow adiposity, abnormal bone microarchitecture, and abnormal fat distribution highlight the risks of long-term treatment-related morbidity and mortality in alloHSCT recipients after TBI. Trabecular deterioration was associated with marrow and visceral adiposity. Furthermore, long-term survivors demonstrated sarcopenic obesity, insulin resistance, and vertebral deformities. Future studies are needed to identify strategies to prevent and treat metabolic and skeletal complications in this growing population of childhood alloHSCT survivors.

Purpose To develop a method to assess volumetric cortical bone porosity in clinically practical acquisition times by measuring the signal decay at only two echo times (TEs) as part of a single three-dimensional ultrashort TE (UTE) magnetic resonance (MR) examination. Materials and Methods The study was approved by the institutional review board and complied with HIPAA guidelines. Written informed consent was obtained from all subjects. A marker of cortical bone porosity called porosity index was defined as the ratio of UTE image intensities at a long and short TE, and the results were compared with biexponential analysis. Porosity index of midtibia cortical bone samples obtained from 16 donors was compared with ground-truth porosity by using micro–computed tomographic (CT) imaging and bone mineral density by peripheral quantitative CT scanner. Reproducibility of porosity index were tested in volunteers and clinical feasibility evaluated in postmenopausal women. Interparameter associations were assessed by using Pearson or Spearman correlation coefficient. Results Bone specimen porosity index was correlated with micro-CT imaging porosity (R2 = 0.79) and pore size (R2 = 0.81); age (R2 = 0.64); peripheral quantitative CT scanner density (R2 = 0.49, negatively); and pore water fraction (R2 = 0.62) and T2* (R2 = 0.64) by biexponential analysis. The reproducibility study yielded a coefficient of variation of 2.2% and intraclass correlation coefficient of 0.97. The study that involved postmenopausal women showed a wide range of porosity index (15%–38%). Conclusion A two-point MR imaging method to assess cortical bone porosity in humans was conceived and validated. This approach has the potential for clinical use to assess changes in cortical bone porosity that result from disease or in response to therapy.