Corticospinal Tract Injury Estimated From Acute Stroke Imaging Predicts Upper Extremity Motor Recovery After Stroke.

Background and Purpose- Injury to the corticospinal tract (CST) has been shown to have a major effect on upper extremity motor recovery after stroke. This study aimed to examine how well CST injury, measured from neuroimaging acquired during the acute stroke workup, predicts upper extremity motor recovery. Methods- Patients with upper extremity weakness after ischemic stroke were assessed using the upper extremity Fugl-Meyer during the acute stroke hospitalization and again at 3-month follow-up. CST injury was quantified and compared, using 4 different methods, from images obtained as part of the stroke standard-of-care workup. Logistic and linear regression were performed using CST injury to predict ΔFugl-Meyer. Injury to primary motor and premotor cortices were included as potential modifiers of the effect of CST injury on recovery. Results- N=48 patients were enrolled 4.2±2.7 days poststroke and completed 3-month follow-up (median 90-day modified Rankin Scale score, 3; interquartile range, 1.5). CST injury distinguished patients who reached their recovery potential (as predicted from initial impairment) from those who did not, with area under the curve values ranging from 0.70 to 0.8. In addition, CST injury explained ≈20% of the variance in the magnitude of upper extremity recovery, even after controlling for the severity of initial impairment. Results were consistent when comparing 4 different methods of measuring CST injury. Extent of injury to primary motor and premotor cortices did not significantly influence the predictive value that CST injury had for recovery. Conclusions- Structural injury to the CST, as estimated from standard-of-care imaging available during the acute stroke hospitalization, is a robust way to distinguish patients who achieve their predicted recovery potential and explains a significant amount of the variance in poststroke upper extremity motor recovery.

Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading.

Sclerostin, a product of the SOST gene produced mainly by osteocytes, is a potent negative regulator of bone formation that appears to be responsive to mechanical loading, with SOST expression increasing following mechanical unloading. We tested the ability of a murine sclerostin antibody (SclAbII) to prevent bone loss in adult mice subjected to hindlimb unloading (HLU) via tail suspension for 21 days. Mice (n = 11-17/group) were assigned to control (CON, normal weight bearing) or HLU and injected with either SclAbII (subcutaneously, 25 mg/kg) or vehicle (VEH) twice weekly. SclAbII completely inhibited the bone deterioration due to disuse, and induced bone formation such that bone properties in HLU-SclAbII were at or above values of CON-VEH mice. For example, hindlimb bone mineral density (BMD) decreased -9.2% ± 1.0% in HLU-VEH, whereas it increased 4.2% ± 0.7%, 13.1% ± 1.0%, and 30.6% ± 3.0% in CON-VEH, HLU-SclAbII, and CON-SclAbII, respectively (p < 0.0001). Trabecular bone volume, assessed by micro-computed tomography (µCT) imaging of the distal femur, was lower in HLU-VEH versus CON-VEH (p < 0.05), and was 2- to 3-fold higher in SclAbII groups versus VEH (p < 0.001). Midshaft femoral strength, assessed by three-point bending, and distal femoral strength, assessed by micro-finite element analysis (µFEA), were significantly higher in SclAbII versus VEH-groups in both loading conditions. Serum sclerostin was higher in HLU-VEH (134 ± 5 pg/mL) compared to CON-VEH (116 ± 6 pg/mL, p < 0.05). Serum osteocalcin was decreased by hindlimb suspension and increased by SclAbII treatment. Interestingly, the anabolic effects of sclerostin inhibition on some bone outcomes appeared to be enhanced by normal mechanical loading. Altogether, these results confirm the ability of SclAbII to abrogate disuse-induced bone loss and demonstrate that sclerostin antibody treatment increases bone mass by increasing bone formation in both normally loaded and underloaded environments.

Caloric restriction leads to high marrow adiposity and low bone mass in growing mice.

The effects of caloric restriction (CR) on the skeleton are well studied in adult rodents and include lower cortical bone mass but higher trabecular bone volume. Much less is known about how CR affects bone mass in young, rapidly growing animals. This is an important problem because low caloric intake during skeletal acquisition in humans, as in anorexia nervosa, is associated with low bone mass, increased fracture risk, and osteoporosis in adulthood. To explore this question, we tested the effect of caloric restriction on bone mass and microarchitecture during rapid skeletal growth in young mice. At 3 weeks of age, we weaned male C57Bl/6J mice onto 30% caloric restriction (10% kcal/fat) or normal diet (10% kcal/fat). Outcomes at 6 (n = 4/group) and 12 weeks of age (n = 8/group) included body mass, femur length, serum leptin and insulin-like growth factor 1 (IGF-1) values, whole-body bone mineral density (WBBMD, g/cm(2)), cortical and trabecular bone architecture at the midshaft and distal femur, bone formation and cellularity, and marrow fat measurement. Compared with the normal diet, CR mice had 52% and 88% lower serum leptin and 33% and 39% lower serum IGF-1 at 6 and 12 weeks of age (p < .05 for all). CR mice were smaller, with lower bone mineral density, trabecular, and cortical bone properties. Bone-formation indices were lower, whereas bone-resorption indices were higher (p < .01 for all) in CR versus normal diet mice. Despite having lower percent of body fat, bone marrow adiposity was elevated dramatically in CR versus normal diet mice (p < .05). Thus we conclude that caloric restriction in young, growing mice is associated with impaired skeletal acquisition, low leptin and IGF-1 levels, and high marrow adiposity. These results support the hypothesis that caloric restriction during rapid skeletal growth is deleterious to cortical and trabecular bone mass and architecture, in contrast to potential skeletal benefits of CR in aging animals.