Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity.

Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11b+CD45+ myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11b+CD45+ cells trafficking to ischemic brain. TREM1 inhibition genetically or pharmacologically improved outcome via protective antioxidant and anti-inflammatory mechanisms. Positron electron tomography imaging using radiolabeled antibody recognizing TREM1 revealed elevated TREM1 expression in spleen and, unexpectedly, in intestine. In the lamina propria, noradrenergic-dependent increases in gut permeability induced TREM1 on inflammatory Ly6C+MHCII+ macrophages, further increasing epithelial permeability and facilitating bacterial translocation across the gut barrier. Thus, following stroke, peripheral TREM1 induction amplifies proinflammatory responses to both brain-derived and intestinal-derived immunogenic components. Critically, targeting this specific innate immune pathway reduces cerebral injury.

Physiological blood-brain transport is impaired with age by a shift in transcytosis.

The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.

Moving a missing hand: children born with below elbow deficiency can enact hand grasp patterns with their residual muscles.

Children with a unilateral congenital below elbow deficiency (UCBED) have one typical upper limb and one that lacks a hand, ending below the elbow at the proximal/mid forearm. UCBED is an isolated condition, and affected children otherwise develop normal sensorimotor control. Unlike adults with upper limb absence, the majority of whom have an acquired loss, children with UCBED never developed a hand, so their residual muscles have never actuated an intact limb. Their ability to purposefully modulate affected muscle activity is often assumed to be limited, and this assumption has influenced prosthetic design and prescription practices for this population as many modern devices derive control signals from affected muscle activity. To better understand the motor capabilities of the affected muscles, we used ultrasound imaging to study 6 children with UCBED. We examined the extent to which subjects activate their affected muscles when performing mirrored movements with their typical and missing hands. We demonstrate that all subjects could intentionally and consistently enact at least five distinct muscle patterns when attempting different missing hand movements (e.g., power grasp) and found similar performance across affected and typically developed limbs. These results suggest that although participants had never actuated the missing hand they could distinctively and consistently activate the residual muscle patterns associated with actions on the unaffected side. These findings indicate that motor control still develops in the absence of the normal effector, and can serve as a guide for developing prostheses that leverage the full extent of these children's motor control capabilities.

Neuromuscular Dysfunction in Clubfeet Associated With Constriction Band Syndrome.

INTRODUCTION: Constriction band syndrome (CBS) is a congenital limb anomaly frequently associated with clubfoot. Clubfeet in CBS patients may be associated with peroneal nerve dysfunction in the involved lower extremity; however, the etiology of this neuromuscular dysfunction is not clear. We sought to characterize the distribution of constriction bands on lower extremities with clubfoot and determine if neuromuscular deficit (NMD), defined here as having absent ankle dorsiflexion, was associated with ipsilateral proximal bands. Our secondary aim was to compare the treatment and outcomes of clubfeet with NMD to those without NMD. METHODS: We performed a retrospective review of all patients with CBS and clubfoot presenting to our facility between January 1, 1998 and December 31, 2018. Treatment with the Ponseti method, at least 1 year of follow-up at this facility, and a detailed physical exam describing lower extremity neuromuscular function and the presence and location of constriction bands were required for inclusion in the study cohort. RESULTS: Twenty children with 26 clubfeet were included. Forty-six percent (12/26) of the clubfeet had NMD. Clubfeet with and without NMD had ipsilateral thigh or leg constriction bands at similar rates [42% (5/12) vs. 43% (6/14), P =0.106], and the majority (7/12) of clubfeet with NMD did not have an ipsilateral thigh or leg band. While children with an NMD clubfoot tended toward more casts, relapses, and surgical procedures, these differences did not reach statistical significance. The use of a daytime AFO beyond age four was higher in the NMD clubfeet [58% (7/12) vs. 14% (2/14), P =0.04]. CONCLUSION: Clubfeet with neuromuscular deficits may occur in the absence of proximal ipsilateral constriction bands, suggesting they may be caused by mechanisms other than direct damage from visible constriction bands to underlying nerves. They can also coexist with arthrogrypotic conditions. Clubfeet with an NMD tended toward more casts, relapses, and surgeries than those without NMD, but these differences did not reach statistical significance. These patients often elect long-term use of a daytime AFO.

Human umbilical cord plasma proteins revitalize hippocampal function in aged mice.

Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

Maternal Epidemiology of Brachial Plexus Birth Injuries in California: 1996 to 2012.

OBJECTIVE: This study aimed to evaluate the incidence of brachial plexus birth injury (BPBI) and its associations with maternal demographic factors. Additionally, we sought to determine whether longitudinal changes in BPBI incidence differed by maternal demographics. STUDY DESIGN: We conducted a retrospective cohort study of over 8 million maternal-infant pairs using California's Office of Statewide Health Planning and Development Linked Birth Files from 1991 to 2012. Descriptive statistics were used to determine BPBI incidence and the prevalence of maternal demographic factors (race, ethnicity, age). Multivariable logistic regression was used to determine associations of year, maternal race, ethnicity, and age with BPBI. Excess population-level risk associated with these characteristics was determined by calculating population attributable fractions. RESULTS: The incidence of BPBI between 1991 and 2012 was 1.28 per 1,000 live births, with peak incidence of 1.84 per 1,000 in 1998 and low of 0.9 per 1,000 in 2008. Incidence varied by demographic group, with infants of Black (1.78 per 1,000) and Hispanic (1.34 per 1,000) mothers having higher incidences compared with White (1.25 per 1,000), Asian (0.8 per 1,000), Native American (1.29 per 1,000), other race (1.35 per 1,000), and non-Hispanic (1.15 per 1,000) mothers. After controlling for delivery method, macrosomia, shoulder dystocia, and year, infants of Black (adjusted odds ratio [AOR] = 1.88, 95% confidence interval [CI] = 1.70, 2.08), Hispanic (AOR = 1.25, 95% CI = 1.18, 1.32), and advanced-age mothers (AOR = 1.16, 95% CI = 1.09, 1.25) were at increased risk. Disparities in risk experienced by Black, Hispanic, and advanced-age mothers contributed to a 5, 10, and 2% excess risk at the population level, respectively. Longitudinal trends in incidence did not vary among demographic groups. Population-level changes in maternal demographics did not explain changes in incidence over time. CONCLUSION: Although BPBI incidence has decreased in California, demographic disparities exist. Infants of Black, Hispanic, and advanced-age mothers are at increased BPBI risk compared with White, non-Hispanic, and younger mothers. KEY POINTS: · The incidence of BPBI has decreased over time.. · Demographic disparities in BPBI incidence and risk exist.. · Infants of Black, Hispanic, and advanced age mothers are at greatest risk of BPBI..

Long-Term Outcomes of Biceps Rerouting for Flexible Supination Contractures in Children With Brachial Plexus Birth Injuries.

PURPOSE: Forearm supination contractures occur in 7% of children with brachial plexus birth injuries (BPBI). Biceps rerouting is proposed when pronation has deteriorated but is passively correctable to at least 0° (neutral). The purpose of this investigation was to evaluate long-term outcomes of biceps rerouting for this indication, including magnitude and maintenance of correction, complications, and subsequent osteotomy. METHODS: We conducted a retrospective review of all children with BPBI and forearm supination contractures treated with biceps rerouting alone, for the above indications, from 1993 to 2017 with at least 2 years follow-up. Demographic information, BPBI characteristics, surgical details, and ranges of motion were obtained from medical records. Pre- and postoperative active pronation (AP) and supination (AS), elbow flexion contracture, and arc of forearm rotation (Arc) were analyzed using linear mixed-effect models. RESULTS: Twenty-five children (13 females; 13 left forearms; 15 global BPBI) underwent biceps rerouting at age 7 ± 3 years and were followed for 6 ± 3 years. Before surgery, the mean AP and AS were 6° ± 29° and 62° ± 27°, respectively. At the final follow-up, the mean AP, AS, and Arc were 39° ± 36°, 18° ± 34°, and 57° ± 42°, respectively. AP was significantly improved and AS was significantly decreased by 2 years after surgery and at the final follow-up. Neither Arc nor elbow flexion contracture changed significantly. Two of 25 (8%) children underwent subsequent forearm osteotomy. CONCLUSIONS: Biceps rerouting in children with BPBI improves the forearm position when pronation is deteriorating by shifting the arc from supination to pronation without decreasing the arc of motion or worsening elbow flexion contractures. There is a low risk of complications and a limited need for subsequent forearm osteotomy. These results are maintained over time. When performed before passive pronation is reduced beyond neutral, this procedure may prevent severe supination contractures and reduce the need for forearm osteotomy. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Comparison of Different Methods of Measuring Finger Range of Motion via Telehealth.

PURPOSE: This study examined the accuracy and reliability of measuring total motion of the fingers via telehealth using the following three different methods: (1) goniometry, (2) visual estimation, and (3) electronic protractor. Measurements were compared with in-person measurement, which was assumed to be the reference standard. METHODS: Thirty clinicians measured finger range of motion from prerecorded videos of a mannequin hand with articulating fingers, which was posed in extension and flexion that simulated a telehealth visit, using a goniometer with results blinded to the clinician (blinded goniometry), visual estimation, and an electronic protractor, in random order. Total motion was calculated for each finger and for all four fingers in sum. The experience level, familiarity with measuring finger range of motion, and opinions of measurement difficulty were assessed. RESULTS: Measurement with the electronic protractor was the only method equivalent to the reference standard within 20°. Remote goniometer and visual estimation did not fall within the acceptable error margin of equivalence, and both underestimated total motion. Electronic protractor also had the highest interrater reliability (intraclass correlation [upper limit, lower limit], 0.95 [0.92, 0.95]); goniometry (intraclass correlation, 0.94 [0.91, 0.97]) was nearly identical, whereas visual estimation (intraclass correlation, 0.82 [0.74, 0.89]) was much lower. Clinicians' experience and familiarity with range of motion measurements had no relationship with the findings. Clinicians reported visual estimation as the most difficult (80%) and electronic protractor as the easiest method (73%). CONCLUSIONS: This study showed that traditional in-person forms of measurement underestimate finger range of motion via telehealth; a new computer-based method (ie, electronic protractor) was found to be more accurate. CLINICAL RELEVANCE: The use of an electronic protractor can be beneficial to clinicians measuring range of motion in patients virtually.

The Green Transfer-Long-Term Results.

PURPOSE: The purpose of this study was to determine the long-term results of the Green transfer (flexor carpi ulnaris to extensor carpi radialis brevis) for patient-reported outcomes, wrist position, and range of motion. METHODS: We re-examined 13 patients from a previous prospective study involving surgery for hemiplegia that included a Green transfer. The average follow-up was 8 years with the range from 5 to 11 years. The wrist range of motion and the postoperative position of the wrists were measured. The surgical outcomes were measured via the Pediatric Orthopedic Data Collection Instrument, the Shriner's Hospital Upper Extremity Evaluation, Pediatric Quality of Life, and visual analog score for appearance from the patient and the parent. RESULTS: At this follow-up, only 7 of the 13 patients had a wrist position near neutral with the ability to flex and extend the wrist. Wrist range of motion was improved in four, decreased in four, and stayed the same in five patients. In contrast to these positional wrist results, statistically significant improvements were noted in several aspects of the Pediatric Orthopedic Data Collection Instrument, visual analog scores, and Shriner's Hospital Upper Extremity Evaluation scores. CONCLUSIONS: Long-term follow-up of the flexor carpi ulnaris to extensor carpi radialis brevis tendon transfer in hemiplegic patients reveals the results to be variable but favorable from a patient-reported outcome standpoint. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Do Nails and Nubbins Matter? A Comparison of Symbrachydactyly and Transverse Deficiency Phenotypes.

PURPOSE: Transverse deficiency (TD) and symbrachydactyly may be difficult to distinguish due to shared phenotypes and a lack of pathognomonic features. The 2020 Oberg-Manske-Tonkin classification update modified these anomalies to include "with ectodermal elements" for symbrachydactyly and "without ectodermal elements" for TD as a defining differentiating characteristic. The purpose of this investigation was to characterize ectodermal elements and the level of deficiency and to examine whether ectodermal elements versus the level of deficiency was a greater determining factor for Congenital Upper Limb Differences (CoULD) surgeons making the diagnosis. METHODS: This was a retrospective review of 254 extremities from the CoULD registry with a diagnosis of symbrachydactyly or TD by pediatric hand surgeons. Ectodermal elements and the level of deficiency were characterized. A review of the registry radiographs and photographs was used to classify the diagnosis and compare it with the diagnosis given by the pediatric hand surgeons. The presence/absence of nubbins versus the level of deficiency as the determining factor to differentiate the pediatric hand surgeons' diagnosis of symbrachydactyly (with nubbins) versus TD (without nubbins) was analyzed. RESULTS: Based on radiographs and photographs of the 254 extremities, 66% had nubbins on the distal end of the limb; of the limbs with nubbins, nails were present on 51%. The level of deficiency was amelia/humeral (n = 9), <1/3 transverse forearm (n = 23), 1/3 to 2/3 transverse forearm (n = 27), 2/3 to full forearm TD (n = 38), and metacarpal/phalangeal (n = 103). The presence of nubbins was associated with a four times higher likelihood of a pediatric hand surgeon's diagnosis of symbrachydactyly. However, a distal deficiency is associated with a 20-times higher likelihood of a diagnosis of symbrachydactyly than a proximal deficiency. CONCLUSIONS: Although both the level of deficiency and ectodermal elements are important, the level of deficiency was a greater determining factor for a diagnosis of symbrachydactyly versus TD. Our results suggest that the level of deficiency and nubbins should both be described to help provide greater clarity in the diagnosis of symbrachydactyly versus TD. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV.

Reliability of the Masada Classification for Forearm Involvement in Patients With Hereditary Multiple Osteochondromas (HMO).

BACKGROUND: Classifications describing forearm lesions in patients with Hereditary Multiple Osteochondromatosis (HMO) have been used to recommend surgical intervention and stratify outcomes; however, there is no consensus on which classification offers greater reliability. The purpose of this study was to determine the reliability of the Masada classification and newer classifications among pediatric hand surgeons. METHODS: One hundred one patients with HMO between June 2014 and October 2019 were enrolled in the Congenital Upper Limb Differences (CoULD) Registry. Of those, 67 patients with 101 forearms were included. Four pediatric hand surgeons from the CoULD study group undertook an online evaluation. Each rater classified radiographs according to the Masada classification. Six weeks later, raters were asked to reclassify images according to the Masada, Gottschalk, and Jo classifications. Rater agreement for these classifications was assessed by estimating Fleiss kappa along with a 95% CI. RESULTS: Interrater agreement for Masada classification after the first reading was poor (κ=0.35; 95% CI=0.30-0.41) across all raters. Interrater agreement across the 4 raters decreased for the Masada classification from the first to the second reading (κ=0.35 vs 0.21; P <0.001). Intrarater agreement for the Masada classification ranged from 0.32 to 0.63 from the first to the second study reading. Gottschalk and Jo classifications yielded significantly better interrater agreement compared with Masada (κ=0.43 vs 0.21; P <0.001). Unclassifiable cases were highest in the Masada classification (34% to 44%) and lower in the Jo (17%) and Gottschalk (14%) classifications. CONCLUSION: Despite wide use, the Masada classification was found to have low reliability when classifying forearm deformities in HMO. Gottschalk offered more options for location, yet lacked deformity description including radial head dislocation. Jo classification offered more locations than Masada and incorporated radial head dislocation in some patterns. Based on the shortcomings in all 3 classification systems, the development of a more inclusive and reliable classification is warranted. LEVEL OF EVIDENCE: Level II; Diagnostic.

Patient-reported Outcomes for Children With Unilateral Congenital Below Elbow Deficiency.

BACKGROUND: The Patient Reported Outcomes Measurement Information System (PROMIS ® ) is a validated tool used to evaluate different domains of function in patients with chronic health conditions. This tool has not been validated in children with unilateral congenital below elbow deficiency (UCBED). The purpose of this study was to determine whether PROMIS discerns functional impairment for children with UCBED and whether children with UCBED differ from the general population with respect to PROMIS outcomes. We hypothesized that children with UCBED report mild impairment in upper extremity function but normal mobility, pain interference and peer relations. METHODS: A retrospective chart review of children aged 5 to 17 years with a diagnosis of UCBED who completed a PROMIS questionnaire at their clinic visit at the [blinded locations] was conducted between April 1, 2017 and March 31, 2020. The mean PROMIS scores of UCBED patients were compared with that of the general reference population. Mann Whitney and ANOVA tests were used to explore the differences across the PROMIS upper extremity function domain by arm length and prosthesis use. RESULTS: Fifty-five children (28 boys) with a mean age of 11±3.6 years met the inclusion criteria. Children with UCBED had similar PROMIS scores as the reference population in mobility (51.9±6.2), peer relations (53.5±9.4), and pain interference (40.1±7.2), with mild impairment in the upper extremity function (44.3±10.7). Compared with the 8 to 17-year-old cohort, the parent-proxy (5 to 7-year-old group) reported significantly more upper extremity function impairment (31.3±5.9) vs (48.0±8.8) ( P =0.000). The two age groups did not differ with respect to mobility, pain interference and peer relations. CONCLUSIONS: Our study confirms previous findings that children with UCBED report upper extremity function, peer relationships, pain interference, and mobility, similar to the reference population. In addition, parents of younger children with UCBED report more upper extremity functional impairment than is self-reported by older children with UCBED. LEVEL OF EVIDENCE: Prognostic Level III (comparison with reference population).

Tau PET imaging with 18F-PI-2620 in aging and neurodegenerative diseases.

PURPOSE: In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD). METHODS: Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aß+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum. RESULTS: SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aß+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient. CONCLUSION: Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

Patient-reported Outcomes Measurement Information System (PROMIS) Scores for Children With Brachial Plexus Birth Injury.

BACKGROUND: Patient-reported Outcomes Measurement Information System (PROMIS) for pediatrics is a validated patient-reported or parent-proxy-reported outcomes assessment tool used to evaluate health-related quality of life in children and adolescents with chronic medical conditions. The health-related quality of life of children with brachial plexus birth injury (BPBI) as measured by PROMIS is not well understood. We hypothesized that children with BPBI would report impaired upper extremity (UE) function but normal mobility, pain interference, and peer relationships compared with a reference pediatric population, and that UE function PROMIS scores would be associated with BPBI severity and patient age. METHODS: This is a retrospective cohort study of 180 children with BPBI ages 5 to 17 years old who responded to 4 pediatric PROMIS domains (mobility, pain interference, peer relationships, and UE function) between April 2017 and April 2019. Responses were converted to a T score, which allows comparison with a reference pediatric population (mean reference score=50). Multivariable linear regression was used to quantify the association between PROMIS scores and age, sex, Narakas type, and composite Mallet score. RESULTS: Children with BPBI had normal PROMIS mobility (49.6±8.5), pain interference (44.6±9.7), and peer relationships (52.4±10.6) scores, but reported mild impairment in UE function (40.8±12.1). Age (P<0.0001) and Narakas type (P=0.02) were associated with PROMIS UE function scores, but sex and composite Mallet scores were not. There were no significant associations between the other PROMIS domains and age, sex, Narakas Type, or composite Mallet scores. CONCLUSIONS: Children with BPBI reported PROMIS scores for mobility, pain interference, and peer relationships similar to the reference population but impairment in UE function. Reported UE function decreased with increasing disease severity and increased with age. These PROMIS domains seem to be useful tools for the clinician to evaluate children with BPBI and better understand the challenges they face. Further study is needed to assess their utility in measuring the effects of treatment interventions. LEVEL OF EVIDENCE: Level III.

Radionuclide Imaging for Neuroscience: Current Opinion and Future Directions.

This meeting report summarizes a Consultants Meeting that was held at International Atomic Energy Agency headquarters in Vienna to provide an update on radionuclide imaging for neuroscience applications.

TSPO-PET imaging using [18F]PBR06 is a potential translatable biomarker for treatment response in Huntington's disease: preclinical evidence with the p75NTR ligand LM11A-31.

Huntington's disease (HD) is an inherited neurodegenerative disorder that has no cure. HD therapeutic development would benefit from a non-invasive translatable biomarker to track disease progression and treatment response. A potential biomarker is using positron emission tomography (PET) imaging with a translocator protein 18 kDa (TSPO) radiotracer to detect microglial activation, a key contributor to HD pathogenesis. The ability of TSPO-PET to identify microglial activation in HD mouse models, essential for a translatable biomarker, or therapeutic efficacy in HD patients or mice is unknown. Thus, this study assessed the feasibility of utilizing PET imaging with the TSPO tracer, [18F]PBR06, to detect activated microglia in two HD mouse models and to monitor response to treatment with LM11A-31, a p75NTR ligand known to reduce neuroinflammation in HD mice. [18F]PBR06-PET detected microglial activation in striatum, cortex and hippocampus of vehicle-treated R6/2 mice at a late disease stage and, notably, also in early and mid-stage symptomatic BACHD mice. After oral administration of LM11A-31 to R6/2 and BACHD mice, [18F]PBR06-PET discerned the reductive effects of LM11A-31 on neuroinflammation in both HD mouse models. [18F]PBR06-PET signal had a spatial distribution similar to ex vivo brain autoradiography and correlated with microglial activation markers: increased IBA-1 and TSPO immunostaining/blotting and striatal levels of cytokines IL-6 and TNFα. These results suggest that [18F]PBR06-PET is a useful surrogate marker of therapeutic efficacy in HD mice with high potential as a translatable biomarker for preclinical and clinical HD trials.

Development of a CD19 PET tracer for detecting B cells in a mouse model of multiple sclerosis.

BACKGROUND: B cells play a central role in multiple sclerosis (MS) through production of injurious antibodies, secretion of pro-inflammatory cytokines, and antigen presentation. The therapeutic success of monoclonal antibodies (mAbs) targeting B cells in some but not all individuals suffering from MS highlights the need for a method to stratify patients and monitor response to treatments in real-time. Herein, we describe the development of the first CD19 positron emission tomography (PET) tracer, and its evaluation in a rodent model of MS, experimental autoimmune encephalomyelitis (EAE). METHODS: Female C57BL/6 J mice were induced with EAE through immunization with myelin oligodendrocyte glycoprotein (MOG1-125). PET imaging of naïve and EAE mice was performed 19 h after administration of [64Cu]CD19-mAb. Thereafter, radioactivity in organs of interest was determined by gamma counting, followed by ex vivo autoradiography of central nervous system (CNS) tissues. Anti-CD45R (B220) immunostaining of brain tissue from EAE and naïve mice was also conducted. RESULTS: Radiolabelling of DOTA-conjugated CD19-mAb with 64Cu was achieved with a radiochemical purity of 99% and molar activity of 2 GBq/µmol. Quantitation of CD19 PET images revealed significantly higher tracer binding in whole brain of EAE compared to naïve mice (2.02 ± 0.092 vs. 1.68 ± 0.06 percentage of injected dose per gram, % ID/g, p = 0.0173). PET findings were confirmed by ex vivo gamma counting of perfused brain tissue (0.22 ± 0.020 vs. 0.12 ± 0.003 % ID/g, p = 0.0010). Moreover, ex vivo autoradiography of brain sections corresponded with PET imaging results and the spatial distribution of B cells observed in B220 immunohistochemistry-providing further evidence that [64Cu]CD19-mAb enables visualization of B cell infiltration into the CNS of EAE mice. CONCLUSION: CD19-PET imaging can be used to detect elevated levels of B cells in the CNS of EAE mice, and has the potential to impact the way we study, monitor, and treat clinical MS.

cRel expression regulates distinct transcriptional and functional profiles driving fibroblast matrix production in systemic sclerosis.

OBJECTIVES: NF-κB regulates genes that control inflammation, cell proliferation, differentiation and survival. Dysregulated NF-κB signalling alters normal skin physiology and deletion of cRel limits bleomycin-induced skin fibrosis. This study investigates the role of cRel in modulating fibroblast phenotype in the context of SSc. METHODS: Fibrosis was assessed histologically in mice challenged with bleomycin to induce lung or skin fibrosis. RNA sequencing and pathway analysis was performed on wild type and Rel-/- murine lung and dermal fibroblasts. Functional assays examined fibroblast proliferation, migration and matrix production. cRel overexpression was investigated in human dermal fibroblasts. cRel immunostaining was performed on lung and skin tissue sections from SSc patients and non-fibrotic controls. RESULTS: cRel expression was elevated in murine lung and skin fibrosis models. Rel-/- mice were protected from developing pulmonary fibrosis. Soluble collagen production was significantly decreased in fibroblasts lacking cRel while proliferation and migration of these cells was significantly increased. cRel regulates genes involved in extracellular structure and matrix organization. Positive cRel staining was observed in fibroblasts in human SSc skin and lung tissue. Overexpression of constitutively active cRel in human dermal fibroblasts increased expression of matrix genes. An NF-κB gene signature was identified in diffuse SSc skin and nuclear cRel expression was elevated in SSc skin fibroblasts. CONCLUSION: cRel regulates a pro-fibrogenic transcriptional programme in fibroblasts that may contribute to disease pathology. Targeting cRel signalling in fibroblasts of SSc patients could provide a novel therapeutic avenue to limit scar formation in this disease.

Outcomes of Botulinum Toxin Injection for Shoulder Internal Rotation Contractures in Infants with Brachial Plexus Birth Injury.

PURPOSE: Shoulder internal rotation contractures (IRC) are common sequela of brachial plexus birth injuries (BPBI). Botulinum toxin A (BTX-A) injection into targeted muscles has been described to facilitate functional improvement at the shoulder joint and prevent glenohumeral dysplasia. The purpose of this study was to assess the outcomes of BTX-A injections on shoulder IRC in children with BPBI. METHODS: We conducted a retrospective analysis of 47 children with shoulder IRC due to BPBI, who were treated with BTX-A. Shoulder passive external rotation in adduction and Active Movement Scale external rotation scores were recorded before and after BTX-A injection. We also recorded the number of children who underwent secondary surgical balancing procedures to improve shoulder motion after BTX-A injection. RESULTS: Mean age at the time of injection was 12 months (range, 5-23 months). Subjects demonstrated a significant increase in passive external rotation of 46° (range, 10° to 90) at 4 months; an average improvement of 18° (range, -30° to 80°) persisted at 11 months after injection. A total of 28 patients (60%) underwent subsequent external rotation tendon transfer. At 5-year follow-up, 7 patients (15%) had adequate functional shoulder range of motion and did not undergo external rotation tendon transfer. CONCLUSIONS: Botulinum toxin A injections result in improvement in IRC due to BPBI, which is sustained beyond the expected half-life of 3 months. As many as 15% of patients who have this treatment avoid external rotation tendon transfer. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV.

Thumb Hypoplasia Occurring in Patients With Preaxial Polydactyly.

PURPOSE: Thumb polydactyly and thumb hypoplasia are generally regarded as separate clinical entities. However, several case reports indicate that hypoplasia of both the thumb and the radius can occur in patients with thumb polydactyly and improved understanding of the genetics of the developing upper limb may give an embryologic explanation for this occurrence. Our hypothesis was that patients with preaxial polydactyly can have ipsilateral thumb hypoplasia that may not be recognized until after surgical reconstruction of the extra digit. METHODS: We searched our surgical database for all procedures performed on patients with a diagnosis of preaxial polydactyly between 2002 and 2014. We reviewed the medical record for demographic data, surgical procedures, and follow-up information. In addition, all available radiographs were reviewed. Through this, we identified patients with a diagnosis of ipsilateral thumb hypoplasia, including when in the course of treatment the diagnosis was made, and any related subsequent procedures. RESULTS: We reviewed 132 patients who underwent reconstruction of thumb polydactyly, 10 of whom were identified as having evidence of ipsilateral thumb hypoplasia, an incidence of 8.2%. The diagnosis of thumb hypoplasia was made before surgery in 3 of the 10 patients. One additional patient was noted to have a duplicate thumb on one side and a hypoplastic thumb on the contralateral side. CONCLUSIONS: This study supports the hypothesis that children with preaxial polydactyly can have ipsilateral thumb hypoplasia that may not be noted before surgery. In this study group, 8% of patients with preaxial polydactyly had ipsilateral hypoplasia. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.