BACKGROUND:Dementia with Lewy bodies shares clinical and pathological features with both Parkinson's disease and Alzheimer's disease, but the local biological factors that render specific cortical regions vulnerable to atrophy remain poorly defined. In particular, it is unclear whether cortical thinning in dementia with Lewy bodies reflects generic neurodegenerative mechanisms, processes shared with Parkinson's disease and Alzheimer's disease, or dementia with Lewy bodies-specific molecular and network susceptibilities. METHODS:A total of 89 patients with dementia with Lewy bodies and 89 matched controls underwent T1-weighted brain MRI. Scans were processed to generate surface-based cortical thickness maps. Regional cortical thickness estimates, after slice-by-slice manual correction, were mapped to gene expression data from healthy postmortem human brains to identify transcriptomic signatures associated with decreased thickness in dementia with Lewy bodies. We assessed whether genes whose expression was increased with regional thinning converged onto established Parkinson's disease- and Alzheimer's disease-related pathways and identified genes uniquely implicated in dementia with Lewy bodies. Spatial annotation mapping was then used to test whether patterns of cortical thinning overlapped with in vivo neurotransmitter system distributions and whether the observed thickness pattern was constrained by large-scale structural connectivity, consistent with a network-based propagation process. RESULTS:Cortical thinning predominated in regions that, in the healthy brain, show higher expression of genes involved in mitochondrial function and synaptic transmission. The transcriptomic profile associated with thinning significantly overlapped with genes belonging to Parkinson's disease and Alzheimer's disease pathways, supporting shared pathogenic mechanisms across Lewy body- and Alzheimer-type neurodegeneration. However, 90 genes associated with cortical thinning did not overlap with Parkinson's disease or Alzheimer's disease pathways and were enriched for GABAergic signalling. Spatial mapping analyses showed that regions with greatest thickness reductions colocalized with GABAA, serotoninergic 5-HT1A, 5-HT1B, 5-HT4, and dopaminergic D2 receptor distributions, and that the thickness pattern followed structural connectivity. CONCLUSIONS:MRI-derived cortical thickness changes in dementia with Lewy bodies reflect selective molecular and network vulnerabilities rather than a non-specific degenerative process. Mitochondrial and synaptic genes, together with a distinct GABAergic association and connectivity constraints, delineate mechanisms explaining why some cortical territories are more affected in dementia with Lewy bodies.

BACKGROUND:Synucleinopathies include a spectrum of disorders varying in features and severity, including idiopathic/isolated REM sleep behaviour disorder (iRBD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Distinct brain atrophy patterns may already be seen in iRBD; however, how brain atrophy begins and progresses remains unclear. METHODS:A multicentric cohort of 1276 participants (451 polysomnography-confirmed iRBD, 142 PD with probable RBD, 87 DLB, and 596 controls) underwent T1-weighted MRI and longitudinal clinical assessments. Brain atrophy was quantified using vertex-based cortical surface reconstruction and volumetric segmentation. The unsupervised machine learning algorithm, Subtype and Stage Inference (SuStaIn), was used to reconstruct spatiotemporal patterns of brain atrophy progression. FINDINGS:SuStaIn identified two distinct subtypes of brain atrophy progression: 1) a "cortical-first" subtype, with atrophy beginning in the frontal lobes and involving the subcortical structures at later stages; and 2) a "subcortical-first" subtype, with atrophy beginning in the limbic areas and involving cortical structures at later stages. Both cortical- and subcortical-first subtypes were associated with a higher rate of increase in MDS-UPDRS-III scores over time, but cognitive decline was subtype-specific, being associated with advancing stages in patients classified as cortical-first but not subcortical-first. Classified patients were more likely to phenoconvert over time compared to stage 0/non-classified patients. Among the 88 patients with iRBD who phenoconverted during follow-up, those classified within the cortical-first subtype had a significantly increased likelihood of developing DLB compared to PD, unlike those classified within the subcortical-first subtype. INTERPRETATION:There are two distinct atrophy progression subtypes in iRBD, with the cortical-first subtype linked to an increased likelihood of developing DLB, while both subtypes were associated with worsening parkinsonian motor features. This underscores the potential utility of subtype identification and staging for monitoring disease progression and patient selection for trials. FUNDING:This study was supported by grants to S.R. from Alzheimer Society Canada (0000000082) and by Parkinson Canada (PPG-2023-0000000122). The work performed in Montreal was supported by the Canadian Institutes of Health Research (CIHR), the Fonds de recherche du Québec - Santé (FRQS), and the W. Garfield Weston Foundation. The work performed in Oxford was funded by Parkinson's UK (J-2101) and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The work performed in Prague was funded by the Czech Health Research Council (grant NU21-04-00535) and by The National Institute for Neurological Research (project number LX22NPO5107), financed by the European Union - Next Generation EU. The work performed in Newcastle was funded by the NIHR Newcastle BRC based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. The work performed in Paris was funded by grants from the Programme d'investissements d'avenir (ANR-10-IAIHU-06), the Paris Institute of Neurosciences - IHU (IAIHU-06), the Agence Nationale de la Recherche (ANR-11-INBS-0006), Électricité de France (Fondation d'Entreprise EDF), the EU Joint Programme-Neurodegenerative Disease Research (JPND) for the Control-PD Project (Cognitive Propagation in Prodromal Parkinson's disease), the Fondation Thérèse et René Planiol, the Fonds Saint-Michel; by unrestricted support for research on Parkinson's disease from Energipole (M. Mallart) and the Société Française de Médecine Esthétique (M. Legrand); and by a grant from the Institut de France to Isabelle Arnulf (for the ALICE Study). The work performed in Sydney was supported by a Dementia Team Grant from the National Health and Medical Research Council (#1095127). The work performed in Cologne was funded by the Else Kröner-Fresenius-Stiftung (grant number 2019_EKES.02), the Köln Fortune Program, Faculty of Medicine, University of Cologne, and the "Netzwerke 2021 Program (Ministry of Culture and Science of Northrhine Westphalia State). The work performed in Aarhus was supported by funding from the Lundbeck Foundation, Parkinsonforeningen (The Danish Parkinson Association), and the Jascha Foundation.

Mild Cognitive Impairment (MCI) may be caused by mixed pathologies. Blood markers indicative of Alzheimer pathology or neurodegeneration have not been extensively explored in patients with MCI who have features of Lewy Body disease (LB-MCI) (cognitive fluctuations, parkinsonism, hallucinations, and REM-sleep behavior disorder (RBD)). We compared plasma levels of amyloid beta (Aß), tau, glial-fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) between participants in COMPASS-ND who met criteria for LB-MCI with participant with MCI without these features, healthy controls (HC), and participants with Parkinson's disease (PD) with and without MCI. Participants with MCI, HC, and PD were recruited as part of the COMPASS-ND study and underwent assessment of demographic and clinical features. Participants with MCI were classified as LB-MCI based on one or more criteria for LB disease. Plasma biomarkers were determined for amyloid species (Aß 42/40 ratio), tau-181, GFAP, and (NfL using Simoa. Groups were compared using ANOVA with post hoc comparisons. Age and sex adjustment was done in ANCOVA models. Among participants with MCI in COMPASS-ND, there were 159 (97 M/62 F) with MCI but without LB features and 105 (46 M/32 F) with one or more of the LB-MCI criteria. There were 161 HC (54 M/107 F), 79 PD (42 M/37 F), and 41 PD-MCI (35 M/7 F). The Aß 42/40 ratio and tau-181 differed between groups, with the LB-MCI group showing a lower Aß 42/40 ratio and higher tau-181 than the other groups. Post hoc comparison indicated that the ratio was lower in LB-MCI than HC, PD, and PD-MCI while tau-181 was higher than HC, PD, and MCI without LB features. GFAP and NfL did not differ across groups. Age and sex adjustment did not alter the main findings. In COMPASS-ND, participants with features of LB-MCI showed a biomarker profile suggestive of high Alzheimer co-pathology. Higher tau-181 suggests that these individuals might have a higher pathological burden than the other groups. The influence of other co-pathologies (i.e., vascular) and the influence on outcomes will be examined in this cohort. Future studies should examine for the presence of synuclein pathology across these groups.

Accurate quantification of REM sleep without atonia (RSWA) is essential in the diagnosis of idiopathic/isolated REM sleep behaviour disorder (iRBD). This study aims to validate RBDtector, a free and open-source tool for automated RSWA quantification using the Sleep Innsbruck Barcelona (SINBAR) scoring method, by comparing its performance against human visual scoring in a large independent cohort of subjects with iRBD and healthy controls. Muscle activity from 118 iRBD participants and 37 healthy controls that underwent polysomnography was analysed by RBDtector and compared with human visual scoring. Diagnostic performance was evaluated using receiver operating characteristic curves, and optimal cut-offs for iRBD screening and diagnosis were determined. The results of RSWA quantification were applied to survival analyses of time to phenoconversion. RBDtector showed excellent agreement with human visual scoring, particularly in 'any' RSWA activity (Pearson's correlation = 0.89, R 2 = 0.79, p < 0.001). RBDtector identified iRBD subjects with 95.6% sensitivity and 95.5% specificity by using a cutoff of 33.0% for combined 'any' RSWA activity in the submentalis and flexor digitorum superficialis muscles, with each muscle in isolation providing comparable results. In iRBD patients, each 10% increase in submentalis 'any' activity was associated with a 23% increase in the risk of phenoconversion (HR = 1.23, 95% CI [1.06, 1.44], p = 0.008), while no associations were observed with increased activity in the flexor digitorum superficialis or tibialis anterior. RBDtector provides accurate, automated RSWA quantification comparable to human visual scoring, offering a reliable and efficient method to support the diagnosis of iRBD and identify iRBD at a higher risk of phenoconversion.

The neurodegenerative synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson’s disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson’s disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson’s disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

BackgroundSince 2014, there has been increasing public outreach effort regarding isolated/idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) in Montreal. ObjectiveTo assess if, over time, milder iRBD cases are presenting earlier. MethodsDisease-free survival was compared in two iRBD recruitment epochs: 2004 to 2013 ("earlier") versus 2014to 2022 ("later") and by referral type ("self-referral" vs. "conventional-referral") in three large centers. ResultsIn Montreal, among 209 subjects followed prospectively, shorter time to phenoconversion was observed in the earlier epoch (5-year phenoconversion = 42% earlier vs. 23% later); diagnosis before 2014 had a 1.8-fold phenoconversion hazard. However, no difference was observed in 248 subjects from Barcelona and 166 from Innsbruck. Analysis of Montreal data found that increased survival in the later epoch was driven by an increasing number of self-referrals, who phenoconverted at 1/3 the rate of physician-referred subjects. ConclusionsIncreased patient awareness of iRBD results in earlier presentation to clinical attention, with a longer time to phenoconversion.

Current treatment options for generalized dystonia can be limited by efficacy, side effects, and accessibility; moreover, treatments are generally symptomatic and do not address the underlying cause. To address the unmet need for novel treatments, Caffall and colleagues used high-throughput in vitro screening and in vivo testing to identify potential disease-modifying treatments for DYT1-associated dystonia. The most common causative mutation in DYT1 dystonia eliminates a single glutamic acid residue in the TorsinA protein (ΔE TorsinA). Unlike wildtype TorsinA, which spreads diffusely within the cytosol, mutant TorsinA mislocalizes into small puncta in cell culture. The authors exploited this feature to screen a library of nearly 3000 small molecule drugs already approved for use in humans. One candidate molecule, ritonavir, a US Food and Drug Administration (FDA)approved protease inhibitor used to treat HIV, not only reversed ΔE TorsinA mislocalization in cell culture, but could also restore abnormal striatal neurophysiology in ΔE TorsinA knock-in mice. Going further, administration of ritonavir in the perinatal period produced long-lasting normalization of structural abnormalities as assessed by diffusion tensor magnetic resonance imaging. This long-duration benefit is an important finding, since a therapeutic critical period for restoring TorsinA function likely exists in humans. Ritonavir appears to exert these effects in a mechanism distinct from its known target, HIV-1 protease. Instead, molecular assays suggest a role for its modulation of eukaryotic translation initiation factor 2 subunit α (eIF2α), a key component of the endoplasmic reticular-integrated stress response that may be a generalizable mechanism for dystonia. Drug repurposing strategies have the attractive premise of using already well-characterized and thoroughly vetted drugs for uses unrelated to the original indication, thus potentially saving on drug development costs and maximizing clinical utility. Although preliminary, the study provides evidence that a currently FDA-approved antiretroviral drug could be used to treat generalized dystonia. Despite this, significant challenges remain with drug repurposing, and for ritonavir, incomplete central nervous system penetration is a major issue (which probably requires reformulation, potentially negating the advantage of using already-approved medications). Moreover, as this study demonstrates, many drugs affect multiple targets, and off-target side effects can be difficult to predict from data generated for a different clinical indication. For example, ritonavir is also a potent proteasome inhibitor, which could impact upon normal synaptic development in otherwise healthy children. Thus, a key unresolved question is whether ritonavir would need to be given early in childhood development; if so, the 30% penetrance and variable severity of DYT-1 dystonia would raise thorny issues of who and when to treat. Nonetheless, the hope remains that sometimes it is possible to teach an old drug a new trick.

Background Gait impairment is a debilitating and progressive feature of Parkinson’s disease (PD). Increasing evidence suggests that gait control is partly mediated by cholinergic signaling from the pedunculopontine nucleus (PPN). Objective We investigated whether PPN structural connectivity correlated with quantitative gait measures in PD. Methods Twenty PD patients and 15 controls underwent diffusion tensor imaging to quantify structural connectivity of the PPN. Whole brain analysis using tract-based spatial statistics and probabilistic tractography were performed using the PPN as a seed region of interest for cortical and subcortical target structures. Gait metrics were recorded in subjects’ medication ON and OFF states, and were used to determine if specific features of gait dysfunction in PD were related to PPN structural connectivity. Results Tract-based spatial statistics revealed reduced structural connectivity involving the corpus callosum and right superior corona radiata, but did not correlate with gait measures. Abnormalities in PPN structural connectivity in PD were lateralized to the right hemisphere, with pathways involving the right caudate nucleus, amygdala, pre-supplementary motor area, and primary somatosensory cortex. Altered connectivity of the right PPN-caudate nucleus was associated with worsened cadence, stride time, and velocity while in the ON state; altered connectivity of the right PPN-amygdala was associated with reduced stride length in the OFF state. Conclusion Our exploratory analysis detects a potential correlation between gait dysfunction in PD and a characteristic pattern of connectivity deficits in the PPN network involving the right caudate nucleus and amygdala, which may be investigated in future larger studies.

BACKGROUND:Gait impairments are common in Parkinson's Disease (PD) and are likely caused by degeneration in multiple brain circuits, including the basal ganglia, thalamus and mesencephalic locomotion centers (MLC). Diffusion tensor imaging (DTI) assesses fractional anisotropy (FA) and mean diffusivity (MD) that reflect the integrity of neuronal microstructure. We hypothesized that DTI changes in motor circuits correlate with gait changes in PD.OBJECTIVE:We aimed to identify microstructural changes of brain locomotion control centers in PD via DTI and their correlations with clinical and quantitative measures of gait.METHODS:Twenty-one PD patients reporting gait impairment and 15 controls were recruited. Quantitative gait and clinical tests were recorded in PD subjects' medication ON and OFF states. Region of Interest (ROI) analysis of the thalamus, basal ganglia and MLC was performed using ExploreDTI. Correlations between FA/MD with clinical gait parameters were examined.RESULTS:Microstructural changes were seen in the thalamus, caudate and MLC in the PD compared to the control group. Thalamic microstructural changes significantly correlated with gait parameters in the pace domain including the Timed Up and Go in the ON state. Caudate changes correlated with cadence and stride time in the OFF state.CONCLUSIONS:Our pilot study suggests that PD is associated with a characteristic regional pattern of microstructural degradation in the thalamus, caudate and MLC. The DTI changes may represent subcortical locomotion network failure. Overall, DTI ROI analyses might provide a useful tool for assessing PD for functional status and specific motor domains, such as gait, and potentially could serve as an imaging marker.

© Author(s) (or their employer(s)) 2021. No commercial reuse. See rights and permissions. Published by BMJ. A 51yearold man had a 4month history of back pain and progressive leg weakness. The back pain was on the left side, radiating down his left buttock and leg to the dorsum of the foot. He had gradually developed bilateral leg weakness with a right foot drop such that he required a fourwheeled walker. There was accompanying left anterior thigh numbness and saddle anaesthesia, together with urinary urgency and one episode of faecal incontinence. He had been previously well, though 13 years before had sustained a nonspecific back injury in a motor vehicle collision that did not require surgical intervention. On examination, there were lower limb hyperreflexia, patchy sensory loss in all modalities in both legs, a positive Beevor’s sign (upward movement of the umbilicus with attempted neck flexion due to weakness of the lower rectus abdominis) and absent rectal tone. Muscle strength was normal in the upper limbs, but 2/5 bilaterally in hip flexion, 4/5 bilaterally in knee flexion and extension, and 4–/5 in ankle dorsiflexion on the right. Cerebrospinal fluid (CSF) was normal apart from mildly elevated protein at 0.49 g/L, with no oligoclonal bands, normal angiotensinconverting enzyme concentration, and negative cytology and flow cytometry. Syphilis, HIV, acidfast bacilli and CSF viral panel were negative and serum cyanocobalamin concentration was normal. MR scan of the thoracic spine showed T2 hyperintensity from T4 to T11 with oedema at T10 and flow voids at T7 and between T9 and T10 (figure 1A). There was contrast enhancement in the area of oedema at T9–T10 (figure 1B,C). Due to the presence of flow voids on MR imaging, we arranged CT angiography of the spine, which showed abnormal vessels that were intradural and extramedullary along the posterior left lateral aspect of the cord extending from T6 to T9/T10 (figure 2A), with a prominent vessel at the T7/T8 level (figure 2B). Spinal angiogram

To determine if variables of the pupillary light response mature with age and sex in a healthy pediatric cohort and the utility of pupillometry in assessment among pediatric participants. After 1 min in a dark room to establish baseline, pupillometry was performed on 323 healthy, pediatric participants (646 eyes; 2–21 years; 175 females). Variables included initial pupil diameter, pupil diameter after light stimulus, percent pupillary constriction, latency to onset of constriction, average constriction velocity, maximum constriction velocity, average dilation velocity, and time from light stimulus to 75% of the initial pupil diameter. Data analyses employed ANOVAs and non-linear regressions. Analyses of age group differences revealed that participants 12–21 years old had a larger initial pupil diameter and pupil diameter after light stimulus, with males aged 12–18 years demonstrating a larger pupil diameter than all younger participants (ps < 0.05). Participants 12–18 years old had a slower maximum constriction velocity than participants 6–11 years old, with no sex differences (ps < 0.05). Furthermore, males aged 12–18 years old had a smaller percent constriction than males 6–11 years old (ps < 0.05). Regressions revealed that percent constriction and dilation velocity seemed to mature linearly, initial pupil diameter and ending pupil diameter matured quadratically, and the constriction velocity terms matured cubically. Results revealed maturation of the pupillary light response by age and sex in healthy pediatric participants. Given the value of the pupillary light response as a biomarker, the results provide normative benchmarks for comparison in health and disease, including opiate-exposed and concussion patients.

Parkinson's disease (PD) and other synucleinopathies, namely dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), are common degenerative neurological disorders that share synuclein pathology. Although certain cardinal features of parkinsonism, including bradykinesia and rigidity, respond well to levodopa, axial features, such as gait and balance impairment, are less reliably responsive to dopaminergic therapy and surgical interventions. Consequently, falls are common in PD and other synucleinopathies and are a major contributor toward injury and loss of independence. This underscores the need for appropriate fall risk assessment and implementation of preventative measures in all patients with parkinsonism. The aim of this review is therefore to explore modifiable and non-modifiable risk factors for falls in synucleinopathies. We next review and evaluate the evidence for pharmacological, nonpharmacological, and surgical approaches for fall prevention, and emphasize individualized and multifaceted approaches.

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The aim of this study was to characterise lung function and bronchoalveolar lavage sphingolipid profile in newborn mice during hyperoxia exposure and recovery in room air, and to examine the effect of d-sphingosine supplementation during recovery. Newborn mice were exposed to 80% oxygen for 4 weeks and allowed to recover in room air for another 4 weeks. Lung function measurements and morphometrical analysis of lung tissue were performed and bronchoalveolar lavage fluid was collected during hyperoxia and recovery with and without d-sphingosine supplementation. Hyperoxia exposure altered lung function, which partially recovered in room air. Lungs had fewer and enlarged alveoli which persisted during recovery. Multiple sphingolipids were significantly increased after hyperoxia. Ceramides were increased after 2 weeks of recovery, but normalised to control values after 4 weeks. The addition of d-sphingosine during the first 5 days of recovery accelerated the normalisation of ceramide levels at 2 weeks and partially reversed the hyperoxia-induced increase in alveolar size and arrest in alveolarisation at 4 weeks. Exposure of newborn mice to hyperoxia caused restrictive and obstructive lung function changes that partially recovered in room air, while alveolar morphology remained abnormal. Hyperoxia increased ceramide levels, with normalisation after recovery. d-sphingosine addition during recovery reduced ceramide levels and ameliorated hyperoxia-induced alveolar arrest.

To explore the physiological functions of endothelin-2 (ET-2), we generated gene-targeted mouse models. Global Et2 knockout mice exhibited severe growth retardation and juvenile lethality. Despite normal milk intake, they suffered from internal starvation characterized by hypoglycemia, ketonemia, and increased levels of starvation-induced genes. Although ET-2 is abundantly expressed in the gastrointestinal tract, the intestine was morphologically and functionally normal. Moreover, intestinal epithelium-specific Et2 knockout mice showed no abnormalities in growth and survival. Global Et2 knockout mice were also profoundly hypothermic. Housing Et2 knockout mice in a warm environment significantly extended their median lifespan. However, neuron-specific Et2 knockout mice displayed a normal core body temperature. Low levels of Et2 mRNA were also detected in the lung, with transient increases soon after birth. The lungs of Et2 knockout mice showed emphysematous structural changes with an increase in total lung capacity, resulting in chronic hypoxemia, hypercapnia, and increased erythropoietin synthesis. Finally, systemically inducible ET-2 deficiency in neonatal and adult mice fully reproduced the phenotype previously observed in global Et2 knockout mice. Together, these findings reveal that ET-2 is critical for the growth and survival of postnatal mice and plays important roles in energy homeostasis, thermoregulation, and the maintenance of lung morphology and function.

The disruption of angiogenic pathways, whether through genetic predisposition or as a consequence of life-saving interventions, may underlie many pulmonary diseases of infancy, including bronchopulmonary dysplasia. Neuropilin-1 (Nrp1) is a transmembrane receptor that plays essential roles in normal and pathological vascular development and binds two distinct ligand families: vascular endothelial growth factor (Vegf) and class 3 semaphorins (Sema3). Although Nrp1 is critical for systemic vascular development, the importance of Nrp1 in pulmonary vascular morphogenesis is uncertain. We hypothesized that Sema3-Nrp1 and Vegf-Nrp1 interactions are important pathways in the orchestration of pulmonary vascular development during alveolarization. Complete ablation of Nrp1 signaling would therefore lead to interruption of normal angiogenic and vascular maturation processes that are relevant to the pathogenesis of bronchopulmonary dysplasia. We have previously shown that congenital loss of Sema3-Nrp1 signaling in transgenic Nrp1(Sema-) mice resulted in disrupted alveolar-capillary interface formation and high neonatal mortality. Here, pathohistological examination of Nrp1(Sema-) survivors in the alveolar period revealed moderate to severe respiratory distress, alveolar hemorrhaging, abnormally dilated capillaries, and disintegrating alveolar septa, demonstrating continued instability of the alveolar-capillary interface. Moreover, consistent with a reduced capillary density and consequent increases in vascular resistance, hypertensive remodeling was observed. In contrast, conditional Nrp1 deletion beginning at postnatal day 5 had only a transient effect upon alveolar and vascular development or pneumocyte differentiation despite an increase in mortality. Our results demonstrate that although Sema3-Nrp1 signaling is critical during fetal pulmonary development, Nrp1 signaling does not appear to be essential for alveolar development or vascular function in the postnatal period.

Respiratory diseases of the newborn can arise from the disruption of essential angiogenic pathways. Neuropilin-1 (NRP1), which is a critical receptor implicated in systemic vascular growth and remodeling, binds two distinct ligand families: vascular endothelial growth factor (VEGF) and class 3 semaphorins (SEMA3). Although the function of VEGF-NRP1 interactions in vascular development is well described, the importance of SEMA3-NRP1 signaling in systemic or pulmonary vascular morphogenesis is debated. We sought to characterize the effect of deficient SEMA3-NRP1 signaling on fetal pulmonary vascular development in a mouse model. Temporospatial expression of Nrp1 and Sema3 mRNA and protein during murine fetal lung development was investigated, and the development of the pulmonary vasculature in transgenic mice deficient in Sema3-Nrp1 signaling was examined by histology, immunostaining, and electron microscopy. Loss of Sema3-Nrp1 signaling resulted in acute respiratory distress and high neonatal mortality. Pathohistological examination of mutants revealed immature and atelectatic regions in the lung, severely reduced capillary density, thickened alveolar septa containing centrally located dilated capillaries, hypertensive changes in arteriolar walls, anomalous and misaligned pulmonary veins, and reduced pulmonary surfactant secretion. Notably, many features are reminiscent of the fatal pulmonary disorder alveolar capillary dysplasia. These findings indicate a critical role for Sema3-Nrp1 signaling in fetal pulmonary development, which may have clinical relevance for treatment of various neonatal respiratory disorders, including alveolar capillary dysplasia. (Am J Pathol 2012,181: 2003-2017: http://dx.doi.org/10.1016/j.ajpath.2012.08.037)