The role of psychiatric symptoms, sociodemographic factors, and baseline sleep variables on pediatric insomnia treatment outcomes in a clinically referred population.

STUDY OBJECTIVES: The current study aimed to examine clinically relevant psychiatric and sociodemographic predictors of insomnia treatment outcomes in pediatric patients clinically referred for insomnia. METHODS: Pediatric patients (N = 1428; ages 1.5 - 18 years), presenting for insomnia evaluation in a medical/sleep center-based behavioral sleep clinic were followed for treatment as clinically indicated. According to patient age, parent/patients completed validated measures of insomnia severity, psychiatric symptoms, and sociodemographic measures. Patients were also categorized by treatment outcome status (i.e., not recommended to follow-up after initial evaluation and treatment session, successful treatment completion, lost to follow-up after initial evaluation and treatment session, and early termination) according to the clinically indicated treatment recommended and dose of treatment received. RESULTS: Youth had elevated scores on psychiatric screening indexes with affective problems being highest for all age groups. Other co-morbid sleep disorders were present in nearly 25% of insomnia patients and use of sleep aids (melatonin; hypnotics) was commonplace. Baseline insomnia severity significantly predicted sleep treatment trajectories and post-treatment insomnia severity with large effects for all age groups. Other clinically relevant predictors of insomnia treatment outcomes included medication use and externalizing mental health concerns in younger patients and internalizing mental health concerns and chronological age in older patients. Lack of treatment follow-up and premature treatment termination was observed for patients with the worst insomnia symptoms at time of initial evaluation. CONCLUSIONS: Pediatric health providers delivering insomnia treatment should take a developmentally sensitive approach that is proactive with regards to managing treatment barriers that are likely influenced by severity of insomnia and co-morbid mental health concerns.

A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer's mouse model.

INTRODUCTION: Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Aß) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction. METHODS: PTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APPL/S) and wild-type controls. Effects on memory and hippocampal long-term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing. RESULTS: In APPL/S mice, BD10-2 treatment improved memory and LTP deficits. This was accompanied by normalized phosphorylation of protein kinase B (Akt), calcium-calmodulin-dependent kinase II (CaMKII), and AMPA-type glutamate receptors containing the subunit GluA1; enhanced activity-dependent recruitment of synaptic proteins; and increased excitatory synapse number. BD10-2 also had potentially favorable effects on LTP-dependent complement pathway and synaptic gene transcription. DISCUSSION: BD10-2 prevented APPL/S/Aß-associated memory and LTP deficits, reduced abnormalities in synapse-related signaling and activity-dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response. HIGHLIGHTS: Small molecule modulation of tropomyosin related kinase B (TrkB) and C (TrkC) restores long-term potentiation (LTP) and behavior in an Alzheimer's disease (AD) model. Modulation of TrkB and TrkC regulates synaptic activity-dependent transcription. TrkB and TrkC receptors are candidate targets for translational therapeutics. Electrophysiology combined with transcriptomics elucidates synaptic restoration. LTP identifies neuron and microglia AD-relevant human-mouse co-expression modules.

Advancing Patient-Centered Care: An International Survey of Adolescent Perspectives on Insomnia.

OBJECTIVE: The study objective was to inform patient-centered care for adolescent insomnia by describing adolescents' perspectives on insomnia. Specific constructs of interest included: 1) factors that contributed to insomnia development or maintenance, 2) impact of insomnia on day-to-day life, 3) recommended research priorities, and 4) overall experience living with insomnia. METHOD: A convenience sample of adolescents (ages 13-18 years) self-identifying with insomnia symptoms was recruited through social media. Respondents (n = 3,014) completed an online survey. Responses to an open-ended item assessing patient experience were coded using thematic analysis. RESULTS: Participants identified as 70.8% White non-Hispanic, 77.0% female, and lived in one of five English-speaking countries (United States, United Kingdom, Canada, Australia, or New Zealand). Most (87.5%) met DSM-V diagnostic criteria for insomnia. The most common contributory factors to insomnia endorsed were stress (72.1%) and depressed mood (63.6%), while common impact areas were mood (72.2%), focus (61.0%), and pain (49.7%). Patient-centered research priorities were identifying insomnia causes (66.4%) and early detection (66.1%). Common adolescent experiences included high distress levels, feelings of invalidation, and helplessness about their insomnia. CONCLUSIONS: Adolescents with insomnia offer a unique perspective that should inform patient-centered research and care. There is a need for heightened screening and awareness about insomnia as a condition that causes significant distress and impairment for adolescents. To provide validating care, providers should recognize the multifaceted causes of insomnia.

Current Considerations in the Diagnosis and Treatment of Circadian Rhythm Sleep-Wake Disorders in Children.

Circadian Rhythm Sleep-Wake Disorders (CRSWDs) are important sleep disorders whose unifying feature is a mismatch between the preferred or required times for sleep and wakefulness and the endogenous circadian drives for these. Their etiology, presentation, and treatment can be different in pediatric patients as compared to adults. Evaluation of these disorders must be performed while viewed through the lens of a patient's comorbid conditions. Newer methods of assessment promise to provide greater diagnostic clarity and critical insights into how circadian physiology affects overall health and disease states. Effective clinical management of CRSWDs is multimodal, requiring an integrated approach across disciplines. Therapeutic success depends upon appropriately timed nonpharmacologic and pharmacologic interventions. A better understanding of the genetic predispositions for and causes of CRSWDs has led to novel clinical opportunities for diagnosis and improved therapeutics.

A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer's mouse model.

Introduction: TrkB and TrkC receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid-ß (Aß)-toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction. Methods: PTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APP L/S ) and wild-type controls (WT). Effects on memory and hippocampal long-term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA-sequencing. Results: Memory and LTP deficits in APP L/S mice were attenuated by treatment with BD10-2. BD10-2 prevented aberrant AKT, CaMKII, and GLUA1 phosphorylation, and enhanced activity-dependent recruitment of synaptic proteins. BD10-2 also had potentially favorable effects on LTP-dependent complement pathway and synaptic gene transcription. Conclusions: BD10-2 prevented APP L/S /Aß-associated memory and LTP deficits, reduced abnormalities in synapse-related signaling and activity-dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response.

Pharmacological Co-Activation of TrkB and TrkC Receptor Signaling Ameliorates Striatal Neuropathology and Motor Deficits in Mouse Models of Huntington's Disease.

BACKGROUND: Loss of neurotrophic support in the striatum, particularly reduced brain-derived neurotrophic factor (BDNF) levels, contributes importantly to Huntington's disease (HD) pathogenesis. Another neurotrophin (NT), NT-3, is reduced in the cortex of HD patients; however, its role in HD is unknown. BDNF and NT-3 bind with high affinity to the tropomyosin receptor-kinases (Trk) B and TrkC, respectively. Targeting TrkB/TrkC may be an effective HD therapeutic strategy, as multiple links exist between their signaling pathways and HD degenerative mechanisms. We developed a small molecule ligand, LM22B-10, that activates TrkB and TrkC to promote cell survival. OBJECTIVE: This study aimed to determine if upregulating TrkB/TrkC signaling with LM22B-10 would alleviate the HD phenotype in R6/2 and Q140 mice. METHODS: LM22B-10 was delivered by concomitant intranasal-intraperitoneal routes to R6/2 and Q140 mice and then motor performance and striatal pathology were evaluated. RESULTS: NT-3 levels, TrkB/TrkC phosphorylation, and AKT signaling were reduced in the R6/2 striatum; LM22B-10 counteracted these deficits. LM22B-10 also reduced intranuclear huntingtin aggregates, dendritic spine loss, microglial activation, and degeneration of dopamine- and cyclic AMP-regulated phosphoprotein with a molecular weight of 32 kDa (DARPP-32) and parvalbumin-containing neurons in the R6/2 and/or Q140 striatum. Moreover, both HD mouse models showed improved motor performance after LM22B-10 treatment. CONCLUSIONS: These results reveal an NT-3/TrkC signaling deficiency in the striatum of R6/2 mice, support the idea that targeting TrkB/TrkC alleviates HD-related neurodegeneration and motor dysfunction, and suggest a novel, disease-modifying, multi-target strategy for treating HD.

Factors affecting pediatric adherence to positive airway pressure: Patient- and caregiver-reported treatment barriers and sleep difficulties.

OBJECTIVE/BACKGROUND: Adherence to positive airway pressure (PAP) treatment among children and adolescents is often suboptimal. Little is understood about modifiable determinants of PAP adherence. We evaluated whether patient and caregiver-perceived treatment barriers (across behavioral, environmental, emotional, and physical domains), as well as insomnia severity, were associated with PAP adherence among youth with sleep disordered breathing (SDB). PATIENTS/METHODS: We conducted a retrospective review of 188 patients prescribed PAP, ages 2-19 years. At the clinical visit, PAP adherence was assessed via objective download/smartcard and patients and their caregivers completed validated standardized questionnaires on barriers to PAP adherence and sleep onset and maintenance difficulties. We tested predictors of PAP adherence using linear regression. RESULTS: On average, patients wore their PAP 2/3 of nights for 5.3 ± 3.4 h. Patients reported more barriers overall compared to caregivers, and specifically more behavioral and emotional barriers (e.g., over a third of patients reported they just want to forget about sleep apnea). After controlling for demographic/treatment characteristics, patient-reported barriers accounted for a significant proportion of the variance in percent nights used (51%) and average nightly use (42%). Greater difficulties with sleep maintenance predicted poorer PAP adherence (percent nights and nightly duration). CONCLUSIONS: Study findings suggest that assessment of both patient and caregiver-perceived barriers to PAP adherence, as well as evaluating for sleep maintenance concerns, may provide important treatment targets for promoting PAP adherence among youth. Results also support the potential benefit of a multi-disciplinary team-based approach to managing SDB and promoting PAP adherence.

Small molecule modulation of TrkB and TrkC neurotrophin receptors prevents cholinergic neuron atrophy in an Alzheimer's disease mouse model at an advanced pathological stage.

Degeneration of basal forebrain cholinergic neurons (BFCNs) in the nucleus basalis of Meynert (NBM) and vertical diagonal band (VDB) along with their connections is a key pathological event leading to memory impairment in Alzheimer's disease (AD). Aberrant neurotrophin signaling via Trks and the p75 neurotrophin receptor (p75NTR) contributes importantly to BFCN dystrophy. While NGF/TrkA signaling has received the most attention in this regard, TrkB and TrkC signaling also provide trophic support to BFCNs and these receptors may be well located to preserve BFCN connectivity. We previously identified a small molecule TrkB/TrkC ligand, LM22B-10, that promotes cell survival and neurite outgrowth in vitro and activates TrkB/TrkC signaling in the hippocampus of aged mice when given intranasally, but shows poor oral bioavailability. An LM22B-10 derivative, PTX-BD10-2, with improved oral bioavailability has been developed and this study examined its effects on BFCN atrophy in the hAPPLond/Swe (APPL/S) AD mouse model. Oral delivery of PTX-BD10-2 was started after appreciable amyloid and cholinergic pathology was present to parallel the clinical context, as most AD patients start treatment at advanced pathological stages. PTX-BD10-2 restored cholinergic neurite integrity in the NBM and VDB, and reduced NBM neuronal atrophy in symptomatic APPL/S mice. Dystrophy of cholinergic neurites in BF target regions, including the cortex, hippocampus, and amygdala, was also reduced with treatment. Finally, PTX-BD10-2 reduced NBM tau pathology and improved the survival of cholinergic neurons derived from human induced pluripotent stem cells (iPSCs) after amyloid-ß exposure. These data provide evidence that targeting TrkB and TrkC signaling with PTX-BD10-2 may be an effective disease-modifying strategy for combating cholinergic dysfunction in AD. The potential for clinical translation is further supported by the compound's reduction of AD-related degenerative processes that have progressed beyond early stages and its neuroprotective effects in human iPSC-derived cholinergic neurons.

Relationship of overweight and obesity to insomnia severity, sleep quality, and insomnia improvement in a clinically referred pediatric sample.

STUDY OBJECTIVES: Children with overweight or obesity are more likely to experience sleep disorders, although the role of weight in pediatric insomnia treatment has not been examined. The current study examined the relationships of high body mass with pretreatment insomnia severity and global sleep problems and the potential moderating impact of weight on changes in insomnia severity following insomnia treatment. METHODS: Participants included 1,133 youth ages 2-18 years clinically referred for insomnia treatment. The Pediatric Insomnia Severity Index was collected at the initial assessment and throughout treatment as part of routine clinical care. Treatment status was coded as no treatment, early termination, and completed treatment. Secondary measures of global sleep problems at the initial assessment included the Adolescent Sleep Wake Scale, Adolescent Sleep Hygiene Scale, and Children's Sleep Habits Questionnaire. Medical chart review of visits within ± 3 months of baseline was used to obtain age-adjusted and sex-adjusted body mass index Z-score. RESULTS: Among adolescents, regression analyses found that higher body mass index Z-score modestly predicted baseline insomnia severity (P = .021) and worse sleep hygiene (P < .001). For children, higher body mass index Z-score was modestly associated with baseline total sleep problems (P = .006) but not insomnia severity (P = .792). Across ages, body mass index Z-score predicted neither treatment status nor insomnia improvement (P > .05). Findings were similar in categorical analyses comparing patients with overweight/obesity to healthy weight. CONCLUSIONS: Although there is evidence that children of higher body mass present for insomnia treatment with greater sleep concerns, body mass does not predict treatment completion or insomnia improvement. Data suggest insomnia treatment is effective irrespective of weight status. CITATION: Duraccio KM, Simmons DM, Beebe DW, Byars KC. Relationship of overweight and obesity to insomnia severity, sleep quality, and insomnia improvement in a clinically referred pediatric sample. J Clin Sleep Med. 2022;18(4):1083-1091.

Neuroimaging, Urinary, and Plasma Biomarkers of Treatment Response in Huntington's Disease: Preclinical Evidence with the p75NTR Ligand LM11A-31.

Huntington's disease (HD) is caused by an expansion of the CAG repeat in the huntingtin gene leading to preferential neurodegeneration of the striatum. Disease-modifying treatments are not yet available to HD patients and their development would be facilitated by translatable pharmacodynamic biomarkers. Multi-modal magnetic resonance imaging (MRI) and plasma cytokines have been suggested as disease onset/progression biomarkers, but their ability to detect treatment efficacy is understudied. This study used the R6/2 mouse model of HD to assess if structural neuroimaging and biofluid assays can detect treatment response using as a prototype the small molecule p75NTR ligand LM11A-31, shown previously to reduce HD phenotypes in these mice. LM11A-31 alleviated volume reductions in multiple brain regions, including striatum, of vehicle-treated R6/2 mice relative to wild-types (WTs), as assessed with in vivo MRI. LM11A-31 also normalized changes in diffusion tensor imaging (DTI) metrics and diminished increases in certain plasma cytokine levels, including tumor necrosis factor-alpha and interleukin-6, in R6/2 mice. Finally, R6/2-vehicle mice had increased urinary levels of the p75NTR extracellular domain (ecd), a cleavage product released with pro-apoptotic ligand binding that detects the progression of other neurodegenerative diseases; LM11A-31 reduced this increase. These results are the first to show that urinary p75NTR-ecd levels are elevated in an HD mouse model and can be used to detect therapeutic effects. These data also indicate that multi-modal MRI and plasma cytokine levels may be effective pharmacodynamic biomarkers and that using combinations of these markers would be a viable and powerful option for clinical trials.

Reduced cognitive deficits after FLASH irradiation of whole mouse brain are associated with less hippocampal dendritic spine loss and neuroinflammation.

AIM: To evaluate the impact of ultra-rapid FLASH mouse whole brain irradiation on hippocampal dendritic spines and neuroinflammation, factors associated with cognitive impairment after brain irradiation. METHODS: We administered 30 Gy whole brain irradiation to C57BL6/J mice in sub-second (FLASH) vs. 240 s conventional delivery time keeping all other parameters constant, using a custom configured clinical linac. Ten weeks post-irradiation, we evaluated spatial and non-spatial object recognition using novel object location and object recognition testing. We measured dendritic spine density by tracing Golgi-stained hippocampal neurons and evaluated neuroinflammation by CD68 immunostaining, a marker of activated microglia, and expression of 10 pro-inflammatory cytokines using a multiplex immunoassay. RESULTS: At ten weeks post-irradiation, compared to unirradiated controls, conventional delivery time irradiation significantly impaired novel object location and recognition tasks whereas the same dose given in FLASH delivery did not. Conventional delivery time, but not FLASH, was associated with significant loss of dendritic spine density in hippocampal apical dendrites, with a similar non-significant trend in basal dendrites. Conventional delivery time was associated with significantly increased CD68-positive microglia compared to controls whereas FLASH was not. Conventional delivery time was associated with significant increases in 5 of 10 pro-inflammatory cytokines in the hippocampus (and non-significant increases in another 3), whereas FLASH was associated with smaller increases in only 3. CONCLUSION: Reduced cognitive impairment and associated neurodegeneration were observed with FLASH compared to conventional delivery time irradiation, potentially through decreased induction of neuroinflammation, suggesting a promising approach to increasing therapeutic index in radiation therapy of brain tumors.

Receptor dependence of BDNF actions in superficial dorsal horn: relation to central sensitization and actions of macrophage colony stimulating factor 1.

Peripheral nerve injury elicits an enduring increase in the excitability of the spinal dorsal horn. This change, which contributes to the development of neuropathic pain, is a consequence of release and prolonged exposure of dorsal horn neurons to various neurotrophins and cytokines. We have shown in rats that nerve injury increases excitatory synaptic drive to excitatory neurons but decreases drive to inhibitory neurons. Both effects, which contribute to an increase in dorsal horn excitability, appear to be mediated by microglia-derived BDNF. We have used multiphoton Ca2+ imaging and whole cell recording of spontaneous excitatory postsynaptic currents in defined-medium organotypic cultures of GAD67-GFP+ mice spinal cord to determine the receptor dependence of these opposing actions of BDNF. In mice, as in rats, BDNF enhances excitatory transmission onto excitatory neurons. This is mediated via presynaptic TrkB and p75 neurotrophin receptors and exclusively by postsynaptic TrkB. By contrast with findings from rats, in mice BDNF does not decrease excitation of inhibitory neurons. The cytokine macrophage colony-stimulating factor 1 (CSF-1) has also been implicated in the onset of neuropathic pain. Nerve injury provokes its de novo synthesis in primary afferents, its release in spinal cord, and activation of microglia. We now show that CSF-1 increases excitatory drive to excitatory neurons via a BDNF-dependent mechanism and decreases excitatory drive to inhibitory neurons via BDNF-independent processes. Our findings complete missing steps in the cascade of events whereby peripheral nerve injury instigates increased dorsal horn excitability in the context of central sensitization and the onset of neuropathic pain. NEW & NOTEWORTHY Nerve injury provokes synthesis of macrophage colony-stimulating factor 1 (CSF-1) in primary afferents and its release in the dorsal horn. We show that CSF-1 increases excitatory drive to excitatory dorsal horn neurons via BDNF activation of postsynaptic TrkB and presynaptic TrkB and p75 neurotrophin receptors. CSF-1 decreases excitatory drive to inhibitory neurons via a BDNF-independent processes. This completes missing steps in understanding how peripheral injury instigates central sensitization and the onset of neuropathic pain.

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.

Modulating Neurotrophin Receptor Signaling as a Therapeutic Strategy for Huntington's Disease.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the IT15 gene which encodes the huntingtin (HTT) protein. Currently, no treatments capable of preventing or slowing disease progression exist. Disease modifying therapeutics for HD would be expected to target a comprehensive set of degenerative processes given the diverse mechanisms contributing to HD pathogenesis including neuroinflammation, excitotoxicity, and transcription dysregulation. A major contributor to HD-related degeneration is mutant HTT-induced loss of neurotrophic support. Thus, neurotrophin (NT) receptors have emerged as therapeutic targets in HD. The considerable overlap between NT signaling networks and those dysregulated by mutant HTT provides strong theoretical support for this approach. This review will focus on the contributions of disrupted NT signaling in HD-related neurodegeneration and how targeting NT receptors to augment pro-survival signaling and/or to inhibit degenerative signaling may combat HD pathologies. Therapeutic strategies involving NT delivery, peptidomimetics, and the targeting of specific NT receptors (e.g., Trks or p75NTR), particularly with small molecule ligands, are discussed.

Neurotrophin Receptor Signaling as a Therapeutic Target for Huntington's Disease.

Effective non-genetic disease modifying treatments for Huntington's disease (HD) will necessarily target multiple diverse neurodegenerative processes triggered by mutant huntingtin. Neurotrophin receptors are well-positioned for this task as they regulate signaling pathways that largely overlap with signaling networks contributing to HD-related synaptic dysfunction, glial activation, excitotoxicity, and other degenerative processes. This review will discuss the contributions of disrupted neurotrophin receptor-related signaling to primary HD neuropathologies, and prospects for harnessing this signaling to develop therapeutics to counteract HD degenerative mechanisms. Application of the native protein ligands has been challenging pharmacologically, but progress has been made with the advent of small molecule compounds that can selectively bind to and activate specific Trk receptors or p75NTR to promote trophic and/or inhibit degenerative signaling in cell populations preferentially affected in HD.

A small molecule TrkB/TrkC neurotrophin receptor co-activator with distinctive effects on neuronal survival and process outgrowth.

Neurotrophin (NT) receptors are coupled to numerous signaling networks that play critical roles in neuronal survival and plasticity. Several non-peptide small molecule ligands have recently been reported that bind to and activate specific tropomyosin-receptor kinase (Trk) NT receptors, stimulate their downstream signaling, and cause biologic effects similar to, though not completely overlapping, those of the native NT ligands. Here, in silico screening, coupled with low-throughput neuronal survival screening, identified a compound, LM22B-10, that, unlike prior small molecule Trk ligands, binds to and activates TrkB as well as TrkC. LM22B-10 increased cell survival and strongly accelerated neurite outgrowth, superseding the effects of brain-derived neurotrophic factor (BDNF), NT-3 or the two combined. Additionally, unlike the NTs, LM22B-10 supported substantial early neurite outgrowth in the presence of inhibiting glycoproteins. Examination of the mechanisms of these actions suggested contributions of the activation of both Trks and differential interactions with p75(NTR), as well as a requirement for involvement of the Trk extracellular domain. In aged mice, LM22B-10 activated hippocampal and striatal TrkB and TrkC, and their downstream signaling, and increased hippocampal dendritic spine density. Thus, LM22B-10 may constitute a new tool for the study of TrkB and TrkC signaling and their interactions with p75(NTR), and provides groundwork for the development of ligands that stimulate unique combinations of Trk receptors and activity patterns for application to selected neuronal populations and deficits present in various disease states.

A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice.

Decreases in the ratio of neurotrophic versus neurodegenerative signalling play a critical role in Huntington's disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75NTR signalling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75NTR-associated deleterious signalling and decreases survival signalling suggesting that p75NTR could be a valuable therapeutic target. This hypothesis was investigated by examining the effects of an orally bioavailable, small molecule p75NTR ligand, LM11A-31, on HD-related neuropathology in HD mouse models (R6/2, BACHD). LM11A-31 restored striatal AKT and other pro-survival signalling while inhibiting c-Jun kinase (JNK) and other degenerative signalling. Normalizing p75NTR signalling with LM11A-31 was accompanied by reduced Htt aggregates and striatal cholinergic interneuron degeneration as well as extended survival in R6/2 mice. The p75NTR ligand also decreased inflammation, increased striatal and hippocampal dendritic spine density, and improved motor performance and cognition in R6/2 and BACHD mice. These results support small molecule modulation of p75NTR as an effective HD therapeutic strategy. LM11A-31 has successfully completed Phase I safety and pharmacokinetic clinical trials and is therefore a viable candidate for clinical studies in HD.

A small molecule p75NTR ligand, LM11A-31, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression.

Degeneration of basal forebrain cholinergic neurons contributes significantly to the cognitive deficits associated with Alzheimer's disease (AD) and has been attributed to aberrant signaling through the neurotrophin receptor p75 (p75NTR). Thus, modulating p75NTR signaling is considered a promising therapeutic strategy for AD. Accordingly, our laboratory has developed small molecule p75NTR ligands that increase survival signaling and inhibit amyloid-ß-induced degenerative signaling in in vitro studies. Previous work found that a lead p75NTR ligand, LM11A-31, prevents degeneration of cholinergic neurites when given to an AD mouse model in the early stages of disease pathology. To extend its potential clinical applications, we sought to determine whether LM11A-31 could reverse cholinergic neurite atrophy when treatment begins in AD mouse models having mid- to late stages of pathology. Reversing pathology may have particular clinical relevance as most AD studies involve patients that are at an advanced pathological stage. In this study, LM11A-31 (50 or 75 mg/kg) was administered orally to two AD mouse models, Thy-1 hAPPLond/Swe (APPL/S) and Tg2576, at age ranges during which marked AD-like pathology manifests. In mid-stage male APPL/S mice, LM11A-31 administered for 3 months starting at 6-8 months of age prevented and/or reversed atrophy of basal forebrain cholinergic neurites and cortical dystrophic neurites. Importantly, a 1 month LM11A-31 treatment given to male APPL/S mice (12-13 months old) with late-stage pathology reversed the degeneration of cholinergic neurites in basal forebrain, ameliorated cortical dystrophic neurites, and normalized increased basal forebrain levels of p75NTR. Similar results were seen in female Tg2576 mice. These findings suggest that LM11A-31 can reduce and/or reverse fundamental AD pathologies in late-stage AD mice. Thus, targeting p75NTR is a promising approach to reducing AD-related degenerative processes that have progressed beyond early stages.

Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice.

As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts--in which circulatory systems of young and aged animals are connected--identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function.

A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington's disease.

Loss of neurotrophic support in the striatum caused by reduced brain-derived neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease (HD) pathogenesis. BDNF acts via TrkB and p75 neurotrophin receptors (NTR), and restoring its signaling is a prime target for HD therapeutics. Here we sought to determine whether a small molecule ligand, LM22A-4, specific for TrkB and without effects on p75(NTR), could alleviate HD-related pathology in R6/2 and BACHD mouse models of HD. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to maximize brain levels. The ligand reached levels in the R6/2 forebrain greater than the maximal neuroprotective dose in vitro and corrected deficits in activation of striatal TrkB and its key signaling intermediates AKT, PLCγ, and CREB. Ligand-induced TrkB activation was associated with a reduction in HD pathologies in the striatum including decreased DARPP-32 levels, neurite degeneration of parvalbumin-containing interneurons, inflammation, and intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward climbing and grip strength compared with those given vehicle, though these groups had comparable rotarod performances and survival times. In BACHD mice, long-term LM22A-4 treatment (6 months) produced similar ameliorative effects. These results support the hypothesis that targeted activation of TrkB inhibits HD-related degenerative mechanisms, including spine loss, and may provide a disease mechanism-directed therapy for HD and other neurodegenerative conditions.