Research Discoveries in February 2024

Journal: Frontiers Neuroscience

Background: Frontotemporal dementia (FTD) represents a collection of neurobehavioral and neurocognitive syndromes that are associated with a significant degree of clinical, pathological, and genetic heterogeneity. Such heterogeneity hinders the identification of effective biomarkers, preventing effective targeted recruitment of participants in clinical trials for developing potential interventions and treatments. In the present study, we aim to automatically differentiate patients with three clinical phenotypes of FTD, behavioral-variant FTD (bvFTD), semantic variant PPA (svPPA), and nonfluent variant PPA (nfvPPA), based on their structural MRI by training a deep neural network (DNN).

Methods: Data from 277 FTD patients (173 bvFTD, 63 nfvPPA, and 41 svPPA) recruited from two multi-site neuroimaging datasets: the Frontotemporal Lobar Degeneration Neuroimaging Initiative and the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration databases. Raw T1-weighted MRI data were preprocessed and parcellated into patch-based ROIs, with cortical thickness and volume features extracted and harmonized to control the confounding effects of sex, age, total intracranial volume, cohort, and scanner difference. A multi-type parallel feature embedding framework was trained to classify three FTD subtypes with a weighted cross-entropy loss function used to account for unbalanced sample sizes. Feature visualization was achieved through post-hoc analysis using an integrated gradient approach.

Results: The proposed differential diagnosis framework achieved a mean balanced accuracy of 0.80 for bvFTD, 0.82 for nfvPPA, 0.89 for svPPA, and an overall balanced accuracy of 0.84. Feature importance maps showed more localized differential patterns among different FTD subtypes compared to groupwise statistical mapping.

Conclusion: In this study, we demonstrated the efficiency and effectiveness of using explainable deep-learning-based parallel feature embedding and visualization framework on MRI-derived multi-type structural patterns to differentiate three clinically defined subphenotypes of FTD: bvFTD, nfvPPA, and svPPA, which could help with the identification of at-risk populations for early and precise diagnosis for intervention planning.

Ma D, Stocks J, Rosen H, Kantarci K, Lockhart SN, Bateman JR, Craft S, Gurcan MN, Popuri K, Beg MF, Wang L; ALLFTD consortium. Differential diagnosis of frontotemporal dementia subtypes with explainable deep learning on structural MRI. Front Neurosci. 2024 Feb 7;18:1331677. doi: 10.3389/fnins.2024.1331677. PMID: 38384484; PMCID: PMC10879283.

Journal: Physiology (Bethesda)

Bees are the most important insect pollinators of the crops humans grow, and Apis mellifera, the Western honey bee, is the most commonly managed species for this purpose. In addition to providing agricultural services, the complex biology of honey bees has been the subject of scientific study since the 18th century, and the intricate behaviors of honey bees and ants - fellow Hymenopterans - inspired much sociobiological inquest. Unfortunately, honey bees are constantly exposed to parasites, pathogens, and xenobiotics, all of which pose threats to their health. Despite our curiosity about and dependence on honey bees, defining the molecular mechanisms underlying their interactions with biotic and abiotic stressors has been challenging. The very aspects of their physiology and behavior that make them so important to agriculture also make them challenging to study, relative to canonical model organisms. But because we rely on A. mellifera so much for pollination, we must continue our efforts to understand what ails them. Here, we review major advancements in our knowledge of honey bee physiology, focussing on immunity and detoxification, and highlight some challenges that remain.

Foster LJ, Tsvetkov N, McAfee A. Mechanisms of pathogen and pesticide resistance in honey bees. Physiology (Bethesda). 2024 Feb 27. doi: 10.1152/physiol.00033.2023. Epub ahead of print. PMID: 38411571.

Journal: The Journal of Comparative Neurology

Birds have a comprehensive network of sensorimotor projections extending from the forebrain and midbrain to the cerebellum via the pontine nuclei, but the organization of these circuits in the pons is not thoroughly described. Inputs to the pontine nuclei include two retinorecipient areas, nucleus lentiformis mesencephali (LM) and nucleus of the basal optic root (nBOR), which are important structures for analyzing optic flow. Other crucial regions for visuomotor control include the retinorecipient ventral lateral geniculate nucleus (GLv), and optic tectum (TeO). These visual areas, together with the somatosensory area of the anterior (rostral) Wulst, which is homologous to the primary somatosensory cortex in mammals, project to the medial and lateral pontine nuclei (PM, PL). In this study, we used injections of fluorescent tracers to study the organization of these visual and somatosensory inputs to the pontine nuclei in zebra finches. We found a topographic organization of inputs to PM and PL. The PM has a lateral subdivision that predominantly receives projections from the ipsilateral anterior Wulst. The medial PM receives bands of inputs from the ipsilateral GLv and the nucleus laminaris precommisulis, located medial to LM. We also found that the lateral PL receives a strong ipsilateral projection from TeO, while the medial PL and region between the PM and PL receive less prominent projections from nBOR, bilaterally. We discuss these results in the context of the organization of pontine inputs to the cerebellum and possible functional implications of diverse somato-motor and visuomotor inputs and parcellation in the pontine nuclei.

Gaede AH, Gutiérrez-Ibáñez C, Wu PH, Pilon MC, Altshuler DL, Wylie DR. Topography of visual and somatosensory inputs to the pontine nuclei in zebra finches (Taeniopygia guttata). J Comp Neurol. 2024 Feb;532(2):e25556. doi: 10.1002/cne.25556. Epub 2023 Nov 8. PMID: 37938923.

Journal: Lancet Neurology

Background: Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease.

Methods: LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21-55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014-000418-75, and is now complete.

Findings: Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI -1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference -1·76% [95% CI -2·67 to -0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]).

Interpretation: Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington's disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments.

Funding: Teva Pharmaceutical Industries.

Reilmann R, Anderson KE, Feigin A, Tabrizi SJ, Leavitt BR, Stout JC, Piccini P, Schubert R, Loupe P, Wickenberg A, Borowsky B, Rynkowski G, Volkinshtein R, Li T, Savola JM, Hayden M, Gordon MF; LEGATO-HD Study Group. Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Neurol. 2024 Mar;23(3):243-255. doi: 10.1016/S1474-4422(23)00454-4. Epub 2024 Jan 24. PMID: 38280392.

Journal: Brain Communications

Apathy is one of the most prevalent non-motor symptoms of Parkinson's disease and is characterized by decreased goal-directed behaviour due to a lack of motivation and/or impaired emotional reactivity. Despite its high prevalence, the neurophysiological mechanisms underlying apathy in Parkinson's disease, which may guide neuromodulation interventions, are poorly understood. Here, we investigated the neural oscillatory characteristics of apathy in Parkinson's disease using EEG data recorded during an incentivized motor task. Thirteen Parkinson's disease patients with apathy and 13 Parkinson's disease patients without apathy as well as 12 healthy controls were instructed to squeeze a hand grip device to earn a monetary reward proportional to the grip force they used. Event-related spectral perturbations during the presentation of a reward cue and squeezing were analysed using multiset canonical correlation analysis to detect different orthogonal components of temporally consistent event-related spectral perturbations across trials and participants. The first component, predominantly located over parietal regions, demonstrated suppression of low-beta (12-20 Hz) power (i.e. beta desynchronization) during reward cue presentation that was significantly smaller in Parkinson's disease patients with apathy compared with healthy controls. Unlike traditional event-related spectral perturbation analysis, the beta desynchronization in this component was significantly correlated with clinical apathy scores. Higher monetary rewards resulted in larger beta desynchronization in healthy controls but not Parkinson's disease patients. The second component contained gamma and theta frequencies and demonstrated exaggerated theta (4-8 Hz) power in Parkinson's disease patients with apathy during the reward cue and squeezing compared with healthy controls (HCs), and this was positively correlated with Montreal Cognitive Assessment scores. The third component, over central regions, demonstrated significantly different beta power across groups, with apathetic groups having the lowest beta power. Our results emphasize that altered low-beta and low-theta oscillations are critical for reward processing and motor planning in Parkinson's disease patients with apathy and these may provide a target for non-invasive neuromodulation.

Lee S, Song E, Zhu M, Appel-Cresswell S, McKeown MJ. Apathy scores in Parkinson's disease relate to EEG components in an incentivized motor task. Brain Commun. 2024 Feb 9;6(1):fcae025. doi: 10.1093/braincomms/fcae025. PMID: 38370450; PMCID: PMC10873141.

Journal: The Journal of Nutrition

Background: Nutrition plays a vital role in shaping the intestinal microbiome. However, many hospitalized children undergo periods of fasting during medical treatment. Changes to the small intestinal microbiota in early life in the setting of enteral deprivation have not been well described.

Objective: The aim of this study was to investigate the impact of enteral deprivation on the small intestinal mucosal microbiome and to identify factors that shape this interaction in infancy.

Methods: Intestinal biopsies were collected from proximal (fed) and distal (unfed) small bowel at the time of ostomy closure in children with a small intestinal enterostomy. Mucosal and luminal microbiome comparisons were performed including β-diversity and differential abundance and correlations with clinical factors were analyzed. Host proteomics were compared between fed and unfed samples and correlated with microbiome parameters. Finally, microbial results were validated in another cohort of pediatric patients.

Results: Samples from 13 children (median age 84 d) were collected. Mucosal microbiome communities in the fed and unfed segments were strikingly similar [paired UniFrac distance (β-diversity)], whereas luminal effluent differed significantly from fed samples (PERMANOVA, P = 0.003). Multivariate analysis revealed patient as the strongest predictor of the UniFrac distance. Environmental variables did not influence the intrapatient microbial dissimilarity. Host proteomics were similar intrapatient (paired fed-unfed Euclidian distance) and showed a correlation with the UniFrac distance (Spearman rho = 0.71, P < 0.001). Specific proteins and functional clusters were significantly different between paired samples, including lipid metabolism and intracellular trafficking, whereas no difference was seen in innate immune proteins. The microbiome results were validated in a different cohort with similar characteristics.

Conclusion: We found the host to be the most dominant factor in the structure of the early life small intestinal mucosal microbiome. Nutrient deprivation was associated with specific changes in the host proteome. Further research is needed to better understand this host-microbe-nutrition interaction.

Bar-Yoseph H, Krekhno Z, Cirstea M, Holani R, Moon KM, Foster LJ, Wieck M, Piper HG, Finlay BB. The Effect of Nutrient Deprivation on Early Life Small Intestinal Mucosal Microbiome and Host Proteome. J Nutr. 2024 Feb;154(2):412-423. doi: 10.1016/j.tjnut.2023.12.020. Epub 2023 Dec 16. PMID: 38110179.

Journal: Experimental Eye Research

Rod and cone photoreceptors are named for the distinct morphologies of their outer segment organelles, which are either cylindrical or conical, respectively. The morphologies of the stacked disks that comprise the rod and cone outer segments also differ: rod disks are completely sealed and are discontinuous from the plasma membrane, while cone disks remain partially open to the extracellular space. These morphological differences between photoreceptor types are more prominent in non-mammalian vertebrates, whose cones typically possess a greater proportion of open disks and are more tapered in shape. In mammals, the tetraspanin prph2 generates and maintains the highly curved disk rim regions by forming extended oligomeric structures with itself and a structurally similar paralog, rom1. Here we determined that in addition to these two proteins, there is a third Prph2 family paralog in most non-mammalian vertebrate species, including X. laevis: Glycoprotein 2-like protein or “Gp2l”. A survey of multiple genome databases revealed a single invertebrate Prph2 ‘pro-ortholog’ in Amphioxus, several echinoderms and in a diversity of protostomes indicating an ancient divergence from other tetraspanins. Based on phylogenetic analysis, duplication of the vertebrate predecessor likely gave rise to the Gp2l and Prph2/Rom1 clades, with a further duplication distinguishing the Prph2 and Rom1 clades. Mammals have lost Gp2l and their Rom1 has undergone a period of accelerated evolution such that it has lost several features that are retained in non-mammalian vertebrate Rom1. Specifically, Prph2, Gp2l and non-mammalian Rom1 encode proteins with consensus N-linked glycosylation and outer segment localization signals; mammalian rom1 lacks these motifs. We determined that X. laevis gp2l is expressed exclusively in cones and green rods, while X. laevis rom1 is expressed exclusively in rods, and prph2 is present in both rods and cones. The presence of three Prph2-related genes with distinct expression patterns as well as the rapid evolution of mammalian Rom1, may contribute to the more pronounced differences in morphology between rod and cone outer segments and rod and cone disks observed in non-mammalian versus mammalian vertebrates.

Tam BM, Taylor JS, Moritz OL. Identification and cellular localization in Xenopus laevis photoreceptors of three Peripherin-2 family members, Prph2, Rom1 and Gp2l, which arose from gene duplication events in the common ancestors of jawed vertebrates. Exp Eye Res. 2024 Feb;239:109760. doi: 10.1016/j.exer.2023.109760. Epub 2023 Dec 28. PMID: 38158174.

Journal: Canadian Journal of Emergency Medicine

As digital technologies continue to impact medicine, emergency medicine providers have an opportunity to work together to harness these technologies and shape their implementation within our healthcare system. COVID-19 and the rapid scaling of virtual care provide an example of how profoundly emergency medicine can be affected by digital technology, both positively and negatively. This example also strengthens the case for why EM providers can help lead the integration of digital technologies within our broader healthcare system. As virtual care becomes a permanent fixture of our system, and other technologies such as AI and wearables break into Canadian healthcare, more advocacy, research, and health system leadership will be required to best leverage these tools. This paper outlines the purpose and outputs of the newly founded CAEP Digital Emergency Medicine (DigEM) Committee, with the hope of inspiring further interest amongst CAEP members and creating opportunities to collaborate with other organizations within CAEP and across EM groups nationwide.

Grant KL, Tsang J, Ho K. Implementing digital emergency medicine: a call to action. CJEM. 2024 Feb;26(2):75-77. doi: 10.1007/s43678-023-00620-0. Epub 2023 Nov 25. PMID: 38001328.

Journal: Drugs

 Depression is the most commonly experienced mood state over the life span in individuals with bipolar disorder (BD) and is the primary driver of functional impairment and suicidality in BD. Despite this, there are few effective treatments for BD depression, with only a handful of atypical anti-psychotics and inconsistent evidence for traditional mood stabilizing agents. There have been few major 'breakthroughs' in the treatment of BD depression, and until recently, few agents that work via novel mechanisms of action to exert therapeutic effects. Here, we review treatments for BD depression which are emergent or on the horizon. Included are new atypical anti-psychotics, glutamate modulators (ketamine and cycloserine/lurasidone), neurosteroid modulators (zuranolone), anti-inflammatories and mitochondrial modulators, cannabidiol (CBD) and psilocybin. New atypical anti-psychotics lumateperone and cariprazine have demonstrated efficacy in large-scale, placebo-controlled, double-blind randomized controlled trials (RCT) in treatment of BD depression. Non-racemic amisulpride showed potential therapeutic benefit in one RCT which requires replication. Three small RCTs examined the efficacy of intravenous ketamine in BD depression and showed rapid antidepressant and anti-suicidal effects after a single infusion. Anti-inflammatory and mitochondrial modulators show inconsistent evidence for efficacy. There are currently no adequately powered RCTs of zuranolone, psilocybin or CBD in BD depression to support their use. While there are potentially efficacious, mechanistically novel agents on the horizon, they require further study and validation. Further investigation on how these agents may impact specific subgroups of patients will also advance the field.

Keramatian K, Chakrabarty T, DuBow A, Saraf G, Yatham LN. New Pharmacologic Approaches to the Treatment of Bipolar Depression. Drugs. 2023 Jul;83(10):843-863. doi: 10.1007/s40265-023-01872-x. Epub 2023 May 25. Erratum in: Drugs. 2024 Feb 12;: PMID: 37227597.

Journal: Bipolar Disorder

Objectives: To understand treatment practices for bipolar disorders (BD), this study leveraged the Global Bipolar Cohort collaborative network to investigate pharmacotherapeutic treatment patterns in multiple cohorts of well-characterized individuals with BD in North America, Europe, and Australia.

Methods: Data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities were provided from each participating cohort. Individual site and regional pooled proportional meta-analyses with generalized linear mixed methods were conducted to identify prescription patterns.

Results: This study included 10,351 individuals from North America (n = 3985), Europe (n = 3822), and Australia (n = 2544). Overall, participants were predominantly female (60%) with BD-I (60%; vs. BD-II = 33%). Cross-sectionally, mood-stabilizing anticonvulsants (44%), second-generation antipsychotics (42%), and antidepressants (38%) were the most prescribed medications. Lithium was prescribed in 29% of patients, primarily in the Australian (31%) and European (36%) cohorts. First-generation antipsychotics were prescribed in 24% of the European versus 1% in the North American cohort. Antidepressant prescription rates were higher in BD-II (47%) compared to BD-I (35%). Major limitations were significant differences among cohorts based on inclusion/exclusion criteria, data source, and time/year of enrollment into cohort.

Conclusions: Mood-stabilizing anticonvulsants, second-generation antipsychotics, and antidepressants were the most prescribed medications suggesting prescription patterns that are not necessarily guideline concordant. Significant differences exist in the prescription practices across different geographic regions, especially the underutilization of lithium in the North American cohorts and the higher utilization of first-generation antipsychotics in the European cohorts. There is a need to conduct future longitudinal studies to further explore these differences and their impact on outcomes, and to inform and implement evidence-based guidelines to help improve treatment practices in BD.

Singh B, Yocum AK, Strawbridge R, Burdick KE, Millett CE, Peters AT, Sperry SH, Fico G, Vieta E, Verdolini N, Godin O, Leboyer M, Etain B, Tso IF, Coombes BJ, McInnis MG, Nierenberg AA, Young AH, Ashton MM, Berk M, Williams LJ, Keramatian K, Yatham LN, Overs BJ, Fullerton JM, Roberts G, Mitchell PB, Andreassen OA, Andreazza AC, Zandi PP, Pham D, Biernacka JM, Frye MA; FACE-BD Collaborators, The Global Bipolar Cohort Collaborative. Patterns of pharmacotherapy for bipolar disorder: A GBC survey. Bipolar Disord. 2024 Feb;26(1):22-32. doi: 10.1111/bdi.13366. Epub 2023 Jul 18. PMID: 37463846; PMCID: PMC10794603.

Journal: Journal of Clinical Medicine

This study offers a biexponential model to estimate corneal endothelial cell decay (ECD) following preloaded “endothelium-in” Descemet membrane endothelial keratoplasty (DMEK) in Fuchs’ endothelial corneal dystrophy (FECD) patients; (2) Methods: A total of 65 eyes undergoing DMEK alone or combined with cataract surgery were evaluated. The follow-up period was divided into an early phase (first 6 months) and a late phase (up to 36 months). Endothelial cell count (ECC) and endothelial cell loss (ECL) were analyzed; (3) Results: The half time of the ECD was 3.03 months for the early phase and 131.50 months for the late phase. The predicted time-lapse interval to reach 500 cells/mm2 was 218 months (18.17 years), while the time-lapse interval to reach 250 cells/mm2 was 349 months (29.08 years). There was no statistically significant difference between the ECL in DMEK combined with cataract extraction and DMEK alone at 24 months (p ≥ 0.20). At the late phase, long-term ECL prediction revealed a lower ECC half time in patients undergoing DMEK combined with cataract surgery (98.05 months) than DMEK alone (250.32 months); (4) Conclusions: Based on the mathematical modeling, a predicted average half-life of a DMEK graft could reach 18 years in FECD. Moreover, combining cataract extraction with DMEK could result in excessive ECL in the long term.

Viola P, Neri E, Occhipinti T, Parekh M, Cian R, Ponzin D, Moramarco A, Iovieno A. Predicting Long-Term Endothelial Cell Loss after Preloaded Descemet Membrane Endothelial Keratoplasty in Fuchs' Endothelial Corneal Dystrophy: A Mathematical Model. J Clin Med. 2024 Feb 2;13(3):877. doi: 10.3390/jcm13030877. PMID: 38337570; PMCID: PMC10856122.

Journal: Ophthalmology Retina

Purpose
To evaluate the outer retinal bands using OCT in ABCA4- and PRPH2-associated retinopathy and develop a novel imaging biomarker to differentiate between these 2 genotypes.

Design
Multicenter case-control study.

Participants
Patients with a clinical and genetic diagnosis of ABCA4- or PRPH2-associated retinopathy and an age-matched control group.

Methods
Macular OCT was used to measure the thickness of the outer retinal bands 2 and 4 by 2 independent examiners at 4 retinal loci.

Main Outcome Measures
Outcome measures included the thicknesses of band 2, band 4, and the band 2/band 4 ratio. Linear mixed modeling was used to make comparisons across the 3 groups. Receiver operating characteristic (ROC) analysis determined the optimal cutoff for the band 2/band 4 ratio to distinguish PRPH2- from ABCA4-associated retinopathy.

Results
We included 45 patients with ABCA4 variants, 45 patients with PRPH2 variants, and 45 healthy controls. Band 2 was significantly thicker in patients with PRPH2 compared with ABCA4 (21.4 vs. 15.9 μm, P < 0.001) variants, whereas band 4 was thicker in patients with ABCA4 variants than those with PRPH2 variants (27.5 vs. 21.7 μm, P < 0.001). Similarly, the band 2/band 4 ratio was significantly different (1.0 vs. 0.6 for PRPH2 vs. ABCA4, P < 0.001). The area under the ROC curve was 0.87 for either band 2 (> 18.58 μm) or band 4 (< 26.17 μm) alone and 0.99 (95% confidence interval: 0.97–0.99) for the band 2/band 4 ratio with a cutoff threshold of 0.79, providing 100% specificity.

Conclusions
We report an altered outer retinal band profile whereby the band 2/band 4 ratio was able to discriminate between PRPH2- and ABCA4-associated retinopathy. This may have future clinic utility in predicting the genotype and provide further insight into the anatomic correlate of band 2.

Financial Disclosure(s)
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Heath Jeffery RC, Lo J, Thompson JA, Lamey TM, McLaren TL, De Roach JN, Ayton LN, Vincent AL, Sharma A, Chen FK. Analysis of the Outer Retinal Bands in ABCA4 and PRPH2-Associated Retinopathy using OCT. Ophthalmol Retina. 2024 Feb;8(2):174-183. doi: 10.1016/j.oret.2023.05.010. Epub 2023 May 18. PMID: 37209970.

Journal: Cell Mol Gastroenterol Hepatol.

Background & aims: Micronutrient deficiency (MND) (ie, lack of vitamins and minerals) during pregnancy is a major public health concern. Historically, studies have considered micronutrients in isolation; however, MNDs rarely occur alone. The impact of co-occurring MNDs on public health, mainly in shaping mucosal colonization by pathobionts from the Enterobacteriaceae family, remains undetermined due to lack of relevant animal models.

Methods: To establish a maternal murine model of multiple MND (MMND), we customized a diet deficient in vitamins (A, B12, and B9) and minerals (iron and zinc) that most commonly affect children and women of reproductive age. Thereafter, mucosal adherence by Enterobacteriaceae, the associated inflammatory markers, and proteomic profile of intestines were determined in the offspring of MMND mothers (hereafter, low micronutrient [LM] pups) via bacterial plating, flow cytometry, and mass spectrometry, respectively. For human validation, Enterobacteriaceae abundance, assessed via 16s sequencing of 3-month-old infant fecal samples (n = 100), was correlated with micronutrient metabolites using Spearman's correlation in meconium of children from the CHILD birth cohort.

Results: We developed an MMND model and reported an increase in colonic abundance of Enterobacteriaceae in LM pups at weaning. Findings from CHILD cohort confirmed a negative correlation between Enterobacteriaceae and micronutrient availability. Furthermore, pro-inflammatory cytokines and increased infiltration of lymphocyte antigen 6 complex high monocytes and M1-like macrophages were evident in the colons of LM pups. Mechanistically, mitochondrial dysfunction marked by reduced expression of nicotinamide adenine dinucleotide (NAD)H dehydrogenase and increased expression of NAD phosphate oxidase (Nox) 1 contributed to the Enterobacteriaceae bloom.

Conclusion: This study establishes an early life MMND link to intestinal pathobiont colonization and mucosal inflammation via damaged mitochondria in the offspring.

Holani R, Littlejohn PT, Edwards K, Petersen C, Moon KM, Stacey RG, Bozorgmehr T, Gerbec ZJ, Serapio-Palacios A, Krekhno Z, Donald K, Foster LJ, Turvey SE, Finlay BB. A Murine Model of Maternal Micronutrient Deficiencies and Gut Inflammatory Host-microbe Interactions in the Offspring. Cell Mol Gastroenterol Hepatol. 2024 Feb 1:S2352-345X(24)00021-3. doi: 10.1016/j.jcmgh.2024.01.018. Epub ahead of print. PMID: 38307490.

Journal: Acta Neuropathologica Communications

Excitotoxicity from the impairment of glutamate uptake constitutes an important mechanism in neurodegenerative diseases such as Alzheimer’s, multiple sclerosis, and Parkinson's disease. Within the eye, excitotoxicity is thought to play a critical role in retinal ganglion cell death in glaucoma, diabetic retinopathy, retinal ischemia, and optic nerve injury, yet how excitotoxic injury impacts different retinal layers is not well understood. Here, we investigated the longitudinal effects of N-methyl-D-aspartate (NMDA)-induced excitotoxic retinal injury in a rat model using deep learning-assisted retinal layer thickness estimation. Before and after unilateral intravitreal NMDA injection in nine adult Long Evans rats, spectral-domain optical coherence tomography (OCT) was used to acquire volumetric retinal images in both eyes over 4 weeks. Ten retinal layers were automatically segmented from the OCT data using our deep learning-based algorithm. Retinal degeneration was evaluated using layer-specific retinal thickness changes at each time point (before, and at 3, 7, and 28 days after NMDA injection). Within the inner retina, our OCT results showed that retinal thinning occurred first in the inner plexiform layer at 3 days after NMDA injection, followed by the inner nuclear layer at 7 days post-injury. In contrast, the retinal nerve fiber layer exhibited an initial thickening 3 days after NMDA injection, followed by normalization and thinning up to 4 weeks post-injury. Our results demonstrated the pathological cascades of NMDA-induced neurotoxicity across different layers of the retina. The early inner plexiform layer thinning suggests early dendritic shrinkage, whereas the initial retinal nerve fiber layer thickening before subsequent normalization and thinning indicates early inflammation before axonal loss and cell death. These findings implicate the inner plexiform layer as an early imaging biomarker of excitotoxic retinal degeneration, whereas caution is warranted when interpreting the ganglion cell complex combining retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer thicknesses in conventional OCT measures. Deep learning-assisted retinal layer segmentation and longitudinal OCT monitoring can help evaluate the different phases of retinal layer damage upon excitotoxicity

Ma D, Deng W, Khera Z, Sajitha TA, Wang X, Wollstein G, Schuman JS, Lee S, Shi H, Ju MJ, Matsubara J, Beg MF, Sarunic M, Sappington RM, Chan KC. Early inner plexiform layer thinning and retinal nerve fiber layer thickening in excitotoxic retinal injury using deep learning-assisted optical coherence tomography. Acta Neuropathol Commun. 2024 Feb 1;12(1):19. doi: 10.1186/s40478-024-01732-z. PMID: 38303097; PMCID: PMC10835918.

Journal: Proceedings. Biological Sciences

The detection of optic flow is important for generating optomotor responses to mediate retinal image stabilization, and it can also be used during ongoing locomotion for centring and velocity control. Previous work in hummingbirds has separately examined the roles of optic flow during hovering and when centring through a narrow passage during forward flight. To develop a hypothesis for the visual control of forward flight velocity, we examined the behaviour of hummingbirds in a flight tunnel where optic flow could be systematically manipulated. In all treatments, the animals exhibited periods of forward flight interspersed with bouts of spontaneous hovering. Hummingbirds flew fastest when they had a reliable signal of optic flow. All optic flow manipulations caused slower flight, suggesting that hummingbirds had an expected optic flow magnitude that was disrupted. In addition, upward and downward optic flow drove optomotor responses for maintaining altitude during forward flight. When hummingbirds made voluntary transitions to hovering, optomotor responses were observed to all directions. Collectively, these results are consistent with hummingbirds controlling flight speed via mechanisms that use an internal forward model to predict expected optic flow whereas flight altitude and hovering position are controlled more directly by sensory feedback from the environment.

Baliga VB, Dakin R, Wylie DR, Altshuler DL. Hummingbirds use distinct control strategies for forward and hovering flight. Proc Biol Sci. 2024 Jan 10;291(2014):20232155. doi: 10.1098/rspb.2023.2155. Epub 2024 Jan 10. 

Journal: medRxiv

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD.

Methods: Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed.

Findings: We found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase.

Interpretation: Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD.

Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK

Gustavsson EK, Follett J, Trinh J, Barodia SK, Real R, Liu Z, Grant-Peters M, Fox JD, Appel-Cresswell S, Stoessl AJ, Rajput A, Rajput AH, Auer R, Tilney R, Sturm M, Haack TB, Lesage S, Tesson C, Brice A, Vilariño-Güell C, Ryten M, Goldberg MS, West AB, Hu MT, Morris HR, Sharma M, Gan-Or Z, Samanci B, Lis P, Tocino T, Amouri R, Sassi SB, Hentati F; Global Parkinson’s Genetics Program (GP2); Tonelli F, Alessi DR, Farrer MJ. A pathogenic variant in RAB32 causes autosomal dominant Parkinson's disease and activates LRRK2 kinase. medRxiv [Preprint]. 2024 Jan 18:2024.01.17.24300927. doi: 10.1101/2024.01.17.24300927. PMID: 38293014; PMCID: PMC10827257.

Journal: Journal of Parkinson's Disease

The aim of this review is to examine the intersection of Parkinson's disease (PD) with nutrition, to identify best nutritional practices based on current evidence, and to identify gaps in the evidence and suggest future directions. Epidemiological work has linked various dietary patterns and food groups to changes in PD risk; however, fewer studies have evaluated the role of various diets, dietary components, and supplements in the management of established PD. There is substantial interest in exploring the role of diet-related interventions in both symptomatic management and potential disease modification. In this paper, we evaluate the utility of several dietary patterns, including the Mediterranean (MeDi), Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), Alternative Healthy Eating Index (AHEI), vegan/vegetarian, and ketogenic diet in persons with PD. Additionally, we provide an overview of the evidence relating several individual food groups and nutritional supplements to PD risk, symptoms and progression.

Tosefsky KN, Zhu J, Wang YN, Lam JST, Cammalleri A, Appel-Cresswell S. The Role of Diet in Parkinson's Disease. J Parkinsons Dis. 2024 Jan 13. doi: 10.3233/JPD-230264. Epub ahead of print. PMID: 38251061.

Journal: ACS Sustainable Chemistry & Engineering

Driven by long-term persistence and adverse health impacts of legacy perfluorooctanoic acid (PFOA), production has shifted towards shorter chain analogs (C4, perfluorobutanoic acid (PFBA)) or fluorinated alternatives such as hexafluoropropylene oxide dimer acid (HFPO-DA, known as GenX) and 6:2 fluorotelomer carboxylic acid (6:2 FTCA). Yet, a thorough understanding of treatment processes for these alternatives is limited. Herein, we conducted a comprehensive study using an electrochemical approach with a boron doped diamond anode in Na₂SO₄ electrolyte for the remediation of PFOA common alternatives, i.e., PFBA, GenX, and 6:2 FTCA. The degradability, fluorine recovery, transformation pathway, and contributions from electro-synthesized radicals were investigated. The results indicated the significance of chain length and structure, with shorter chains being harder to break down (PFBA (65.6 ± 5.0%) < GenX (84.9 ± 3.3%) < PFOA (97.9 ± 0.1%) < 6:2 FTCA (99.4 ± 0.0%) within 120 min of electrolysis). The same by-products were observed during the oxidation of both low and high concentrations of parent PFAS (2 and 20 mg L^-1), indicating that the fundamental mechanism of PFAS degradation remained consistent. Nevertheless, the ratio of these by-products to the parent PFAS concentration varied which primarily arises from the more rapid PFAS decomposition at lower dosages. For all experiments, the main mechanism of PFAS oxidation was initiated by direct electron transfer at the anode surface. Sulfate radical (SO₄^•-) also contributed to the oxidation of all PFAS, while hydroxyl radical (^•OH) only played a role in the decomposition of 6:2 FTCA. Total fluorine recovery of PFBA, GenX, and 6:2 FTCA were 96.5%, 94.0%, and 76.4% within 240 min. The more complex transformation pathway of 6:2 FTCA could explain its lower fluorine recovery. Detailed decomposition pathways for each PFAS were also proposed through identifying the generated intermediates and fluorine recovery. The proposed pathways were also assessed using ¹⁹F Nuclear Magnetic Resonance (NMR) spectroscopy.

Asadi Zeidabadi F, Banayan Esfahani E, Moreira R, McBeath ST, Foster J, Mohseni M. Structural dependence of PFAS oxidation in a boron doped diamond-electrochemical system. Environ Res. 2024 Jan 3;246:118103. doi: 10.1016/j.envres.2024.118103. Epub ahead of print. PMID: 38181849.

Journal: mSystems

In eusocial insects, the health of the queens-the colony founders and sole reproductive females-is a primary determinant for colony success. Queen failure in the honey bee Apis mellifera, for example, is a major concern of beekeepers who annually suffer colony losses, necessitating a greater knowledge of queen health. Several studies on the microbiome of honey bees have characterized its diversity and shown its importance for the health of worker bees, the female non-reproductive caste. However, the microbiome of workers differs from that of queens, which, in comparison, is still poorly studied. Thus, direct investigations of the queen microbiome are required to understand colony-level microbiome assembly, functional roles, and evolution. Here, we used metagenomics to comprehensively characterize the honey bee queen microbiome. Comparing samples from different geographic locations and breeder sources, we show that the microbiome of queens is mostly shaped by the environment experienced since early life and is predicted to play roles in the breakdown of the diet and protection from pathogens and xenobiotics. We also reveal that the microbiome of queens comprises only four candidate core bacterial species, Apilactobacillus kunkeei, Lactobacillus apis, Bombella apis, and Commensalibacter sp. Interestingly, in addition to bacteria, we show that bacteriophages infect the queen microbiome, for which Lactobacillaceae are predicted to be the main reservoirs. Together, our results provide the basis to understand the honey bee colony microbiome assemblage, can guide improvements in queen-rearing processes, and highlight the importance of considering bacteriophages for queen microbiome health and microbiome homeostasis in eusocial insects.IMPORTANCEThe queen caste plays a central role in colony success in eusocial insects, as queens lay eggs and regulate colony behavior and development. Queen failure can cause colonies to collapse, which is one of the major concerns of beekeepers. Thus, understanding the biology behind the queen's health is a pressing issue. Previous studies have shown that the bee microbiome plays an important role in worker bee health, but little is known about the queen microbiome and its function in vivo. Here, we characterized the queen microbiome, identifying for the first time the present species and their putative functions. We show that the queen microbiome has predicted nutritional and protective roles in queen association and comprises only four consistently present bacterial species. Additionally, we bring to attention the spread of phages in the queen microbiome, which increased in abundance in failing queens and may impact the fate of the colony.

Caesar L, Rice DW, McAfee A, Underwood R, Ganote C, Tarpy DR, Foster LJ, Newton ILG. Metagenomic analysis of the honey bee queen microbiome reveals low bacterial diversity and Caudoviricetes phages. mSystems. 2024 Jan 23:e0118223. doi: 10.1128/msystems.01182-23. Epub ahead of print. PMID: 38259099.

Journal: Proceedings. Biological Sciences

Evidence for a trade-off between reproduction and immunity has manifested in many animal species, including social insects. However, investigations in social insect queens present a conundrum: new gynes of many social hymenopterans, such as bumble bees and ants, must first mate, then transition from being solitary to social as they establish their nests, thus experiencing confounding shifts in environmental conditions. Worker bumble bees offer an opportunity to investigate patterns of immune protein expression associated with ovary activation while minimizing extraneous environmental factors and genetic differences. Here, we use proteomics to interrogate the patterns of immune protein expression of female bumble bees (Bombus impatiens) by (i) sampling queens at different stages of their life cycle, then (ii) by sampling workers with different degrees of ovary activation. Patterns of immune protein expression in the haemolymph of queens are consistent with a reproduction-immunity trade-off, but equivalent samples from workers are not. This brings into question whether queen bumble bees really experience a reproduction-immunity trade-off, or if patterns of immune protein expression may actually be due to the selective pressure of the different environmental conditions they are exposed to during their life cycle.

McAfee A, Chapman A, Bao G, Tarpy DR, Foster LJ. Investigating trade-offs between ovary activation and immune protein expression in bumble bee (Bombus impatiens) workers and queens. Proc Biol Sci. 2024 Jan 31;291(2015):20232463. doi: 10.1098/rspb.2023.2463. Epub 2024 Jan 24. PMID: 38264776; PMCID: PMC10806398.

Journal: JMIR Formative Research

Background: Hypertension affects 1 in 5 Canadians and is the leading cause of morbidity and mortality globally. Hypertension control is declining due to multiple factors including lack of access to primary care. Consequently, patients with hypertension frequently visit the emergency department (ED) due to high blood pressure (BP). Telehealth for Emergency-Community Continuity of Care Connectivity via Home-Telemonitoring Blood Pressure is a pilot project that implements and evaluates a comprehensive home blood pressure telemonitoring (HBPT) and physician case management protocol designed as a postdischarge management strategy to support patients with asymptomatic elevated BP as they transition from the ED to home.

Objective: Our objective was to conduct a feasibility study of an HBPT program for patients with asymptomatic elevated BP discharged from the ED.

Methods: Patients discharged from an urban, tertiary care hospital ED with asymptomatic elevated BP were recruited in Vancouver, British Columbia, Canada, and provided with HBPT technology for 3 months of monitoring post discharge and referred to specialist hypertension clinics. Participants monitored their BP twice in the morning and evenings and tele-transmitted readings via Bluetooth Sensor each day using an app. A monitoring clinician received these data and monitored the patient's condition daily and adjusted antihypertensive medications. Feasibility outcomes included eligibility, recruitment, adherence to monitoring, and retention rates. Secondary outcomes included proportion of those who were defined as having hypertension post-ED visits, changes in mean BP, overall BP control, medication adherence, changes to antihypertensive medications, quality of life, and end user experience at 3 months.

Results: A total of 46 multiethnic patients (mean age 63, SD 17 years, 69%, n=32 women) found to have severe hypertension (mean 191, SD 23/mean 100, SD 14 mm Hg) in the ED were recruited, initiated on HBPT with hypertension specialist physician referral and followed up for 3 months. Eligibility and recruitment rates were 40% (56/139) and 88% (49/56), respectively. The proportion of participants that completed ≥80% of home BP measurements at 1 and 3 months were 67% (31/46) and 41% (19/46), respectively. The proportion of individuals who achieved home systolic BP and diastolic BP control at 3 months was 71.4% (30/42) and 85.7% (36/42) respectively. Mean home systolic and diastolic BP improved by -13/-5 mm Hg after initiation of HBPT to the end of the study. Patients were prescribed 1 additional antihypertensive medication. No differences in medication adherence from enrollment to 3 months were noted. Most patients (76%, 25/33) were highly satisfied with the HBPT program and 76% (25/33) found digital health tools easy to use.

Conclusions: HBPT intervention is a feasible postdischarge management strategy and can be beneficial in supporting patients with asymptomatic elevated BP from the ED. A randomized trial is underway to evaluate the efficacy of this intervention on BP control.

Tran KC, Mak M, Kuyper LM, Bittman J, Mangat B, Lindsay H, Kim Sing C, Xu L, Wong H, Dawes M, Khan N, Ho K. Home Blood Pressure Telemonitoring Technology for Patients With Asymptomatic Elevated Blood Pressure Discharged From the Emergency Department: Pilot Study. JMIR Form Res. 2024 Jan 30;8:e49592. doi: 10.2196/49592. PMID: 38111177.

Journal: Nucleic Acids Research

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs.

Gargano MA, Matentzoglu N, Coleman B, Addo-Lartey EB, Anagnostopoulos AV, Anderton J, Avillach P, Bagley AM, Bakštein E, Balhoff JP, Baynam G, Bello SM, Berk M, Bertram H, Bishop S, Blau H, Bodenstein DF, Botas P, Boztug K, Čady J, Callahan TJ, Cameron R, Carbon SJ, Castellanos F, Caufield JH, Chan LE, Chute CG, Cruz-Rojo J, Dahan-Oliel N, Davids JR, de Dieuleveult M, de Souza V, de Vries BBA, de Vries E, DePaulo JR, Derfalvi B, Dhombres F, Diaz-Byrd C, Dingemans AJM, Donadille B, Duyzend M, Elfeky R, Essaid S, Fabrizzi C, Fico G, Firth HV, Freudenberg-Hua Y, Fullerton JM, Gabriel DL, Gilmour K, Giordano J, Goes FS, Moses RG, Green I, Griese M, Groza T, Gu W, Guthrie J, Gyori B, Hamosh A, Hanauer M, Hanušová K, He YO, Hegde H, Helbig I, Holasová K, Hoyt CT, Huang S, Hurwitz E, Jacobsen JOB, Jiang X, Joseph L, Keramatian K, King B, Knoflach K, Koolen DA, Kraus ML, Kroll C, Kusters M, Ladewig MS, Lagorce D, Lai MC, Lapunzina P, Laraway B, Lewis-Smith D, Li X, Lucano C, Majd M, Marazita ML, Martinez-Glez V, McHenry TH, McInnis MG, McMurry JA, Mihulová M, Millett CE, Mitchell PB, Moslerová V, Narutomi K, Nematollahi S, Nevado J, Nierenberg AA, Čajbiková NN, Nurnberger JI Jr, Ogishima S, Olson D, Ortiz A, Pachajoa H, Perez de Nanclares G, Peters A, Putman T, Rapp CK, Rath A, Reese J, Rekerle L, Roberts AM, Roy S, Sanders SJ, Schuetz C, Schulte EC, Schulze TG, Schwarz M, Scott K, Seelow D, Seitz B, Shen Y, Similuk MN, Simon ES, Singh B, Smedley D, Smith CL, Smolinsky JT, Sperry S, Stafford E, Stefancsik R, Steinhaus R, Strawbridge R, Sundaramurthi JC, Talapova P, Tenorio Castano JA, Tesner P, Thomas RH, Thurm A, Turnovec M, van Gijn ME, Vasilevsky NA, Vlčková M, Walden A, Wang K, Wapner R, Ware JS, Wiafe AA, Wiafe SA, Wiggins LD, Williams AE, Wu C, Wyrwoll MJ, Xiong H, Yalin N, Yamamoto Y, Yatham LN, Yocum AK, Young AH, Yüksel Z, Zandi PP, Zankl A, Zarante I, Zvolský M, Toro S, Carmody LC, Harris NL, Munoz-Torres MC, Danis D, Mungall CJ, Köhler S, Haendel MA, Robinson PN. The Human Phenotype Ontology in 2024: phenotypes around the world. Nucleic Acids Res. 2024 Jan 5;52(D1):D1333-D1346. doi: 10.1093/nar/gkad1005. PMID: 37953324; PMCID: PMC10767975.

Journal: The Lancet. Neurology

Background: Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease.

Methods: LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21-55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014-000418-75, and is now complete.

Findings: Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI -1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference -1·76% [95% CI -2·67 to -0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]).

Interpretation: Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington's disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments.

Reilmann R, Anderson KE, Feigin A, Tabrizi SJ, Leavitt BR, Stout JC, Piccini P, Schubert R, Loupe P, Wickenberg A, Borowsky B, Rynkowski G, Volkinshtein R, Li T, Savola JM, Hayden M, Gordon MF; LEGATO-HD Study Group. Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Neurol. 2024 Jan 24:S1474-4422(23)00454-4. doi: 10.1016/S1474-4422(23)00454-4. Epub ahead of print. PMID: 38280392.

Journal: Journal of Controlled Release

Efficient delivery of therapeutics to the central nervous system (CNS) remains a major challenge for the treatment of neurological diseases. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion mutation in the HTT gene which codes for a toxic mutant huntingtin (mHTT) protein. Pharmacological reduction of mHTT in the CNS using antisense oligonucleotides (ASO) ameliorates HD-like phenotypes in rodent models of HD, with such therapies being investigated in clinical trials for HD. In this study, we report the optimization of apolipoprotein A-I nanodisks (apoA-I NDs) as vehicles for delivery of a HTT-targeted ASO (HTT ASO) to the brain and peripheral organs for HD. We demonstrate that apoA-I wild type (WT) and the apoA-I K133C mutant incubated with a synthetic lipid, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, can self-assemble into monodisperse discoidal particles with diameters <20 nm that transmigrate across an in vitro blood-brain barrier model of HD. We demonstrate that apoA-I NDs are well tolerated in vivo, and that apoA-I K133C NDs show enhanced distribution to the CNS and peripheral organs compared to apoA-I WT NDs following systemic administration. ApoA-I K133C conjugated with HTT ASO forms NDs (HTT ASO NDs) that induce significant mHTT lowering in the liver, skeletal muscle and heart as well as in the brain when delivered intravenously in the BACHD mouse model of HD. Furthermore, HTT ASO NDs increase the magnitude of mHTT lowering in the striatum and cortex compared to HTT ASO alone following intracerebroventricular administration. These findings demonstrate the potential utility of apoA-I NDs as biocompatible vehicles for enhancing delivery of mutant HTT lowering ASOs to the CNS and peripheral organs for HD.

Caron NS, Aly AE, Findlay Black H, Martin DDO, Schmidt ME, Ko S, Anderson C, Harvey EM, Casal LL, Anderson LM, Rahavi SMR, Reid GSD, Oda MN, Stanimirovic D, Abulrob A, McBride JL, Leavitt BR, Hayden MR. Systemic delivery of mutant huntingtin lowering antisense oligonucleotides to the brain using apolipoprotein A-I nanodisks for Huntington disease. J Control Release. 2024 Jan 24;367:27-44. doi: 10.1016/j.jconrel.2024.01.011. Epub ahead of print. PMID: 38215984.

Journal: Journal of Cell Biology

Cardoen B, Vandevoorde KR, Gao G, Ortiz-Silva M, Alan P, Liu W, Tiliakou E, Vogl AW, Hamarneh G, Nabi IR. Membrane contact site detection (MCS-DETECT) reveals dual control of rough mitochondria-ER contacts. J Cell Biol. 2024 Jan 1;223(1):e202206109. doi: 10.1083/jcb.202206109. Epub 2023 Nov 10. PMID: 37948126; PMCID: PMC10638097.

Journal: Trends in Neurosciences

Movement disorders such as Parkinson's disease (PD) impact oculomotor function - the ability to move the eyes accurately and purposefully to serve a multitude of sensory, cognitive, and secondary motor tasks. Decades of neurophysiological research in monkeys and behavioral studies in humans have characterized the neural basis of healthy oculomotor control. This review links eye movement abnormalities in persons living with PD to the underlying neurophysiological mechanisms and pathways. Building on this foundation, we highlight recent progress in using eye movements to gauge symptom severity, assess treatment effects, and serve as potential precision biomarkers. We conclude that whereas eye movements provide insights into PD mechanisms, based on current evidence they appear to lack sufficient sensitivity and specificity to serve as a standalone diagnostic tool. Their full potential may be realized when combined with other disease indicators in big datasets.

Antoniades CA, Spering M. Eye movements in Parkinson's disease: from neurophysiological mechanisms to diagnostic tools. Trends Neurosci. 2024 Jan;47(1):71-83. doi: 10.1016/j.tins.2023.11.001. Epub 2023 Dec 2. PMID: 38042680.

Journal: Clinical & Experimental Optometry

Recent advances have led to therapeutic options becoming available for people with inherited retinal disease. In particular, gene therapy has been shown to hold great promise for slowing vision loss from inherited retinal disease. Recent studies suggest that gene therapy is likely to be most effective when implemented early in the disease process, making consideration of paediatric populations important. It is therefore necessary to have a comprehensive understanding of retinal imaging in children with inherited retinal diseases, in order to monitor disease progression and to determine which early retinal biomarkers may be used as outcome measures in future clinical trials. In addition, as many optometrists will review children with an inherited retinal disease, an understanding of the expected imaging outcomes can improve clinical care. This review focuses on the most common imaging modality used in research assessment of paediatric inherited retinal diseases: optical coherence tomography. Optical coherence tomography findings can be used in both the clinical and research setting. In particular, the review discusses current knowledge of optical coherence tomography findings in eight paediatric inherited retinal diseases - Stargardt disease, Bests disease, Leber's congenital amaurosis, choroideremia, RPGR related retinitis pigmentosa, Usher syndrome, X-linked retinoschisis and, Batten disease.

Jolly JK, Rodda BM, Edwards TL, Ayton LN, Ruddle JB. Optical coherence tomography in children with inherited retinal disease. Clin Exp Optom. 2024 Jan 22:1-12. doi: 10.1080/08164622.2023.2294807. Epub ahead of print. PMID: 38252959.

Journal: Acta Ophthalmologica

McGuinness MB, Ayton LN, Schofield D, Britten-Jones AC, Chen FK, Grigg JR, Qi Z, Kraindler J, Shrestha R, Mack HG. EQ-5D-5L health utility scores in Australian adults with inherited retinal diseases: A cross-sectional survey. Acta Ophthalmol. 2024 Jan 16. doi: 10.1111/aos.16634. Epub ahead of print. PMID: 38226448.

Journal: Survey of Ophthalmology

Adaptive optics (AO) imaging enables direct, objective assessments of retinal cells. Applications of AO show great promise in advancing our understanding of the etiology of inherited retinal disease (IRDs) and discovering new imaging biomarkers. This scoping review systematically identifies and summarizes clinical studies evaluating AO imaging in IRDs. Ovid MEDLINE and EMBASE were searched on February 6, 2023. Studies describing AO imaging in monogenic IRDs were included. Study screening and data extraction were performed by 2 reviewers independently. This review presents (1) a broad overview of the dominant areas of research; (2) a summary of IRD characteristics revealed by AO imaging; and (3) a discussion of methodological considerations relating to AO imaging in IRDs. From 140 studies with AO outcomes, including 2 following subretinal gene therapy treatments, 75% included fewer than 10 participants with AO imaging data. Of 100 studies that included participants' genetic diagnoses, the most common IRD genes with AO outcomes are CNGA3, CNGB3, CHM, USH2A, and ABCA4. Confocal reflectance AO scanning laser ophthalmoscopy was the most reported imaging modality, followed by flood-illuminated AO and split-detector AO. The most common outcome was cone density, reported quantitatively in 56% of studies. Future research areas include guidelines to reduce variability in the reporting of AO methodology and a focus on functional AO techniques to guide the development of therapeutic interventions.

Britten-Jones AC, Thai L, Flanagan JPM, Bedggood PA, Edwards TL, Metha AB, Ayton LN. Adaptive optics imaging in inherited retinal diseases: A scoping review of the clinical literature. Surv Ophthalmol. 2024 Jan-Feb;69(1):51-66. doi: 10.1016/j.survophthal.2023.09.006. Epub 2023 Sep 29. PMID: 37778667.

Journal: Journal of Alzheimer's Disease

Background: Prognosis of future risk of dementia from neuroimaging and cognitive data is important for optimizing clinical management for patients at early stage of Alzheimer's disease (AD). However, existing studies lack an efficient way to integrate longitudinal information from both modalities to improve prognosis performance.

Objective: In this study, we aim to develop and evaluate an explainable deep learning-based framework to predict mild cognitive impairment (MCI) to AD conversion within four years using longitudinal whole-brain 3D MRI and neurocognitive tests.

Methods: We proposed a two-stage framework that first uses a 3D convolutional neural network to extract single-timepoint MRI-based AD-related latent features, followed by multi-modal longitudinal feature concatenation and a 1D convolutional neural network to predict the risk of future dementia onset in four years.

Results: The proposed deep learning framework showed promising to predict MCI to AD conversion within 4 years using longitudinal whole-brain 3D MRI and cognitive data without extracting regional brain volumes or cortical thickness, reaching a balanced accuracy of 0.834, significantly improved from models trained from single timepoint or single modality. The post hoc model explainability revealed heatmap indicating regions that are important for predicting future risk of AD.

Conclusions: The proposed framework sets the stage for future studies for using multi-modal longitudinal data to achieve optimal prediction for prognosis of AD onset, leading to better management of the diseases, thereby improving the quality of life.

Bapat R, Ma D, Duong TQ. Predicting Four-Year's Alzheimer's Disease Onset Using Longitudinal Neurocognitive Tests and MRI Data Using Explainable Deep Convolutional Neural Networks. J Alzheimers Dis. 2024;97(1):459-469. doi: 10.3233/JAD-230893. PMID: 38143361.