Mechanisms Of Neurodegeneration Research Articles

Exploring miRNAs' Based Modeling Approach for Predicting PIRA in Multiple Sclerosis: A Comprehensive Analysis.

The current hypothesis on the pathophysiology of multiple sclerosis (MS) suggests the involvement of both inflammatory and neurodegenerative mechanisms. Disease Modifying Therapies (DMTs) effectively decrease relapse rates, thus reducing relapse-associated disability in people with MS. In some patients, disability progression, however, is not solely linked to new lesions and clinical relapses but can manifest independently. Progression Independent of Relapse Activity (PIRA) significantly contributes to long-term disability, stressing the urge to unveil biomarkers to forecast disease progression. Twenty-five adult patients with relapsing-remitting multiple sclerosis (RRMS) were enrolled in a cohort study, according to the latest McDonald criteria, and tested before and after high-efficacy Disease Modifying Therapies (DMTs) (6-24 months). Through Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells. Multivariate logistic and linear models with interactions were generated. Robustness was assessed by randomization tests in R. A subset of miRNAs, correlated with PIRA, and the Expanded Disability Status Scale (EDSS), was selected. To refine the patient stratification connected to the disease trajectory, we computed a robust logistic classification model derived from baseline miRNA expression to predict PIRA status (AUC = 0.971). We built an optimal multilinear model by selecting four other miRNA predictors to describe EDSS changes compared to baseline. Multivariate modeling offers a promising avenue to uncover potential biomarkers essential for accurate prediction of disability progression in early MS stages. These models can provide valuable insights into developing personalized and effective treatment strategies.

Neuronal differentiation requires BRAT1 complex to remove REST from chromatin

Repressor element-1 silencing transcription factor (REST) is required for the formation of mature neurons. REST dysregulation underlies a key mechanism of neurodegeneration associated with neurological disorders. However, the mechanisms leading to alterations of REST-mediated silencing of key neurogenesis genes are not known. Here, we show that BRCA1 Associated ATM Activator 1 (BRAT1), a gene linked to neurodegenerative diseases, is required for the activation of REST-responsive genes during neuronal differentiation. We find that INTS11 and INTS9 subunits of Integrator complex interact with BRAT1 as a distinct trimeric complex to activate critical neuronal genes during differentiation. BRAT1 depletion results in persistence of REST residence on critical neuronal genes disrupting the differentiation of NT2 cells into astrocytes and neuronal cells. We identified BRAT1 and INTS11 co-occupying the promoter region of these genes and pinpoint a role for BRAT1 in recruiting INTS11 to their promoters. Disease-causing mutations in BRAT1 diminish its association with INTS11/INTS9, linking the manifestation of disease phenotypes with a defect in transcriptional activation of key neuronal genes by BRAT1/INTS11/INTS9 complex. Finally, loss of Brat1 in mouse embryonic stem cells leads to a defect in neuronal differentiation assay. Importantly, while reconstitution with wild-type BRAT1 restores neuronal differentiation, the addition of a BRAT1 mutant is unable to associate with INTS11/INTS9 and fails to rescue the neuronal phenotype. Taken together, our study highlights the importance of BRAT1 association with INTS11 and INTS9 in the development of the nervous system.

Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid.

This perspective offers an alternative to the amyloid hypothesis in the etiology of Alzheimer's disease (AD). We review evidence for a novel signaling mechanism based on a little-known peptide, T14. T14 could drive neurodegeneration as an aberrantly activated process of plasticity selective to interconnecting subcortical nuclei, the isodendritic core, where cell loss starts at the pre-symptomatic stages of the disease. Each of these cell groups has the capacity to form T14, which can stimulate production of p-Tau and β-amyloid, suggestive of an upstream driver of neurodegeneration. Moreover, results in an animal AD model show that antagonism of T14 with a cyclated variant, NBP14, prevents formation of β-amyloid, and restores cognitive function to that of wild-type counterparts. Any diagnostic and/or therapeutic strategy based on T14-NBP14 awaits validation in clinical trials. However, an understanding of this novel signaling system could bring much-needed fresh insights into the progression of cell loss underlying AD. HIGHLIGHTS: The possible primary mechanism of neurodegeneration upstream of amyloid. Primary involvement of selectively vulnerable subcortical nuclei, isodendritic core. Bioactive peptide T14 trophic in development but toxic in context of mature brain. Potential for early-stage biomarker to detect Alzheimer's disease. Effective therapeutic halting neurodegeneration, validated already in 5XFAD mice.

Neuroinflammation in amyotrophic lateral sclerosis: pathogenic insights and therapeutic implications.

Neuroinflammation appears to be an important pathogenic process in amyotrophic lateral sclerosis (ALS). Dysfunction of central immune pathways, including activation of microglia and astrocytes, and peripherally derived immune cells, initiate noncell autonomous inflammatory mechanisms leading to degeneration. Cell autonomous pathways linked to ALS genetic mutations have been recently identified as contributing mechanism for neurodegeneration. The current review provides insights into the pathogenic importance of central and peripheral inflammatory processes in ALS pathogenesis and appraises their potential as therapeutic targets. ALS is a multistep process mediated by a complex interaction of genetic, epigenetic, and environmental factors. Noncell autonomous inflammatory pathways contribute to neurodegeneration in ALS. Activation of microglia and astrocytes, along with central nervous system infiltration of peripherally derived pro-inflammatory innate (NK-cells/monocytes) and adaptive (cell-mediated/humoral) immune cells, are characteristic of ALS. Dysfunction of regulatory T-cells, elevation of pro-inflammatory cytokines and dysbiosis of gut microbiome towards a pro-inflammatory phenotype, have been reported as pathogenic mechanisms in ALS. Dysregulation of adaptive and innate immunity is pathogenic in ALS, being associated with greater disease burden, more rapid disease course and reduced survival. Strategies aimed at modulating the pro-inflammatory immune components could be of therapeutic utility.

A mutation in the PRKAR1B gene drives pathological mechanisms of neurodegeneration across species.

Protein kinase A (PKA) neuronal function is controlled by the interaction of a regulatory (R) subunit dimer with two catalytic subunits. Recently, the L50R variant in the gene encoding the RIβ subunit was identified in individuals with a novel neurodegenerative disease. However, the mechanisms driving the disease phenotype remained unknown. In this study, we generated a mouse model carrying the RIβ-L50R mutation to replicate the human disease phenotype and study its progression with age. We examined post-mortem brains of affected individuals as well as live cell cultures. Employing biochemical assays, immunohistochemistry and behavioural assessments, we investigated the impact of the mutation on PKA complex assembly, protein aggregation and neuronal degeneration. We reveal that RIβ is an aggregation-prone protein that progressively accumulates in wildtype and Alzheimer's mouse models with age, while aggregation is accelerated in the RIβ-L50R mouse model. We define RIβ-L50R as a causal mutation driving an age-dependent behavioural and disease phenotype in human and mouse models. Mechanistically, this mutation disrupts RIβ dimerization, leading to aggregation of its monomers. Intriguingly, interaction with the catalytic subunit protects the RIβ-L50R from self-aggregating, in a dose-dependent manner. Furthermore, cAMP signaling induces RIβ-L50R aggregation. The pathophysiological mechanism elucidated here for a newly recognized neurodegenerative disease, in which protein aggregation is the result of disrupted homodimerization, sheds light on a remarkably under-appreciated but potentially common mechanism across several neurodegenerative diseases.

Essential Oil Constituents as Anti-Inflammatory and Neuroprotective Agents: An Insight through Microglia Modulation.

Microglia are key players in the brain's innate immune response, contributing to homeostatic and reparative functions but also to inflammatory and underlying mechanisms of neurodegeneration. Targeting microglia and modulating their function may have therapeutic potential for mitigating neuroinflammation and neurodegeneration. The anti-inflammatory properties of essential oils suggest that some of their components may be useful in regulating microglial function and microglial-associated neuroinflammation. This study, starting from the ethnopharmacological premises of the therapeutic benefits of aromatic plants, assessed the evidence for the essential oil modulation of microglia, investigating their potential pharmacological mechanisms. Current knowledge of the phytoconstituents, safety of essential oil components, and anti-inflammatory and potential neuroprotective effects were reviewed. This review encompasses essential oils of Thymus spp., Artemisia spp., Ziziphora clinopodioides, Valeriana jatamansi, Acorus spp., and others as well as some of their components including 1,8-cineole, β-caryophyllene, β-patchoulene, carvacrol, β-ionone, eugenol, geraniol, menthol, linalool, thymol, α-asarone, and α-thujone. Essential oils that target PPAR/PI3K-Akt/MAPK signalling pathways could supplement other approaches to modulate microglial-associated inflammation to treat neurodegenerative diseases, particularly in cases where reactive microglia play a part in the pathophysiological mechanisms underlying neurodegeneration.

Potential neuroprotective effects of 2-hydroxypropyl-β cyclodextrin against amyloid β (1-42)-induced neurotoxicity on the rat hippocampus

The neurodegenerative mechanisms of Alzheimer’s disease (AD) are not fully understood, but it is believed that amyloid beta (Aβ) peptide causes oxidative stress, neuroinflammation, and disrupts metabotropic glutamate receptor 5 (mGluR5) signaling by interacting with cholesterol and caveolin-1 (Cav-1) in pathogenic lipid rafts. This study examined the effect of 2-hydroxypropyl-β-cyclodextrin (HP-CD) on cholesterol, oxidative stress (total oxidant status), neuroinflammation (TNF-α), and mGluR5 signaling molecules such as PKCβ1, PKCβ2, ERK1/2, CREB, BDNF, and NGF in Aβ (1-42)-induced neurotoxicity. The Sprague-Dawley rats were divided into four groups: control (saline), Aβ (1-42), HP-CD (100 mg/kg), and Aβ (1-42) + HP-CD (100 mg/kg). All groups received bilateral stereotaxic injections of Aβ (1–42) or saline into the hippocampus. After surgery, HP-CD was administered intraperitoneally (ip) for 7 days. Cholesterol, TNF-α, and TOS levels were measured in synaptosomes isolated from hippocampus tissue using spectrophotometry, fluorometry, and enzyme immunoassay, respectively. The gene expressions of Cav-1, mGluR5, PKCβ1, PKCβ2, ERK1/2, CREB, BDNF, and NGF in hippocampus tissue were evaluated using reverse transcription PCR after real-time PCR analysis. Treatment with Aβ (1-42) significantly elevated cholesterol, TOS, TNF-α, Cav-1, PKCβ2, and ERK1/2 levels. Additionally, mGluR5, CREB, and BDNF levels were shown to be lowered. HP-CD reduced cholesterol, TOS, and TNF-α levels while increasing mGluR5, CREB, and BDNF in response to Aβ (1–42) treatment. These findings indicate that HP-CD may have neuroprotective activity due to the decreased levels of cholesterol, oxidative stress, and neuroinflammation, as well as upregulated levels of mGluR5, CREB, and BDNF.

Heterogeneity of cognitive impairments in myotonic dystrophy type 1 explained by three distinct cognitive profiles.

Severity and nature of cognitive impairments in Myotonic dystrophy type 1 (DM1) are heterogeneous among studies. We hypothesized that this heterogeneity is explained by different cognitive profiles in DM1, with different clinical, biological and behavioral features. Adult patients with genetically proven DM1 underwent a clinical, neuropsychological and behavioral assessment. We conducted a k-means clustering analysis on 9 cognitive tests representative of different domains (verbal/non-verbal episodic memory, visuo-constructive abilities, visual gnosis, executive functions, information processing speed). We included 124 DM1 patients. Mean age was 45.1 ± 13.5years [19.8-73.2], mean age of onset was 30.4 ± 15.7years [5-72], and mean CTG triplets' expansion size was 489.7 ± 351.8 [50-1600]. We found 3 cognitive clusters, including, respectively, 84, 29 and 11 patients. The first cluster included patients with more preserved cognitive functions; the second included patients with worse cognitive performances which predominate on executive functions; and the third even more pronounced and diffuse cognitive deficits. Younger patients, with a more recent DM1 clinical onset, higher educational level were more frequently classified in the cluster with more preserved cognitive functions. There were no significant differences between clusters regarding CTG triplets' expansion, neither age at DM1 onset, nor most of behavioral measures. We found different cognitive profiles in our DM1 population, which seem influenced by age and DM1 duration. Our findings may explain the heterogeneity of studies about cognition in DM1, and suggest a potential neurodegenerative mechanism in DM1 adults.

α-Synuclein pathology in Drosophila melanogaster is exacerbated by haploinsufficiency of Rop: connecting STXBP1 encephalopathy with α-synucleinopathies.

Syntaxin-binding protein 1 (STXBP1) is a presynaptic protein that plays important roles in synaptic vesicle docking and fusion. STXBP1 haploinsufficiency causes STXBP1 encephalopathy (STXBP1-E), which encompasses neurological disturbances including epilepsy, neurodevelopmental disorders, and movement disorders. Most patients with STXBP1-E present with regression and movement disorders in adulthood, highlighting the importance of a deeper understanding of the neurodegenerative aspects of STXBP1-E. An in vitro study proposed an interesting new role of STXBP1 as a molecular chaperone for α-Synuclein (αSyn), a key molecule in the pathogenesis of neurodegenerative disorders. However, no studies have shown αSyn pathology in model organisms or patients with STXBP1-E. In this study, we used Drosophila models to examine the effects of STXBP1 haploinsufficiency on αSyn-induced neurotoxicity in vivo. We demonstrated that haploinsufficiency of Ras opposite (Rop), the Drosophila ortholog of STXBP1, exacerbates compound eye degeneration, locomotor dysfunction, and dopaminergic neurodegeneration in αSyn-expressing flies. This phenotypic aggravation was associated with a significant increase in detergent-insoluble αSyn levels in the head. Furthermore, we tested whether trehalose, which has neuroprotective effects in various models of neurodegenerative disorders, mitigates αSyn-induced neurotoxicity exacerbated by Rop haploinsufficiency. In flies expressing αSyn and carrying a heterozygous Rop null variant, trehalose supplementation effectively alleviates neuronal phenotypes, accompanied by a decrease in detergent-insoluble αSyn in the head. In conclusion, this study revealed that Rop haploinsufficiency exacerbates αSyn-induced neurotoxicity by altering the αSyn aggregation propensity. This study not only contributes to understanding the mechanisms of neurodegeneration in STXBP1-E patients, but also provides new insights into the pathogenesis of α-synucleinopathies.

Cardiorespiratory Disturbances in Alzheimer's Disease: A Focus on the Contribution of Sympathetic Premotor Neurons

While therapeutic approaches targeting neurodegenerative mechanisms associated with cognitive impairment in Alzheimer's disease (AD) have been intensively explored, other comorbidities closely linked to AD progression, such as sleep-disordered breathing and autonomic dysfunction, have not been thoroughly investigated. In preliminary studies, we showed an increase in neural activity of catecholaminergic premotor neurons located in the rostral ventrolateral medulla region (RVLM-C1), a main region involved in cardiorespiratory regulation, in experimental AD. Therefore, in the present study, we aimed first to characterize cardiorespiratory function in AD patients and then to determine the role of RVLM-C1 neurons in autonomic and sleep-disordered breathing in APP/PS1 double transgenic mice, an experimental model showing AD-like pathology. Sixteen subjects (8 AD and 8 age-matched controls) were enrolled to assess sleep breathing disorders and to record cardiac autonomic function. Whole-body plethysmography and blood pressure monitoring in freely moving mice were used to study sleep-associated cardiorespiratory disorders. Bilateral stereotaxic injections of anti-dopamine β-hydroxylase-saporin (DβH-SAP) into the RVLM were used to selectively destroy C1 neurons. Compared to age-matched healthy subjects, patients with AD showed larger increases in neural sympathetic discharges during autonomic testing. In addition, heart rate variability analysis in AD patients showed a shift in spectral components towards a more sympathetic influence. Remarkably, we found that autonomic function impairment in the APP/PS1 mice resembles what we found in AD patients. Compared to wild type (WT), APP/PS1 mice displayed sympatho-excitation (ΔHR: -80±5 vs -125±10, WT vs APP/PS1, respectively), a higher incidence of cardiac arrhythmias (events/h 6.0±1.0 vs 12±1.5, WT vs APP/PS1, respectively), and sleep-disordered breathing (AHI: 8.5±2.0 vs 18.0±3.0, WT vs APP/PS1, respectively). Partial ablation of RVLM-C1 neurons (~70%) in APP/PS1 mice resulted in a two-fold and three-fold reduction in cardiac sympathetic drive and arrhythmogenesis, respectively. Furthermore, APP/PS1 mice treated with DβH-SAP showed marked improvements in breathing regularity (IS: 7.9±1.1 vs 16.9±2.2, APP/PS1DβH-SAP vs APP/PS1, respectively) and a restoration of normal sleep effciency (SE: 75.5±4.3 vs 58.1±6.4, APP/PS1DβH-SAP vs APP/PS1, respectively) compared to untreated APP/PS1 mice. Our results show that RVLM-C1 neurons play a main role in the development/maintenance of cardiorespiratory disorders in experimental AD. FONDECYT 11220962, 1220950. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

α-Synuclein: A Promising Biomarker for Parkinson's Disease and Related Disorders.

Mutations in the SNCA gene, which encodes α-synuclein (α-syn), play a key role in the development of genetic Parkinson's disease (PD). α-Syn is a major component of Lewy bodies in PD and glial cytoplasmic inclusions in multiple system atrophy (MSA). Rapid eye movement sleep behavior disorder patients often progress to PD, dementia with Lewy bodies, or MSA, which are collectively known as α-synucleinopathies. The loss of dopaminergic neurons with Lewy bodies precedes motor dysfunction in these diseases, but the mechanisms of neurodegeneration due to α-syn aggregation are poorly understood. Monitoring α-syn aggregation in vivo could serve as a diagnostic biomarker and help elucidate pathogenesis, necessitating a simple and accurate detection method. Seed amplification assays (SAAs), such as real-time quaking-induced conversion and protein misfolding cyclic amplification, are used to detect small amounts of abnormally structured α-syn protofibrils, which are central to aggregation. These methods are promising for the early diagnosis of α-synucleinopathy. Differences in α-syn filament structures between α-synucleinopathies, as observed through transmission electron microscopy and cryo-electron microscopy, suggest their role in the pathogenesis of neurodegeneration. SAAs may differentiate between subtypes of α-synucleinopathy and other diseases. Efforts are also being made to identify α-syn from blood using various methods. This review introduces body fluid α-syn biomarkers based on pathogenic α-syn seeds, which are expected to redefine α-synucleinopathy diagnosis and staging, improving clinical research accuracy and facilitating biomarker development.

Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency.

Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic mechanism of neurodegeneration remains limited. Here, we show that cerebellar neurodegeneration caused by Sorting Nexin 14 (SNX14) deficiency is associated with lipid homeostasis defects. Recent studies indicate that SNX14 is an interorganelle lipid transfer protein that regulates lipid transport, lipid droplet (LD) biogenesis, and fatty acid desaturation, suggesting that human SNX14 deficiency belongs to an expanding class of cerebellar neurodegenerative disorders caused by altered cellular lipid homeostasis. To test this hypothesis, we generated a mouse model that recapitulates human SNX14 deficiency at a genetic and phenotypic level. We demonstrate that cerebellar Purkinje cells (PCs) are selectively vulnerable to SNX14 deficiency while forebrain regions preserve their neuronal content. Ultrastructure and lipidomic studies reveal widespread lipid storage and metabolism defects in SNX14-deficient mice. However, predegenerating SNX14-deficient cerebella show a unique accumulation of acylcarnitines and depletion of triglycerides. Furthermore, defects in LD content and telolysosome enlargement in predegenerating PCs suggest lipotoxicity as a pathogenic mechanism of SNX14 deficiency. Our work shows a selective cerebellar vulnerability to altered lipid homeostasis and provides a mouse model for future therapeutic studies.

Understanding multiple sclerosis as a disease spectrum: above and below the clinical threshold.

Research in multiple sclerosis (MS) has long been predicated on clinical groupings that do not reflect the underlying biologic heterogeneity apparent within patient populations. This review explicates the various levels of explanation through which the spectrum of disease is described and investigated both above and below the clinical threshold of detection, as framed by the topographical model of MS, to help advance a cogent mechanistic framework. Contemporary evidence has amended the view of MS as consisting of sequential disease phases in favor of a spectrum of disease with an admixture of interdependent and dynamic pathobiological axes driving tissue injury and progression. Recent studies have shown the presence of acute and compartmentalized inflammation and mechanisms of neurodegeneration beginning early and evolving throughout the disease continuum. Still, the gap between the understanding of immunopathologic processes in MS and the tools used to measure relevant molecular, laboratory, radiologic, and clinical metrics needs attention to enable better prognostication of disease and monitoring for changes along specific pathologic axes and variable treatment outcomes. Aligning on a consistently-applied mechanistic framework at distinct levels of explanation will enable greater precision across bench and clinical research, and inform discourse on drivers of disability progression and delivery of care for individuals with MS.

KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury

Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain and which strategies most potently mitigate these processes. We developed a high-intensity ultrasound platform to inflict mechanical injury to induced pluripotent stem cell (iPSC)-derived cortical organoids. Mechanically injured organoids elicit classic hallmarks of TBI, including neuronal death, tau phosphorylation, and TDP-43 nuclear egress. We found that deep-layer neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes invitro and invivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuronal death after brain injury, and we present a scalable, genetically flexible cerebral organoid model that may enable the identification of additional modifiers of mechanical stress.

White Matter Alterations in Military Service Members With Remote Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is the signature injury experienced by military service members and is associated with poor neuropsychiatric outcomes. Yet, there is a lack of reliable clinical tools for mTBI diagnosis and prognosis. To examine the white matter microstructure and neuropsychiatric outcomes of service members with a remote history of mTBI (ie, mTBI that occurred over 2 years ago) using diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI). This case-control study examined 98 male service members enrolled in a study at the National Intrepid Center of Excellence. Eligible participants were active duty status or able to enroll in the Defense Enrollment Eligibility Reporting system, ages 18 to 60 years, and had a remote history of mTBI; controls were matched by age. Remote history of mTBI. White matter microstructure was assessed using a region-of-interest approach of skeletonized diffusion images, including DTI (fractional anisotropy, mean diffusivity, radial diffusivity and axial diffusivity) and NODDI (orientation dispersion index [ODI], isotropic volume fraction, intra-cellular volume fraction). Neuropsychiatric outcomes associated with posttraumatic stress disorder (PTSD) and postconcussion syndrome were assessed. A total of 65 male patients with a remote history of mTBI (mean [SD] age, 40.5 [5.0] years) and 33 age-matched male controls (mean [SD] age, 38.9 [5.6] years) were included in analysis. Compared with the control cohort, the 65 service members with mTBI presented with significantly more severe PTSD-like symptoms (mean [SD] PTSD CheckList-Civilian [PCL-C] version scores: control, 19.0 [3.8] vs mTBI, 41.2 [11.6]; P < .001). DTI and NODDI metrics were altered in the mTBI group compared with the control, including intra-cellular volume fraction of the right cortico-spinal tract (β = -0.029, Cohen d = 0.66; P < .001), ODI of the left posterior thalamic radiation (β = -0.006, Cohen d = 0.55; P < .001), and ODI of the left uncinate fasciculus (β = 0.013, Cohen d = 0.61; P < .001). In service members with mTBI, fractional anisotropy of the left uncinate fasciculus was associated with postconcussion syndrome (β = 5.4 × 10-3; P = .003), isotropic volume fraction of the genu of the corpus callosum with PCL-C (β = 4.3 × 10-4; P = .01), and ODI of the left fornix and stria terminalis with PCL-C avoidance scores (β = 1.2 × 10-3; P = .02). In this case-control study of military-related mTBI, the results suggest that advanced magnetic resonance imaging techniques using NODDI can reveal white matter microstructural alterations associated with neuropsychiatric symptoms in the chronic phase of mTBI. Diffusion trends observed throughout widespread white matter regions-of-interest may reflect mechanisms of neurodegeneration as well as postinjury tissue scarring and reorganization.

What can pediatricians learn from adult inherited metabolic diseases?

The field of inherited metabolic diseases (IMD) has initially emerged and developed over decades in pediatric departments. Still, today, about 50% of patients with IMD are adults, and adult metabolic medicine (AMM) is getting more structured at national and international levels. There are several domains in which pediatricians can learn from AMM. First, long-term evolution of IMD patients, especially those treated since childhood, is critical to determine nutritional and neuropsychiatric outcomes in adults so that these outcomes can be better monitored, and patient care adjusted as much as possible from childhood. Conversely, the observation of attenuated phenotypes in adults of IMD known to present with severe phenotypes in children calls for caution in the development of newborn screening programs and, more largely, in the interpretation of next-generation sequencing data. Third, it is important for pediatricians to be familiar with adult-onset IMD as they expand our understanding of metabolism, including in children, such as oxysterols and glycogen metabolism. Last, the identification of common molecular and cellular mechanisms in neurodevelopment and neurodegeneration opens the way to synergistic therapeutic developments that will benefit both fields of pediatric and adult medicine. Overall, these observations underline the need of strong interdisciplinarity between pediatricians and adult specialists for the diagnosis and the treatment of IMD well beyond the issues of patient transition from pediatric to adult medicine.

Using Drosophila amyloid toxicity models to study Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia and is characterised by a progressive loss of neurons, which manifests as gradual memory decline, followed by cognitive loss. Despite the significant progress in identifying novel biomarkers and understanding the prodromal pathology and symptomatology, AD remains a significant unmet clinical need. Lecanemab and aducanumab, the only Food and Drug Administration approved drugs to exhibit some disease-modifying clinical efficacy, target Aβ amyloid, underscoring the importance of this protein in disease aetiology. Nevertheless, in the absence of a definitive cure, the utilisation of preclinical models remains imperative for the identification of novel therapeutic targets and the evaluation of potential therapeutic agents. Drosophila melanogaster is a model system that can be used as a research tool to investigate neurodegeneration and therapeutic interventions. The short lifespan, low price and ease of husbandry/rearing make Drosophila an advantageous model organism from a practical perspective. However, it is the highly conserved genome and similarity of Drosophila and human neurobiology which make flies a powerful tool to investigate neurodegenerative mechanisms. In addition, the ease of transgenic modifications allows for early proof of principle studies for future therapeutic approaches in neurodegenerative research. This mini review will specifically focus on utilising Drosophila as an in vivo model of amyloid toxicity in AD.

Highly sensitive detection of the neurodegenerative biomarker Tau by using the concentration effect of the pyro-electrohydrodynamic jetting

It is largely documented that neurodegenerative diseases can be effectively treated only if early diagnosed. In this context, the structural changes of some biomolecules such as Tau, seem to play a key role in neurodegeneration mechanism becoming eligible targets for an early diagnosis. Post-translational modifications are responsible to drive the Tau protein towards a transition phase from a native disorder conformation into a preaggregation state, which then straight recruits the final fibrillization process. Here, we show for the first time the detection of pre-aggregated Tau in artificial urine at femto-molar level, through the concentration effect of the pyro-electrohydrodynamic jet (p-jet) technique. An excellent linear calibration curve is demonstrated at the femto-molar level with a limit of detection (LOD) of 130 fM. Moreover, for the first time we show here the structure stability of the protein after p-jet application through a deep spectroscopic investigation. Thanks to the small volumes required and the relatively compact and cost-effective characteristics, this technique represents an innovative breakthrough in monitoring the early stage associated to neurodegeneration syndromes in different scenarios of point of care (POC) and such as for example in long-term human space exploration missions.

Abstract P337: Clonal Hematopoiesis of Indeterminate Potential and Cognitive Decline in Chronic Kidney Disease Patients

Introduction: Patients with chronic kidney disease (CKD) are at substantially increased risk of dementia. Clonal hematopoiesis of indeterminate potential (CHIP), caused by clonal expansion of blood cells with somatic mutations in certain driver genes, is an established risk factor for cardiovascular diseases, including cerebral vascular disease. In contrast, CHIP was recently shown to be associated with a decreased risk of Alzheimer’s disease. Given emerging evidence of a key role of vascular compared to neurodegenerative mechanisms in CKD-related dementia, the relation of CHIP with cognitive decline in CKD patients needs clarity. We investigated the prospective associations of CHIP with cognitive impairment in a cohort of patients with CKD. Methods: Our study included 1989 participants aged 65 years or older from the Chronic Renal Insufficiency Cohort. Participants underwent high-depth targeted gene sequencing to ascertain CHIP status. Cognitive function was assessed by four cognitive tests (see Table ). For each test, incident cognitive impairment was defined as a test score one standard deviation worse than the baseline group mean. Sequential Cox proportional hazards models tested associations between CHIP and cognitive impairment after adjusting for demographics (model 1), clinical measures (model 2), and APOE genotype in a subset with available data (model 3). Results: CHIP carriers were significantly less likely to experience impairment in attention (Trails A) and executive function (Trails B) in our fully adjusted models ( Table ). There were no significant associations between CHIP and impairment in global cognition (3MS) or verbal memory (Buschke). There were no differences in the associations of CHIP with cognitive impairment across sex or race groups (data not shown). Conclusions: In patients with CKD, we observed markedly reduced risks of impairment in cognitive domains of attention and executive function. Further studies are needed to confirm our findings and evaluate mechanisms of these relations.

Investigating a Novel Neurodegenerative Disease Toxic Mechanism Involving Lipid Binding Specificity of Amyloid Oligomers.

Exploring the mechanisms underlying the toxicity of amyloid oligomers (AOs) presents a significant opportunity for discovering cures and developing treatments for neurodegenerative diseases. Recently, using a combination of ion mobility spectrometry-mass spectrometry (IMS-MS) and X-ray crystallography (XRC), we showed that the peptide KVKVLWDVIEV, which is the G95W mutant of αB-Crystallin (90-100) and abbreviated as G6W, self-assembles up to a dodecamer that structurally resembles lipid transport proteins. The glycine to tryptophan mutation promotes not only larger oligomers and enhanced cytotoxicity in brain slices than the wild type but also a narrow hydrophobic cavity suitable for fatty acid or phospholipid binding. Here, we determine the plausibility of a novel cytotoxic mechanism where the G6W's structural motif could perturb lipid homeostasis by determining its lipid binding selectivity and specificity. We show that the G6W oligomers have a strong affinity toward unsaturated phospholipids with a preference toward phospholipids containing 16-C alkyl chains. Molecular dynamics simulations demonstrate how an unsaturated, 16-C phospholipid fits tightly inside and outside G6W's hydrophobic cavity. This binding is exclusive to the G6W peptide, as other amyloid oligomers with different atomic structures, including its wildtype αB-Crystallin (90-100) and several superoxide dismutase 1 (SOD1) peptides that are known to self-assemble into amyloid oligomers (SOD1P28K and SOD1WG-GW), do not experience the same strong binding affinity. While the existing chaperone-lipid hypothesis on amyloid toxicity suggests amyloid-lipid complexes perforate cell membranes, our work provides a new outlook, indicating that soluble amyloid oligomers disrupt lipid homeostasis via selective protein-ligand interactions. The toxic mechanisms may arise from the formation of unique amyloid oligomer structures assisted by lipid ligands or impaired lipid transports.