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Neurology Medical Brain - current issue

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Brain - current issue - Recent Medical Updates

The interneuron hypothesis of amyotrophic lateral sclerosis

National Institutes of Health10.13039/100000002National Institute on Aging10.13039/1000000491ZIAAG000933

How modular are modules in visual cortex?

This scientific commentary refers to ‘Visual feature processing in a large stroke cohort: evidence against modular organization’ by Lugtmeijer, Sobolewska et al. (<a href="https://doi.org/10.1093/brain/awaf009">https://doi.org/10.1093/brain/awaf009</a>).

Converging and conflicting evidence for left temporal lobe regions in acoustic-phonetic perception

This scientific commentary refers to ‘Lesion correlates of impaired acoustic-phonetic perception after unilateral left hemisphere stroke’ by Binder et al. (<a href="https://doi.org/10.1093/brain/awae417">https://doi.org/10.1093/brain/awae417</a>).

Efficacy of MEDI0618, a pH-dependent monoclonal antibody targeting PAR2, in preclinical models of migraine

<div class="boxTitle">Abstract</div>Protease activated receptor 2 (PAR2) is a G-protein coupled receptor expressed in meningeal neurons, fibroblasts and mast cells that may be targeted to treat migraine. MEDI0618, a fully humanized PAR2 monoclonal antibody, engineered to enhance FcRn-dependent recycling and currently in clinical development, was evaluated in human and rodent in vitro assays, in multiple murine in vivo migraine models and in a model of post-traumatic headache.MEDI0618 bound specifically and with high affinity to cells expressing human PAR2 (hPAR2) and prevented matriptase-induced increase in cytosolic calcium. Similarly, MEDI0618 prevented matriptase-induced calcium in primary fibroblasts and microvascular endothelial cells from human dura mater. MEDI0618 had no effect on hPAR1 receptors. Single-cell calcium imaging of acutely dissociated mouse trigeminal ganglion neurons confirmed expression and functionality of mouse PAR2. Studies in vivo used evoked cutaneous allodynia as a surrogate of headache-like pain and, in some experiments, rearing as a measure of non-evoked headache pain. MEDI0618 was administered subcutaneously to C57BL6/J female mice prior to induction of migraine-like pain with (i) systemic nitroglycerin or compound 48/80 (mast cell degranulator); or (ii) with supradural compound 48/80 or an inflammatory mediator (IM) cocktail. To assess possible efficacy against CGRP receptor (CGRP-R)-independent pain, MEDI0618 was also evaluated in the IM model in animals pretreated with systemic olcegepant (CGRP-R antagonist). Migraine-like pain was also induced by inhalational umbellulone, a TRPA1 agonist, in animals primed with restraint stress in the presence or absence of MEDI0618 as well as in a model of post-traumatic headache pain induced by a mild traumatic brain injury.MEDI0618 prevented cutaneous allodynia elicited by systemic nitroglycerin, compound 48/80 and from supradural compound 48/80 and IM. Systemic olcegepant completely blocked periorbital cutaneous allodynia induced by supradural CGRP but failed to reduce IM-induced cutaneous allodynia. In contrast, MEDI0618 fully prevented IM-induced cutaneous allodynia, regardless of pretreatment with olcegepant. Umbellulone elicited cutaneous allodynia only in restraint stress-primed animals, which was prevented by MEDI0618. MEDI0618 prevented the decrease in rearing behaviour elicited by compound 48/80. However, MEDI0618 did not prevent mild traumatic brain injury-related post-traumatic headache measures.These data indicate that MEDI0618 is a potent and selective inhibitor of PAR2 that is effective in human and rodent in vitro cell systems. Further, blockade of PAR2 with MEDI0618 was effective in all preclinical migraine models studied but not in a model of post-traumatic headache. MEDI0618 may represent a novel therapy for migraine prevention with activity against CGRP-dependent and independent attacks.

Preclinical type 2 diabetes mellitus subtypes: new insights into diabetes, depression and dementia

This scientific commentary refers to ‘Machine learning reveals connections between preclinical type 2 diabetes subtypes and brain health’ by Yi et al. (<a href="https://doi.org/10.1093/brain/awaf057">https://doi.org/10.1093/brain/awaf057</a>).

Machine learning reveals connections between preclinical type 2 diabetes subtypes and brain health

<div class="boxTitle">Abstract</div>Previous research has established type 2 diabetes mellitus as a significant risk factor for various disorders, adversely impacting human health. While evidence increasingly links type 2 diabetes to cognitive impairment and brain disorders, understanding the causal effects of its preclinical stage on brain health is yet to be fully known. This knowledge gap hinders advancements in screening and preventing neurological and psychiatric diseases. To address this gap, we employed a robust machine learning algorithm (Subtype and Stage Inference, SuStaIn) with cross-sectional clinical data from the UK Biobank (20 277 preclinical type 2 diabetes participants and 20 277 controls) to identify underlying subtypes and stages for preclinical type 2 diabetes.Our analysis revealed one subtype distinguished by elevated circulating leptin levels and decreased leptin receptor levels, coupled with increased body mass index, diminished lipid metabolism, and heightened susceptibility to psychiatric conditions such as anxiety disorder, depression disorder, and bipolar disorder. Conversely, individuals in the second subtype manifested typical abnormalities in glucose metabolism, including rising glucose and haemoglobin A1c levels, with observed correlations with neurodegenerative disorders. A >10-year follow-up of these individuals revealed differential declines in brain health and significant clinical outcome disparities between subtypes. The first subtype exhibited faster progression and higher risk for psychiatric conditions, while the second subtype was associated with more severe progression of Alzheimer’s disease and Parkinson’s disease and faster progression to type 2 diabetes. Our findings highlight that monitoring and addressing the brain health needs of individuals in the preclinical stage of type 2 diabetes is imperative.

Correction to: Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy

Jintae Kim, Sang Min Park, Hyun Yong Koh, Ara Ko, Hoon-Chul Kang, Won Seok Chang, Dong Seok Kim, Jeong Ho Lee, Threshold of somatic mosaicism leading to brain dysfunction with focal epilepsy. Brain. 2024;147:2983-2990. <a href="https://doi.org/10.1093/brain/awae190">https://doi.org/10.1093/brain/awae190</a>

Correction to: Plasma p-tau217 in Alzheimer's disease: Lumipulse and ALZpath SIMOA head-to-head comparison

Andrea Pilotto, Virginia Quaresima, Chiara Trasciatti, Chiara Tolassi, Diego Bertoli, Cristina Mordenti, Alice Galli, Andrea Rizzardi, Salvatore Caratozzolo, Andrea Zancanaro, José Contador, Oskar Hansson, Sebastian Palmqvist, Giovanni De Santis, Henrik Zetterberg, Kaj Blennow, Duilio Brugnoni, Marc Suárez-Calvet, Nicholas J. Ashton, Alessandro Padovani. Plasma p-tau217 in Alzheimer's disease: Lumipulse and ALZpath SIMOA head-to-head comparison. Brain. 2025;148:408–415. <a href="https://doi.org/10.1093/brain/awae368">https://doi.org/10.1093/brain/awae368</a>

Correction to: Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates

Marie-Laure Arotcarena, Sandra Dovero, Alice Prigent, Mathieu Bourdenx, Sandrine Camus, Gregory Porras, Marie-Laure Thiolat, Maddalena Tasselli, Philippe Aubert, Niels Kruse, Brit Mollenhauer, Ines Trigo Damas, Cristina Estrada, Nuria Garcia-Carrillo, Nishant N Vaikath, Omar M A El-Agnaf, Maria Trinidad Herrero, Miquel Vila, Jose A Obeso, Pascal Derkinderen, Benjamin Dehay, Erwan Bezard. Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates. Brain. 2020;143:1462–1475. <a href="https://doi.org/10.1093/brain/awaa096">https://doi.org/10.1093/brain/awaa096</a>

Intrinsic neuronal resilience as a tool for therapeutic discovery

Visual feature processing in a large stroke cohort: evidence against modular organization

<div class="boxTitle">Abstract</div>Mid-level visual processing represents a crucial stage between basic sensory input and higher-level object recognition. The conventional model posits that fundamental visual qualities, such as colour and motion, are processed in specialized, retinotopic brain regions (e.g. V4 for colour, MT/V5 for motion). Using atlas-based lesion–symptom mapping and disconnectome maps in a cohort of 307 ischaemic stroke patients, we examined the neuroanatomical correlates underlying the processing of eight mid-level visual qualities.Contrary to the predictions of the standard model, our results did not reveal consistent relationships between processing impairments and damage to traditionally associated brain regions. Although we validated our methodology by confirming the established relationship between visual field defects and damage to primary visual areas (V1, V2 and V3), we found no reliable evidence linking processing deficits to specific regions in the posterior brain.These findings challenge the traditional modular view of visual processing and suggest that mid-level visual processing might be more distributed across neural networks than previously thought. This supports alternative models where visual maps represent constellations of co-occurring information rather than specific qualities.

Lesion correlates of impaired acoustic-phonetic perception after unilateral left hemisphere stroke

<div class="boxTitle">Abstract</div>Acoustic-phonetic perception refers to the ability to perceive and discriminate between speech sounds. Acquired impairment of acoustic-phonetic perception is known historically as ‘pure word deafness’ and typically follows bilateral lesions of the cortical auditory system. The extent to which this deficit occurs after unilateral left hemisphere damage and the critical left hemisphere areas involved are not well defined.We tested acoustic-phonetic perception in 73 individuals with chronic left hemisphere stroke and performed multivariate lesion-symptom mapping incorporating controls for non-specific task confounds, pure tone hearing loss, response bias and lesion size. Separate analyses examined place of articulation, manner of articulation, voicing and vowel discriminations. Overlap of the lesion map with transcallosal pathways linking left and right temporal lobes was examined using a probabilistic diffusion tensor tractography map of these pathways obtained from a healthy control cohort.Compared to an age- and education-matched control sample, 18% of the patients had impaired acoustic-phonetic perception overall, with 44% impaired on voicing, 26% on manner, 15% on place and 14% on vowel discrimination. Lesion-symptom mapping revealed the most critical areas to be the transverse temporal gyrus (TTG) and adjacent medial belt cortex, the acoustic radiation and the posterior superior temporal sulcus (pSTS). There were notable differences between lesion correlates for the different types of discrimination, with place discrimination linked to medial TTG, vowel discrimination to lateral TTG and planum temporale, manner discrimination to posterior planum temporale and voicing discrimination to pSTS. Overlap of the main lesion map with transcallosal temporal lobe pathways was minor but included a deep white matter component at the base of the middle and inferior temporal gyri. The extent of overlap between individual lesions and the transcallosal pathway map was not correlated with acoustic-phonetic perception.The results add further evidence that acoustic-phonetic impairments, particularly impairments of voicing perception, are relatively common after unilateral left temporal lobe damage, and they clarify the lesion correlates of these deficits. Differences between the lesion maps for the discrimination types likely reflect differential reliance on spectral versus temporal analysis for these discriminations.

The Sacks epistles: how fame reduces the punch of literary letters

Perceptual rivalry in neuroscience, magic and philosophy

Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder

<div class="boxTitle">Abstract</div>Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have been described in only six individuals carrying five biallelic predicted loss-of-function (pLOF) variants.To define the phenotypic effects of RBL2 mutations in detail, we identified and clinically characterized a cohort of 35 patients from 20 families carrying pLOF variants in RBL2, including 15 new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were observed uniformly, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Disrupted sleep was also evident in some patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements, seizures and non-specific dysmorphic features. Neuroimaging features included cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy.In parallel, we used the fruit fly, Drosophila melanogaster, to investigate how disruption of the conserved RBL2 orthologue Rbf impacts nervous system function and development. We found that Drosophila Rbf LOF mutants recapitulate several features of patients harbouring RBL2 variants, including developmental delay, alterations in head and brain morphology, locomotor defects and perturbed sleep. Surprisingly, in addition to its known role in controlling tissue growth during development, we found that continued Rbf expression is also required in fully differentiated post-mitotic neurons for normal locomotion in Drosophila, and that adult-stage neuronal re-expression of Rbf is sufficient to rescue Rbf mutant locomotor defects.Taken together, our study provides a clinical and experimental basis to understand genotype–phenotype correlations in an RBL2-linked neurodevelopmental disorder and suggests that restoring RBL2 expression through gene therapy approaches might ameliorate some symptoms caused by RBL2 pLOF.

Elevated cholesterol is a common phenotype for dominant and recessive ATAD3-associated disorders

European Rare Disease Research Alliance101156595DFG10.13039/501100001659BR4328.2-1GRK1957Michael J Fox Foundation10.13039/100000864Neurodegenerative Disease Research10.13039/100013278

Rituximab versus placebo for chronic inflammatory demyelinating polyradiculoneuropathy: a randomized trial

<div class="boxTitle">Abstract</div>Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) often requires prolonged ongoing treatment to prevent worsening. The efficacy of rituximab in preventing worsening after the discontinuation of immunoglobulin therapy in patients with CIDP was assessed.In this randomized, double-blind, placebo-controlled study, conducted at seven Italian hospitals, CIDP patients under immunoglobulin therapy were assigned to receive either rituximab (1 g on Days 1, 15 and 180 ± 7) or placebo. Both groups continued their regular immunoglobulin doses for 6 months post-intervention. The primary end point was the proportion of patients who worsened in any of the following three measures at Month 12, within 6 months after immunoglobulin discontinuation: a decrease of at least one point on the adjusted INCAT score, two points on the MRC sum score, or four points on the RODS centile score. Secondary end points included the proportion of patients deteriorating at Month 18 (within 12 months after immunoglobulin discontinuation), treatment cessation due to adverse events or voluntary reasons, and the time until deterioration after immunoglobulin discontinuation. This study was registered with <a href="http://ClinicalTrials.gov">ClinicalTrials.gov</a> (NCT06325943) and EUDRACT (number 2017-005034-36), and is now complete.From April 2019 to March 2022, 39 patients were recruited; two withdrew consent. The remaining 37 patients were assigned to rituximab (n = 19) or placebo (n = 18). Median age was 53 (interquartile range 45–64), with 11 (30%) females. A similar proportion of patients in both the rituximab (12/19, 63.2%) and placebo (12/18, 66.6%) groups worsened at Month 12 [odds ratio (OR) 0.86; 95% confidence interval (CI) 0.22–3.32]. No significant differences were noted at Month 18 (OR 0.62; 95% CI 0.14–2.70), or in the mean scores of each scale at Months 6, 12 and 18. The median time to worsening was 5 months for rituximab and 2 months for placebo (Log-rank P = 0.4372). Treatment was suspended due to adverse events in one rituximab patient.In this study, rituximab was not more effective than placebo in preventing clinical deterioration following the discontinuation of immunoglobulin therapy in CIDP. Further studies might evaluate the efficacy of more frequent or earlier administration of rituximab.

Rethinking phase 2 trials in amyotrophic lateral sclerosis

<div class="boxTitle">Abstract</div>There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on phase 2 data, which then fail in phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression is always expected.Emerging surrogate markers of clinical benefit such as reduction of neurofilament light chain levels may be better suited to phase 2 go/no-go decisions. Over-interpretation of phase 2 data, and overly optimistic communication of exploratory analyses must be avoided to ensure optimal prioritization for the investment needed for definitive phase 3 trials and to minimize the harm of false hope for people living with ALS. Delivering on advances in understanding of the neurobiology of ALS requires urgent attention to phase 2 design and implementation.

From shadows to spotlight: the evolution of migraine stigma since the 17th century

I read William Young’s article on The Historical Context of Migraine Stigma with great interest.<a href="#awae393-B1" class="reflinks">1</a> It seems essential to add further reflections on two aspects: first, the origins of this stigmatization emerging in the 17th century, and second, the evolution and transformation of migraine stigma from this historical period to the present day.

The role of dystrophin isoforms and interactors in the brain

<div class="boxTitle">Abstract</div>Dystrophin is a protein crucial for maintaining the structural integrity of skeletal muscle. So far, attention has been focused on the role of dystrophin in muscle, in view of the devastating progression of weakness and early death that characterizes Duchenne muscular dystrophy. However, in the last few years, the role of shorter dystrophin isoforms, including development and adult expression-specific mechanisms, has been a greater focus.Within the cerebral landscape, various cell types, such as glia, oligodendrocytes and Purkinje, cerebellar granule and vascular-associated cells express a spectrum of dystrophin isoforms, including Dp427, Dp140, Dp71 and Dp40. The interaction of these isoforms with a multitude of proteins suggests their involvement in neurotransmission, influencing several circuit functions.This review presents the intricate interactions among dystrophin isoforms and diverse protein complexes across different cell types and brain regions, as well as the associated clinical complications. We focus on studies investigating protein interactions with dystrophin in the past 30 years at a biochemical level. In essence, the brain's dystrophin landscape is a thrilling exploration of diversity, challenging preconceptions and opening new avenues for understanding CNS physiology. It also holds potential therapeutic implications for neurological complications involving brain dystrophin deficiency. By revealing the molecular complexities related to dystrophin, this review paves the way for future investigations and therapeutic interventions for this CNS aspect of Duchenne muscular dystrophy.

Lewy pathology formation in patient-derived GBA1 Parkinson’s disease midbrain organoids

<div class="boxTitle">Abstract</div>Fibrillary aggregation of α-synuclein in Lewy body inclusions and nigrostriatal dopaminergic neuron degeneration define Parkinson’s disease neuropathology. Mutations in GBA1, encoding glucocerebrosidase, are the most frequent genetic risk factor for Parkinson’s disease. However, the lack of reliable experimental models able to reproduce key neuropathological signatures has hampered clarification of the link between mutant glucocerebrosidase and Parkinson’s disease pathology.Here, we describe an innovative protocol for the generation of human induced pluripotent stem cell-derived midbrain organoids containing dopaminergic neurons with nigral identity that reproduce characteristics of advanced maturation. When applied to patients with GBA1-related Parkinson’s disease, this method enabled the differentiation of midbrain organoids recapitulating dopaminergic neuron loss and fundamental features of Lewy pathology observed in human brains, including the generation of α-synuclein fibrillary aggregates with seeding activity that also propagate pathology in healthy control organoids. Concurrently, we found that the retention of mutant glucocerebrosidase in the endoplasmic reticulum and increased levels of its substrate, glucosylceramide, are determinants of α-synuclein aggregation into Lewy body-like inclusions, and the reduction of glucocerebrosidase activity accelerated α-synuclein pathology by promoting fibrillary α-synuclein deposition.Finally, we demonstrated the efficacy of ambroxol and GZ667161 (two modulators of the glucocerebrosidase pathway in clinical development for the treatment of GBA1-related Parkinson’s disease) in reducing α-synuclein pathology in this model, supporting the use of midbrain organoids as a relevant preclinical platform for investigational drug screening.

ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model

<div class="boxTitle">Abstract</div>Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood.We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harbouring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis. We show that the spinal motor network in ATP1A3 mutant mice has a reduced responsiveness to activity-dependent rises in intracellular sodium and that this is accompanied by loss of the Na+/K+-ATPase-mediated afterhyperpolarization in motor neurons.Taken together, our data support that the alpha3 Na+/K+-ATPase is important for cellular and spinal motor network homeostasis. These insights suggest that it may be useful to consider ways to compensate for this loss of a critical afterhyperpolarization-dependent control of neuronal excitability when developing future therapies for dystonia.

Exploiting blood-based biomarkers to align preclinical models with human traumatic brain injury

<div class="boxTitle">Abstract</div>Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%. While there are several potential explanations for this, previous clinical trials have relied on extrapolation from preclinical studies for critical design considerations, including drug dose optimization, post-injury drug treatment initiation and duration. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to identical (or similar) measurements in humans, link to human TBI biomechanics and pathophysiology, and guide therapeutic decisions. To support this translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used GFAP, UCH-L1, NfL, total-Tau (t-Tau) or phosphorylated-Tau (p-Tau) published in PubMed/EMBASE up to 10 April 2024. Although many factors influence clinical TBI outcomes, many of those cannot routinely be assessed in rodent studies (e.g. intracranial pressure monitoring). Thus we focused on blood biomarkers’ temporal trajectories and discuss our findings in the context of the latest clinical TBI biomarker data.Of 805 original preclinical studies, 74 met the inclusion criteria, with a median quality score of 5 (25th–75th percentiles: 4–7) on the CAMARADES checklist. GFAP was measured in 43 studies, UCH-L1 in 21, NfL in 20, t-Tau in 19 and p-Tau in seven. Data from rodent models indicate that all biomarkers exhibited injury severity-dependent elevations with distinct temporal profiles. GFAP and UCH-L1 peaked within the first day after TBI (30- and 4-fold increases, respectively, in moderate-to-severe TBI versus sham), with the highest levels observed in the contusion TBI model. NfL peaked within days (18-fold increase) and remained elevated up to 6 months post-injury. GFAP and NfL show a pharmacodynamic response in 64.7% and 60%, respectively, of studies evaluating neuroprotective therapies in preclinical models. However, GFAP's rapid decline post-injury may limit its utility for understanding the response to new therapeutics beyond the hyperacute phase after experimental TBI. Furthermore, as in humans, subacute NfL levels inform on chronic white matter loss after TBI. t-Tau and p-Tau levels increased over weeks after TBI (up to 6- and 16-fold, respectively); however, their relationship with underlying neurodegeneration has yet to be addressed. Further investigation into biomarker levels in the subacute and chronic phases after TBI will be needed to fully understand the pathomechanisms underpinning blood biomarkers’ trajectories and select the most suitable experimental model to optimally relate preclinical mechanistic studies to clinical observations in humans. This new approach could accelerate the translation of neuroprotective treatments from laboratory experiments to real-world clinical practices.

Mitochondrial dynamics and bioenergetics in Alzheimer’s induced pluripotent stem cell-derived neurons

<div class="boxTitle">Abstract</div>Mitochondrial dysfunction is a hallmark of Alzheimer’s disease, but the scope and severity of these specific deficits across forms of Alzheimer’s disease are not well characterized. We designed a high-throughput longitudinal phenotypic assay to track mitochondrial dynamics and bioenergetics in glutamatergic induced pluripotent stem cell (iPSC)-derived human neurons possessing mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and the amyloid beta precursor protein (APP).Each gene set was composed of iPSC-derived neurons from an Alzheimer’s disease patient in addition to two to three engineered mutations with appropriate isogenic and age-matched controls. These iPSC-derived neurons were imaged every other day, beginning at 10 days in vitro, to assess how mitochondrial length and content change over a 10 day time course using a mitochondrially targeted reporter. A second cytosolic reporter allowed for visualization of neurites. Bioenergetics assays, focusing on mitochondrial respiration and individual electron transport chain complexes, were also surveyed over this time course.Mutations in all three genes altered mitochondrial function measured by basal, ATP-linked and maximal oxygen consumption rates and by spare respiratory capacity, with PSEN1/PSEN2 alleles being more severe than APP mutations. Electron flow through Complexes I–IV was decreased in PSEN1/PSEN2 mutations but, in contrast, APP alleles had only modest impairments of complexes I and II. We measured aspects of mitochondrial dynamics, including fragmentation and neurite degeneration, both of which were dramatic in PSEN1/PSEN2 alleles, but essentially absent in APP alleles. The marked differences in mitochondrial pathology might occur from the distinct ways in which amyloids are processed into amyloid beta peptides and might be correlated with the disease severity.

Tau, synapse loss and gliosis progress in an Alzheimer’s mouse model after amyloid-β immunotherapy

<div class="boxTitle">Abstract</div>Preclinical studies assessing drugs for Alzheimer’s disease (AD) are conducted in animal models that usually display only one neuropathological feature of AD, whereas patients present with a complex combination of comorbidities and neuropathologies. Importantly, it is well established that amyloid-β (Aβ) plaque and tau tangle accumulation interact in a phase-dependent manner, making it difficult to predict how targeting one might influence the other, as well as downstream degeneration.We developed a transgenic mouse model, APP/PS1xTau22, with progressive cortical Aβ deposition and hippocampal tau neurofibrillary inclusions, to investigate how both neuropathologies act jointly to bring about neural degeneration, synapse loss and glial phenotypes. We then assessed whether applying murine chimeric aducanumab, an anti-amyloid immunotherapy, could impact the synergistic relationship between amyloid and tau.Drug treatment resulted in a ∼70% reduction in Aβ deposition in hippocampal and cortical areas and produced a robust peri-plaque microglial and astrocytic response. Removing amyloid from the brain did not reverse or slow tau pathology or alter synapse loss.Our findings suggest that, once the interaction between amyloid and tau is set in motion, reducing plaque burden by Aβ immunotherapy may stimulate glial responses, but is insufficient to curb degenerative phenotypes in this model.

MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination

<div class="boxTitle">Abstract</div>Muscleblind-like proteins (MBNLs) are a family of RNA-binding proteins that play essential roles in the regulation of RNA metabolism. Beyond their canonical role in RNA regulation, MBNL proteins have emerged as key players in the pathogenesis of myotonic dystrophy type 1. In myotonic dystrophy type 1, sequestration of MBNL proteins by expansion of the CUG repeat RNA leads to functional depletion of MBNL, resulting in deregulated alternative splicing and aberrant RNA processing, which underlie the clinical features of the disease.Although attention on MBNL proteins has focused on their functions in skeletal muscle, new evidence suggests that their importance extends to motor neurons (MNs), pivotal cellular components in the control of motor skills and movement. To address this question, we generated conditional double-knockout (dKO) mice, in which Mbnl1 and Mbnl2 were specifically deleted in motor neurons (MN-dKO). Adult MN-dKO mice develop gait coordination deficits associated with structural and ultrastructural defects in the neuromuscular junction, indicating that MBNL activity in MNs is crucial for the maintenance of the neuromuscular junction. In addition, transcriptome analysis performed on the spinal cord of MN-dKO mice identified mis-splicing events in genes associated with synaptic transmission and neuromuscular junction homeostasis.In summary, our results highlight the complex roles and regulatory mechanisms of MBNL proteins in MNs for muscle function and locomotion. This work provides valuable insights into fundamental aspects of RNA biology and offers promising avenues for therapeutic intervention in myotonic dystrophy type 1 and in a range of diseases associated with RNA dysregulation.

CACNA1A haploinsufficiency leads to reduced synaptic function and increased intrinsic excitability

<div class="boxTitle">Abstract</div>Haploinsufficiency of CACNA1A, encoding the pore-forming α1 subunit of P/Q-type voltage-gated calcium channels, is associated with a clinically variable phenotype ranging from cerebellar ataxia to neurodevelopmental syndromes with epilepsy and intellectual disability.To understand the pathological mechanisms of CACNA1A loss-of-function variants, we characterized a human neuronal model for CACNA1A haploinsufficiency by differentiating isogenic induced pluripotent stem cell lines into glutamatergic neurons and investigated the effect of CACNA1A haploinsufficiency on mature neuronal networks through a combination of electrophysiology, gene expression analysis and in silico modelling.We observed an altered network synchronization in CACNA1A+/− networks alongside synaptic deficits, notably marked by an augmented contribution of GluA2 subunit-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Intriguingly, these synaptic perturbations coexisted with increased non-synaptically driven activity, as characterized by inhibition of N-methyl-D-aspartate and AMPA receptors on micro-electrode arrays. Single-cell electrophysiology and gene expression analysis corroborated this increased intrinsic excitability through reduced potassium channel function and expression. Moreover, we observed partial mitigation of the CACNA1A+/− network phenotype by 4-aminopyridine, a therapeutic intervention for episodic ataxia type 2. Positive modulation of small conductance calcium-activated potassium channels could reverse the CACNA1A+/− network electrophysiological phenotype.In summary, our study pioneers the characterization of a human induced pluripotent stem cell-derived neuronal model for CACNA1A haploinsufficiency and has unveiled new mechanistic insights. Beyond showcasing synaptic deficits, this neuronal model exhibited increased intrinsic excitability mediated by diminished potassium channel function, underscoring its potential as a therapeutic discovery platform with predictive validity.

Radiosurgery versus observation for brainstem cavernous malformations: a 5-year multicentre cohort study

<div class="boxTitle">Abstract</div>The role of radiosurgery in preventing haemorrhage in brainstem cavernous malformations remains a subject of debate. This study aimed to evaluate whether radiosurgery provides a protective benefit against haemorrhage in these patients. This multicentre, prospective observational study was conducted in 17 centres and enrolled eligible patients with brainstem cavernous malformations consecutively. Data collected included clinical baseline information, radiosurgery planning details, periodic follow-up evaluations and any adverse radiation effects. The primary outcome of the study was the incidence of first prospective haemorrhage, and the secondary outcome was the development of new or worsening neurological dysfunctions. The impact of radiosurgery was assessed using multivariate Cox regression analysis. From March 2016 to August 2018, the study enrolled 377 patients: 280 in the observation group receiving standard care alone and 97 in the radiosurgery group receiving both radiosurgery and standard care. The overall cohort consisted of 173 females (45.9%) with a mean age of 40.5 years (range, 18–68 years), and there were no significant differences in baseline characteristics between the two groups. After a median follow-up period of 70 months, haemorrhage occurred in 25.0% (n = 70) of patients in the observation group and 10.3% (n = 10) of patients in the radiosurgery group. Multivariate Cox regression analysis identified radiosurgery as an independent protective factor against haemorrhage (hazard ratio 0.379, 95% confidence interval 0.195–0.738, P = 0.004). Following 1:2 propensity score matching, the incidence of prospective haemorrhage was 24.9% (45/181) in the observation group compared with 10.3% (10/97) in the radiosurgery group (hazard ratio 0.379, 95% confidence interval 0.190–0.755, P = 0.006). Adverse radiation effects were observed in 12 patients (12.4%), with none being permanent. Additionally, new or worsening neurological dysfunctions were significantly more common in the observation group (28.9%) compared with the radiosurgery group (16.5%) (P = 0.016). These results suggest that radiosurgery is associated with a low rate of haemorrhage in patients with brainstem cavernous malformations and could provide a benefit in selected patients. However, further research is required to confirm these findings.

CNS manifestations in acute and chronic graft-versus-host disease

<div class="boxTitle">Abstract</div>Despite the growing evidence supporting the existence of CNS involvement in acute and chronic graft-versus-host disease (CNS-GvHD), the characteristics and course of the disease are still largely unknown. In this multicentre retrospective study, we analysed the clinical, biological, radiological and histopathological characteristics, as well as the clinical course of 66 patients diagnosed with possible CNS-GvHD (pCNS-GvHD), selected by predetermined diagnostic criteria. Results were then contrasted depending on whether pCNS-GvHD onset occurred before or after Day 100 following allogeneic haematopoietic stem cell transplantation (allo-HSCT).The median time between allo-HSCT and pCNS-GvHD onset was 149 days (interquartile range25–75 48–321), and pCNS-GvHD onset occurred before Day 100 following transplantation in 44% of patients. The most frequent findings at presentation were cognitive impairment (41%), paresis (21%), altered consciousness (20%), sensory impairment (18%) and headache (15%). Clinical presentation did not significantly differ between patients with pCNS-GvHD occurring before or after Day 100 following transplantation.Brain MRI found abnormalities compatible with the clinical picture in 57% of patients, while CT detected abnormalities in only 7%. Seven patients had documented spinal cord MRI abnormalities, all of them with pCNS-GvHD occurring after Day 100 following transplantation. In the CSF, the white blood cell count was increased in 56% of the population (median 18 cells/μl). Histopathological analyses were performed on 12 specimens and were suggestive of pCNS-GvHD in 10. All compatible specimens showed parenchymal and perivascular infiltration by CD3+ and CD163+ cells.Immunosuppressive therapy was prescribed in 97% of patients, achieving complete clinical response in 27%, partial improvement in 47% and stable disease in 6%. Response to immunosuppressive therapy did not differ significantly between patients with pCNS-GvHD occurring before or after Day 100 following transplantation. Clinical relapse was observed in 31% of patients who initially responded to treatment. One-year overall survival following pCNS-GvHD onset was 41%. Onset before Day 100 following haematopoietic stem cell transplantation [hazard ratio with 95% confidence interval: 2.1 (1.0–4.5); P = 0.041] and altered consciousness at initial presentation [3.0 (1.3–6.7); P = 0.0077] were associated with a reduced 1-year overall survival probability. Among surviving patients, 61% had neurological sequelae. This study supports that immune-mediated CNS manifestations may occur following allo-HSCT.These can be associated with both acute and chronic GvHD and carry a grim prognosis. The clinical presentation as well as the radiological and biological findings appear variable.

α2δ-2 regulates synaptic GluK1 kainate receptors in Purkinje cells and motor coordination

<div class="boxTitle">Abstract</div>Gabapentin and pregabalin are inhibitory ligands of both α2δ-1 and α2δ-2 proteins (also known as subunits of voltage-activated Ca2+ channels) and are commonly prescribed for the treatment of neuropathic pain and epilepsy. However, these drugs can cause gait disorders and ataxia through unknown mechanisms. α2δ-2 and GluK1, a glutamate-gated kainate receptor subtype, are coexpressed in cerebellar Purkinje cells. In this study, we used a heterologous expression system and Purkinje cells to investigate the potential role of α2δ-2 in regulating GluK1-containing kainate receptor activity.Whole-cell patch-clamp recordings showed that α2δ-2 coexpression augmented GluK1, but not GluK2, currents in HEK293 cells, and pregabalin abolished this augmentation. Pregabalin lost its inhibitory effect on GluK1 currents in HEK293 cells expressing both GluK1 and the α2δ-2(R282A) mutant. Blocking GluK1-containing receptors with UBP310 substantially reduced the amplitude of excitatory post-synaptic currents at parallel fibre–Purkinje cell synapses in mice. Also, pregabalin markedly attenuated the amplitude of excitatory post-synaptic currents and currents elicited by ATPA, a selective GluK1 receptor agonist, in Purkinje cells in Cacna2d1 knockout mice. Co-immunoprecipitation assays indicated that α2δ-2, but not α2δ-1, formed a protein complex with GluK1 in cerebellar tissues and HEK293 cells through its C-terminus. Furthermore, α2δ-2 coexpression potentiated surface expression of GluK1 proteins in HEK293 cells, whereas pregabalin reduced GluK1 proteins in cerebellar synaptosomes.Disrupting α2δ-2–GluK1 interactions using α2δ-2 C-terminus peptide abrogated the potentiating effect of α2δ-2 on GluK1 currents and attenuated the amplitude of GluK1-mediated excitatory post-synaptic currents in Purkinje cells. However, neither pregabalin nor α2δ-2 C-terminus peptide had significant effect on P/Q-type currents in HEK293 cells. Additionally, CRISPR/Cas9-induced conditional knockdown of Cacna2d2 or Grik1 in Purkinje cells, in addition to microinjection of α2δ-2 C-terminus peptide or UBP310 into the cerebellum, substantially impaired beam-walking and rotarod performance in mice.Our study reveals that α2δ-2 directly interacts with GluK1 independently of its conventional role as a voltage-activated Ca2+ channel subunit. α2δ-2 regulates motor coordination by promoting synaptic expression and activity in GluK1-containing kainate receptors in Purkinje cells.

Methylphenidate differentially alters corticostriatal connectivity after traumatic brain injury

<div class="boxTitle">Abstract</div>Traumatic brain injury commonly impairs attention and executive function and disrupts the large-scale brain networks that support these cognitive functions. Abnormalities of functional connectivity are seen in corticostriatal networks, which are associated with executive dysfunction and damage to neuromodulatory catecholaminergic systems caused by head injury. Methylphenidate, a stimulant medication that increases extracellular dopamine and noradrenaline, can improve cognitive function following traumatic brain injury. In this experimental medicine add-on study to a randomized, double-blind, placebo-controlled clinical trial, we test whether administration of methylphenidate alters corticostriatal network function and influences drug response.Forty-three moderate–severe traumatic brain injury patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Twenty-eight patients were included in the neuropsychological and functional imaging analysis (four females, mean age 40.9 ± 12.7 years, range 20–65 years) and underwent functional MRI and neuropsychological assessment after each block. 123I-Ioflupane single-photon emission computed tomography dopamine transporter scans were performed, and specific binding ratios were extracted from caudate subdivisions. Functional connectivity and the relationship to cognition were compared between drug and placebo conditions.Methylphenidate increased caudate to anterior cingulate cortex functional connectivity compared with placebo and decreased connectivity from the caudate to the default mode network. Connectivity within the default mode network was also decreased by methylphenidate administration, and there was a significant relationship between caudate functional connectivity and dopamine transporter binding during methylphenidate administration. Methylphenidate significantly improved executive function in traumatic brain injury patients, and this was associated with alterations in the relationship between executive function and right anterior caudate functional connectivity. Functional connectivity is strengthened to brain regions, including the anterior cingulate, that are activated when attention is focused externally. These results show that methylphenidate alters caudate interactions with cortical brain networks involved in executive control. In contrast, caudate functional connectivity reduces to default mode network regions involved in internally focused attention and that deactivate during tasks that require externally focused attention. These results suggest that the beneficial cognitive effects of methylphenidate might be mediated through its impact on the caudate.Methylphenidate differentially influences how the caudate interacts with large-scale functional brain networks that exhibit co-ordinated but distinct patterns of activity required for attentionally demanding tasks.

Basal ganglia theta power indexes trait anxiety in people with Parkinson's disease

<div class="boxTitle">Abstract</div>Neuropsychiatric symptoms are common and disabling in Parkinson's disease, with troublesome anxiety occurring in one-third of patients. Management of anxiety in Parkinson's disease is challenging, hampered by insufficient insight into underlying mechanisms, lack of objective anxiety measurements and largely ineffective treatments.In this study, we assessed the intracranial neurophysiological correlates of anxiety in patients with Parkinson's disease treated with deep brain stimulation (DBS) in the laboratory and at home. We hypothesized that low-frequency (theta–alpha) activity would be associated with anxiety.We recorded local field potentials from subthalamic nucleus or globus pallidus pars interna DBS implants in three Parkinson's disease cohorts: (i) patients with recordings (subthalamic nucleus) performed in hospital at rest via perioperatively externalized leads, without active stimulation, both ON and OFF dopaminergic medication; (ii) patients with recordings (subthalamic nucleus or globus pallidus pars interna) performed at home while resting, via a chronically implanted commercially available sensing-enabled neurostimulator (Medtronic Percept™ device), ON dopaminergic medication, with stimulation both on and off; and (iii) patients with recordings performed at home while engaging in a behavioural task via subthalamic nucleus and globus pallidus pars interna leads and electrocorticography paddles over the premotor cortex connected to an investigational sensing-enabled neurostimulator, ON dopaminergic medication, with stimulation both on and off.Trait anxiety was measured with validated clinical scales in all participants, and state anxiety was measured with momentary assessment scales at multiple time points in the two at-home cohorts. Power in theta (4–8 Hz) and alpha (8–12 Hz) ranges was extracted from the local field potential recordings, and its relationship with anxiety ratings was assessed using linear mixed-effects models.In total, 33 patients with Parkinson's disease (59 hemispheres) were included. Across three independent cohorts, with stimulation off, basal ganglia theta power was positively related to trait anxiety (all P < 0.05). Also in a naturalistic setting, with individuals at home, at rest, with stimulation and medication ON, basal ganglia theta power was positively related to trait anxiety (P < 0.05). This relationship held regardless of the hemisphere and DBS target. There was no correlation between trait anxiety and premotor cortical theta–alpha power. There was no within-patient association between basal ganglia theta–alpha power and state anxiety.We showed that basal ganglia theta activity indexes trait anxiety in Parkinson's disease. Our data suggest that theta could be a possible physiomarker of neuropsychiatric symptoms and specifically of anxiety in Parkinson's disease, potentially suitable for guiding advanced DBS treatment tailored to the needs of the individual patient, including non-motor symptoms.

Associations between accelerated forgetting, amyloid deposition and brain atrophy in older adults

<div class="boxTitle">Abstract</div>Accelerated long-term forgetting (ALF) is the phenomenon whereby material is retained normally over short intervals (e.g. minutes) but forgotten abnormally rapidly over longer periods (days or weeks). ALF might be an early marker of cognitive decline, but little is known about its relationships with preclinical Alzheimer’s disease pathology and how memory selectivity might influence which material is forgotten.We assessed ALF in ‘Insight 46’, a sub-study of the MRC National Survey of Health and Development (a population-based cohort born during the same week in 1946) (n = 429; 47% female; assessed at age ∼73 years). ALF assessment comprised visual and verbal memory tests: complex figure drawing and the face–name associative memory exam (FNAME). ALF scores were calculated as the percentage of material retained after 7 days, relative to 30 min. In 306 cognitively normal participants, we investigated effects on ALF of β-amyloid pathology (quantified using 18F-Florbetapir-PET, classified as positive/negative) and whole-brain and hippocampal atrophy rate (quantified from serial T1-MRI over ∼2.4 years preceding the ALF assessment), in addition to interactions between these pathologies. We categorized complex figure drawing items as ‘outline’ or ‘detail’, to test our hypothesis that forgetting the outline of the structure would be more sensitive to the effect of brain pathologies. We also investigated associations between ALF and subjective cognitive decline, measured with the MyCog questionnaire.Complex figure ‘outline’ items were better retained than ‘detail’ items (mean retention over 7 days = 94% versus 72%). Amyloid-positive participants showed greater forgetting of the complex figure outline compared with amyloid-negative participants (90% versus 95%; P < 0.01). There were interactions between amyloid pathology and cerebral atrophy, such that whole-brain and hippocampal atrophy predicted greater ALF on complex figure drawing among amyloid-positive participants only [e.g. 1.9 percentage-points lower retention per ml/year of whole-brain atrophy (95% confidence intervals 0.5, 3.7); P < 0.05]. Greater ALF on FNAME was associated with increased rate of hippocampal atrophy. ALF on complex figure drawing was also correlated with subjective cognitive decline [−0.45 percentage-points per MyCog point (−0.85, −0.05); P < 0.05].These results provide evidence of associations between some measures of ALF and biomarkers of brain pathologies and subjective cognitive decline in cognitively normal older adults. On complex figure drawing, ‘outline’ items were better remembered than ‘detail’ items, illustrating the strategic role of memory selectivity, but ‘outline’ items were also relatively more vulnerable to ALF in individuals with amyloid pathology. Overall, our findings suggest that ALF might be a sensitive marker of cognitive changes in preclinical Alzheimer’s disease.

Default mode network tau predicts future clinical decline in atypical early Alzheimer’s disease

<div class="boxTitle">Abstract</div>Identifying individuals with early-stage Alzheimer’s disease (AD) at greater risk of steeper clinical decline would enable better-informed medical, support and life planning decisions. Despite accumulating evidence on the clinical prognostic value of tau PET in typical late-onset amnestic AD, its utility in predicting clinical decline in individuals with atypical forms of AD remains unclear. Across heterogeneous clinical phenotypes, patients with atypical AD consistently exhibit abnormal tau accumulation in the posterior nodes of the default mode network of the cerebral cortex. This evidence suggests that tau burden in this functional network could be a common imaging biomarker for prognostication across the syndromic spectrum of AD.Here, we examined the relationship between baseline tau PET signal and the rate of subsequent clinical decline in a sample of 48 A+/T+/N+ patients with mild cognitive impairment or mild dementia due to AD with atypical clinical phenotypes: Posterior Cortical Atrophy (n = 16); logopenic variant Primary Progressive Aphasia (n = 15); and amnestic syndrome with multi-domain impairment and young age of onset < 65 years (n = 17). All patients underwent MRI, tau PET and amyloid PET scans at baseline. Each patient’s longitudinal clinical decline was assessed by calculating the annualized change in the Clinical Dementia Rating Sum-of-Boxes (CDR-SB) scores from baseline to follow-up (mean time interval = 14.55 ± 3.97 months).Atypical early AD patients showed an increase in CDR-SB by 1.18 ± 1.25 points per year: t(47) = 6.56, P < 0.001, Cohen’s d = 0.95. Across clinical phenotypes, baseline tau in the default mode network was the strongest predictor of clinical decline (R2 = 0.30), outperforming a simpler model with baseline clinical impairment and demographic variables (R2 = 0.10), tau in other functional networks (R2 = 0.11–0.26) and the magnitude of cortical atrophy (R2 = 0.20) and amyloid burden (R2 = 0.09) in the default mode network.Overall, these findings point to the contribution of default mode network tau to predicting the magnitude of clinical decline in atypical early AD patients 1 year later. This simple measure could aid the development of a personalized prognostic, monitoring and treatment plan, which would help clinicians not only predict the natural evolution of the disease but also estimate the effect of disease-modifying therapies on slowing subsequent clinical decline given the patient’s tau burden while still early in the disease course.

Monoallelic de novo variants in DDX17 cause a neurodevelopmental disorder

<div class="boxTitle">Abstract</div>DDX17 is an RNA helicase shown to be involved in critical processes during the early phases of neuronal differentiation. Globally, we compiled a case series of 11 patients with neurodevelopmental phenotypes harbouring de novo monoallelic variants in DDX17. All 11 patients in our case series had a neurodevelopmental phenotype, whereby intellectual disability, delayed speech and language, and motor delay predominated.We performed in utero cortical electroporation in the brain of developing mice, assessing axon complexity and outgrowth of electroporated neurons, comparing wild-type and Ddx17 knockdown. We then undertook ex vivo cortical electroporation on neuronal progenitors to quantitatively assess axonal development at a single cell resolution. Mosaic ddx17 crispants and heterozygous knockouts in Xenopus tropicalis were generated for assessment of morphology, behavioural assays and neuronal outgrowth measurements. We further undertook transcriptomic analysis of neuroblastoma SH-SY5Y cells, to identify differentially expressed genes in DDX17-KD cells compared to controls.Knockdown of Ddx17 in electroporated mouse neurons in vivo showed delayed neuronal migration as well as decreased cortical axon complexity. Mouse primary cortical neurons revealed reduced axon outgrowth upon knockdown of Ddx17 in vitro. The axon outgrowth phenotype was replicated in crispant ddx17 tadpoles and in heterozygotes. Heterozygous tadpoles had clear neurodevelopmental defects and showed an impaired neurobehavioral phenotype. Transcriptomic analysis identified a statistically significant number of differentially expressed genes involved in neurodevelopmental processes in DDX17-KD cells compared to control cells.We have identified potential neurodevelopment disease-causing variants in a gene not previously associated with genetic disease, DDX17. We provide evidence for the role of the gene in neurodevelopment in both mammalian and non-mammalian species and in controlling the expression of key neurodevelopment genes.

Schizophrenia-associated changes in neuronal subpopulations in the human midbrain

<div class="boxTitle">Abstract</div>Dysfunctional GABAergic and dopaminergic neurons are thought to exist in the ventral midbrain of patients with schizophrenia, yet transcriptional changes underpinning these abnormalities have not yet been localized to specific neuronal subsets. In the ventral midbrain, control over dopaminergic activity is maintained by both excitatory (glutamate) and inhibitory (GABA) input neurons. To elucidate neuron pathology at the single-cell level, we characterized the transcriptional diversity of distinct NEUN+ populations in the human ventral midbrain and then tested for schizophrenia-associated changes in neuronal subset proportions and gene activity changes within neuronal subsets.Combining single nucleus RNA-sequencing with fluorescence-activated sorting of NEUN+ nuclei, we analysed 31 669 nuclei. Initially, we detected 18 transcriptionally distinct neuronal populations in the human ventral midbrain, including two ‘mixed’ populations. The presence of neuronal populations in the midbrain was orthogonally validated with immunohistochemical stainings. ‘Mixed’ populations contained nuclei expressing transcripts for vesicular glutamate transporter 2 (SLC17A6) and glutamate decarboxylase 2 (GAD2), but these transcripts were not typically co-expressed by the same nucleus. Upon more fine-grained subclustering of the two ‘mixed’ populations, 16 additional subpopulations were identified that were transcriptionally classified as excitatory or inhibitory. In the midbrains of individuals with schizophrenia, we observed potential differences in the proportions of two (sub)populations of excitatory neurons, two subpopulations of inhibitory neurons, one ‘mixed’ subpopulation, and one subpopulation of TH-expressing neurons.This may suggest that transcriptional changes associated with schizophrenia broadly affect excitatory, inhibitory, and dopamine neurons. We detected 99 genes differentially expressed in schizophrenia compared to controls within neuronal subpopulations identified from the two ‘mixed’ populations, with most (67) changes within small GABAergic neuronal subpopulations. Overall, single-nucleus transcriptomic analyses profiled a high diversity of GABAergic neurons in the human ventral midbrain, identified putative shifts in the proportion of neuronal subpopulations, and suggested dysfunction of specific GABAergic subpopulations in schizophrenia, providing directions for future research.

Dysregulation of protein SUMOylation networks in Huntington’s disease R6/2 mouse striatum

<div class="boxTitle">Abstract</div>Huntington’s disease is a neurodegenerative disorder caused by an expanded CAG repeat mutation in the Huntingtin (HTT) gene. The mutation impacts neuronal protein homeostasis and cortical/striatal circuitry. SUMOylation is a post-translational modification with broad cellular effects including via modification of synaptic proteins.Here, we used an optimized SUMO protein-enrichment and mass spectrometry method to identify the protein SUMOylation/SUMO interaction proteome in the context of Huntington’s disease using R6/2 transgenic and non-transgenic mice.Significant changes in the enrichment of SUMOylated and SUMO-interacting proteins were observed, including those involved in presynaptic function, cytomatrix at the active zone, cytoskeleton organization and glutamatergic signalling. Mitochondrial and RNA-binding proteins also showed altered enrichment. Modified SUMO-associated pathways in Huntington’s disease tissue include clathrin-mediated endocytosis signalling, synaptogenesis signalling, synaptic long-term potentiation and SNARE signalling. To evaluate how modulation of SUMOylation might influence functional measures of neuronal activity in Huntington’s disease cells in vitro, we used primary neuronal cultures from R6/2 and non-transgenic mice. A receptor internalization assay for the metabotropic glutamate receptor 7 (mGLUR7), a SUMO-enriched protein in the mass spectrometry, showed decreased internalization in R6/2 neurons compared to non-transgenic neurons. SiRNA-mediated knockdown of the E3 SUMO ligase protein inhibitor of activated STAT1 (Pias1), which can SUMO modify mGLUR7, reduced this Huntington’s disease phenotype. In addition, microelectrode array analysis of primary neuronal cultures indicated early hyperactivity in Huntington’s disease cells, while later time points demonstrated deficits in several measurements of neuronal activity within cortical neurons. Huntington’s disease phenotypes were rescued at selected time points following knockdown of Pias1.Collectively, our results provide a mouse brain SUMOome resource and show that significant alterations occur within the post-translational landscape of SUMO-protein interactions of synaptic proteins in Huntington’s disease mice, suggesting that targeting of synaptic SUMO networks may provide a proteostatic systems-based therapeutic approach for Huntington’s disease and other neurological disorders.

Direct interrogation of cortical interneuron circuits in amyotrophic lateral sclerosis

<div class="boxTitle">Abstract</div>Cortical hyperexcitability is a key pathogenic feature of amyotrophic lateral sclerosis (ALS), believed to be mediated through complex interplay of cortical interneurons. To date, there has been no technological approach to facilitate the direct capture of cortical interneuron function.Through combination of transcranial magnetic stimulation (TMS) with advanced EEG, the present study examined GABAergic dysfunction in ALS by recording focused cortical output whilst applying TMS over the primary motor cortex contralateral to the site of symptom onset. Using both a single-pulse and a novel inhibitory paired-pulse paradigm, TMS-EEG studies were undertaken on 21 ALS patients and results compared with healthy controls. TMS responses captured by EEG form a discrete waveform known as the transcranial evoked potential (TEP), with positive (P) or upward deflections occurring at 30 (P30), 60 (P60) and 190 ms (P190) after TMS stimulus. Negative (N) or downward deflections occur at 44 (N44), 100 (N100) and 280 ms (N280) after TMS stimulus. The single-pulse TEPs recorded in ALS patients demonstrated novel differences suggestive of cortical GABAergic dysfunction. When compared with controls, the N100 component was significantly reduced (P < 0.05), whereas the P190 component increased (P < 0.05) in ALS patients. Additionally, the N44 component was correlated with muscle weakness (r = −0.501, P < 0.05). These findings were supported by reduced paired-pulse inhibition of TEP components in ALS patients (P60, P < 0.01; N100, P < 0.005), consistent with dysfunction of cortical interneuronal GABAA-ergic circuits. Furthermore, the reduction in short-interval intracortical inhibition, as reflected by changes in paired-pulse inhibition of the N100 component, was associated with longer disease duration in ALS patients (r = −0.698, P < 0.001).In conclusion, intensive and focused interrogation of the motor cortex using novel TMS-EEG combined technologies has established localized dysfunction of GABAergic circuits, supporting the notion that cortical hyperexcitability is mediated by cortical disinhibition in ALS. Dysfunction of GABAergic circuits was correlated with greater clinical disability and disease duration, implying pathophysiological significance.

Somatic instability of the FGF14-SCA27B GAA•TTC repeat reveals a marked expansion bias in the cerebellum

<div class="boxTitle">Abstract</div>Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibits cerebral mosaicism and progressive instability throughout life.We conducted an analysis of the FGF14 GAA•TTC repeat somatic instability across 156 serial blood samples from 69 individuals, fibroblasts, induced pluripotent stem cells and post-mortem brain tissues from six controls and six patients with SCA27B, alongside methylation profiling using targeted long-read sequencing. Peripheral tissues exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. In post-mortem brains, the GAA•TTC repeat was remarkably stable across all regions, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. Additionally, levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14. We found no significant difference in methylation of wild-type and expanded FGF14 alleles in post-mortem cerebellar hemispheres between patients and controls.In conclusion, our study revealed that the FGF14 GAA•TTC repeat exhibits a cerebellar-specific expansion bias, which may explain the pure cerebellar involvement in SCA27B.

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